Human Malformations and Related Anomalies

Human Malformations and Related Anomalies

OXFORD MONOGRAPHS ON MEDICAL GENETICS GENERAL EDITORS

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

Human Malformations and Related Anomalies EDITED BY

Roger E. Stevenson

Judith G. Hall

Greenwood Genetic Center

University of British Columbia

Greenwood, South Carolina

Vancouver, British Columbia

ASSOCIATE EDITORS:

Kathleen K. Sulik

Edith Gilbert-Barness

University of North Carolina

Tampa General Hospital

School of Medicine

Tampa, Florida

Chapel Hill, North Carolina

ASSISTANT EDITOR:

Karen Kiernan Buchanan Greenwood Genetic Center Greenwood, South Carolina

1 2006

Second Edition

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

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

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

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Preface

O

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

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

vi

Preface

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

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

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

Contents

Contributors

3. Systemic Vasculature

xiii

121

Lynne M. Bird and Kenneth Lyons Jones

Part I—Overview 1. Human Malformations and Related Anomalies

3

Roger E. Stevenson

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8

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

Part II—Cardiorespiratory Organs

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

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

4. Lymphatic System

145

Judith E. Allanson

2. Heart

85

Angela E. Lin, John Belmont, and Sadia Malik

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

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

4.1 4.2 4.3 4.4 4.5

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

5. Spleen

183

Arthur S. Aylsworth

5.1 5.2 5.3

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

6. Lower Respiratory Organs

201

Laurie H. Seaver

6.1 6.2 6.3 6.4 6.5

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

202

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Contents

6.6 6.7 6.8 6.9 6.10 6.11 6.12

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

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

327

John C. Carey

Part III—Craniofacial Structures External Ear 7. Skull

221

John M. Graham, Jr.

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

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

8. Facial Bones

267

Karen Gripp and Luis Fernando Escobar

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

Premature Metopic Sutural Synostosis 268 Orbital Hypotelorism 270 Orbital Hypertelorism 273 Midline Facial Skeletal Clefting 278 Absence and Hypoplasia of the Zygoma 280 Midface Retrusion and Hypoplasia 283 Agnathia 287 Micrognathia 288 Congenital Asymmetry of the Facial Skeleton 292 297 Anophthalmia 299 Microphthalmia and Typical Uveal Coloboma Cyclopia and Synophthalmia 302 Cryptophthalmos 303 Blepharophimosis 305 Other Anomalies of the Eyelids 306 Congenital Corneal Anomalies 309 Anterior Segment Dysgenesis 311 Peters Anomaly 313 Hypoplasia of the Iris (Aniridia) 314

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

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

Middle Ear

356

John C. Carey and Albert H. Park

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

Elias I. Traboulsi

9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 9.10

329

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

10.32 Vestibular Dysplasias 366 10.33 Prelingual Hearing Loss 369 300

11. Nose

373

M. Michael Cohen, Jr.

11.1 11.2 11.3 11.4 11.5 11.6

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

374

Contents

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

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

Marilyn Jones

12.1 12.2 12.3

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

13. Tongue

ix

14.6 14.7 14.8 14.9 14.10

13.6 13.7 13.8 13.9 13.10 13.11 13.12 13.13

13.14 13.15 13.16 13.17 13.18 13.19 13.20 13.21 13.22 14.

Teeth

425

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

14.1 14.2 14.3 14.4 14.5

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

469

15. Brain

Alasdair G. W. Hunter

15.1 15.2 15.3 15.4 15.5

405

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

463

Part IV—Neuromuscular Systems

Robert J. Gorlin

13.1 13.2 13.3 13.4 13.5

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

15.6 15.7 15.8 15.9 15.10 15.11 15.12 15.13 15.14

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

16. Brain and Spinal Cord

715

Alasdair G. W. Hunter

16.1

Disorders of Neural Tube Closure

17. Spinal Cord

715

757

Alasdair G. W. Hunter

17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8

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

18. Muscle

783

Judith G. Hall

18.1 18.2 18.3 18.4 18.5 18.6 18.7 18.8 18.9

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

x

Contents

18.10 18.11 18.12 18.13 18.14 18.15 18.16 18.17 18.18

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

21. Hands and Feet

935

David B. Everman

21.1 21.2 21.3 21.4

The The The The

Polydactylies 937 Syndactylies 954 Brachydactylies 968 Oligodactylies 984

22. Skeletal Dysplasias

997

Ju¨rgen Spranger

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

805

Louanne Hudgins and Keith Vaux

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

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

23.1 23.2 23.3

23.4 23.5 23.6 23.7 23.8

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

Breasts

1049

23.9 23.10 23.11 23.12 23.13 23.14 23.15

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

24. Upper Gastrointestinal System

Pharynx 24.1

1065

24.2

1067

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

Esophagus 24.3

Judith G. Hall

1055

H. Eugene Hoyme

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

1027

Ellen Boyd and Roger E. Stevenson

Roger E. Stevenson

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

1023

Cynthia Curry, Ellen Boyd, and Roger E. Stevenson

1071

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

1081

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

Contents

24.16 24.17 24.18 24.19

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

Duodenum

1089

24.20 24.21 24.22 24.23 24.24 24.25

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

xi

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

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

29. Male Genital System 25. Small and Large Intestines

1097

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

26. Rectum and Anus

1115

Cathy A. Stevens

26.1 26.2

Atresia of the Rectus and Anus Rectal Duplication 1122

27. Liver, Gallbladder, and Pancreas

1116

1123

Ian D. Krantz and Arthur S. Aylsworth

27.1 27.2 27.3

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

1161

Jane A. Evans

28.1 28.2 28.3 28.4 28.5

1251

Rick A. Martin

Eberhard Passarge and Roger E. Stevenson

25.1 25.2 25.3 25.4 25.5 25.6 25.7 25.8

1219

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

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

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

30. Female Genital System

1279

Leah W. Burke

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

xii

Contents

Part VIII—Other Systems and Structures 31. Cutaneous Structures

1307

Julie S. Prendiville

31.1

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

1333

35. Umbilical Cord

1339

32.3 32.4 32.5 32.6 32.7 32.8 32.9

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

33. Asymmetry and Hypertrophy

1359

Omar Abdul-Rahman and H. Eugene Hoyme

33.1 33.2

Laterality Sequences 1361 Kartagener Syndrome 1363

Patterns of Asymmetric Growth 33.3 33.4 33.5 34. Twins

1413

Will Blackburn and Nelson Reede Cooley, Jr.

Amy Potter and John A. Phillips III

32.1 32.2

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

1365

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

Mary C. Phelan and Judith G. Hall

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

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

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

Index to Tables of Malformations and Associated Syndromes 1473 Subject Index

1477

Contributors

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

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

Will Blackburn, M.D. Fairhope, Alabama

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

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

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

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

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

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

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

xiii

xiv

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

Contributors

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

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

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

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

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

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

Part I Overview

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1 Human Malformations and Related Anomalies Roger E. Stevenson

M

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

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

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

USA: California{

Canada{

High Prevalence Regionsx

Low Prevalence Regionsx

Rate

Trend

Rate

Rate

Trend

Anencephaly

3.6

;

3.7

2.1

;

Mexico South America

Italy South Africa

Spina bifida

3.8

;

4.3

6.3

;

Mexico South America

Spain England/Wales

Encephalocele

1.6

;

0.9

1.4

Mexico South America

Spain Norway

Hydrocephaly

8.1

;

3.5

7.1

South America France

England/Wales Spain

Anophthalmia/Microphthalmia

2.9

;

1.2

1.1

USA (Atlanta) Ireland (Dublin)

England/Wales Hungary

Anotia/Microtia

1.5

3.3

Mexico South America

Australia England/Wales

Atrial septal defect

25.1

19.7

23.0

:

Ventricular septal defect

37.8

16.0

30.4

:

Tetralogy of Fallot

4.2

2.6

4.2

:

USA (Atlanta) Ireland (Dublin)

England/Wales

Transposition of great vessels

5.4

4.2

4.2

N. Netherlands France

Mexico England/Wales

Truncus arteriosus

0.9

0.6

1.2

Hypoplastic left heart syndrome

3.0

2.5

2.9

USA (Atlanta) France

England/Wales South America

Coarctation of aorta

5.1

:

4.0

4.8

Ireland (Dublin) USA (Atlanta)

England/Wales Spain

Cleft Lip With or Without Cleft Palate

9.0

;

10.4

10.7

Norway Japan

South Africa Canada

Cleft Palate Without Cleft Lip

6.8

4.9

6.3

Malta Finland

South Africa

Esophageal Atresia/Stenosis With or Without Fistula

2.0

1.2

3.4

South America Ireland (Dublin)

England/Wales

Rectal and Large Intestinal Atresia/Stenosis

3.7

2.5

4.5

Neural Tube Defects

;

Cardiac Defects

:

33.7

:

2.3

24.2

Israel Czech Republic

Australia Italy

Renal Agenesis/Hypoplasia

4.5

;

0.5

4.2

Canada Ireland (Dublin)

Hungary Mexico

Diaphragmatic Hernia

2.3

2.5

France Ireland (Dublin)

South Africa Mexico

Bladder Exstrophy

0.1

0.0

Mexico France

England/Wales Japan

Omphalocele

2.6

France South America

Spain England/Wales

Gastroschisis

2.2

4.2

Mexico South America

Spain South Africa

Limb Reduction Defects (Upper)

4.1

3.7

Limb Reduction Defects (Lower)

1.7

Canada France

South Africa Japan

Hypospadias/Epispadias

;

1.3

1.7

g g

: 6.6

4.6

(continued)

4

Human Malformations and Related Anomalies

5

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

USA: California{

Trend

Canada{

Rate

Rate

Trend

High Prevalence Regionsx

Low Prevalence Regionsx

Chromosome Aneuploidies Trisomy 13

1.5

1.1

1.2

:

Ireland (Dublin)

Hungary

Trisomy 18

2.5

1.8

2.1

:

Ireland (Dublin)

Hungary

Trisomy 21

12.5

10.1

12.4

Ireland (Dublin)

Hungary

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

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

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

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

Marden et al., 1964

Sample Size

Major Anomalies (%)

Minor Anomalies (%)

14.7

USA

4412

2.1

Myrianthopoulos and Chung, 1974

USA

53,257

7.1

Mehes, 198350

Hungary

4589

2.2

17.2

Merlob et al., 198529

Israel

3762

1.6

21.0

Leppig et al., 198951

USA

4305

3.8

40.7

CBDMP, 1994*26

USA

>500,000

2.9

–

291,126

2.2

–

30,940

6.9

35.8

20

25

Stoll, 1995

Europe

Queisser-Luft et al., 200224

Germany

7.26

*California Birth Defects Monitoring Program.

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

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

6

Overview

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

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

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

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

Human Malformations and Related Anomalies

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

7

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

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

8

Overview Table 1-3. Minor anomalies Cranium and Scalp

Face and Neck

Horizontal palmar crease (single)

Triple hair whorl

Synophrys

Bridged palmar crease

Absence of hair whorl

Flat bridge of nose

Single crease, finger V

Patent metopic suture

Prominent bridge of nose

Metopic fontanel

Hypotelorism

Skin tags (preauricular, ear lobe, others)

Sagittal fontanel

Hypertelorism

Parietal foramen

Nostrils anteverted

Flat occiput

Long nasal septum

Prominent occiput

Epicanthal fold

Frontal bossing

Iris freckles

Flat brow

Upward palpebral slant

Hypopigmented spots Trunk

Extra nipples Single umbilical artery Umbilical hernia

Microtia

Cleft uvula

Darwinian point

Cleft lip microform

Darwinian tubercle

Cleft gum

Lack of helical folding

Long philtrum

Bridged concha

Short philtrum

Ear lobe crease

Smooth philtrum

Ear lobe notched

Microstomia

Ear lobe bifid

Macrostomia

Lop ear

Macroglossia

Cup-shaped ear

Microglossia

Retroverted ear

Broad alveolar ridge

Thickened helix

Micrognathia

Helix excessively folded

Webbed neck

Helix attached to scalp

Redundant neck skin

Sinuses

Ptosis

Branchial

Skin

Overlapping digits

Preauricular

Shoulder dimples

Prominent heel

Ear lobe

Sacrum dimples

Helical

Dimples over other bones

Pilonidal

Sole crease

Diastasis rectus Glandular hypospadias Shawl scrotum Vaginal tag Limbs

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

Percent With Major Malformations Marden et al., 196418 USA

Mehes, 198350 Hungary

Leppig et al., 198751 USA

1.4

1.2

2.3

1

2.9

3.8

3.7

2

10.8

12.5

6.7

90

26


3

Pigmented spots

Short palpebral fissures

Table 1-4. Concurrence of minor and major anomalies at birth in three series

0

Nevi

Downward palpebral slant

Ears

Number of Minor Malformations

Hemangioma

19.6

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

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

Human Malformations and Related Anomalies

Connectional Terms

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

9

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

10

Overview

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

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

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

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

Human Malformations and Related Anomalies

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

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

11

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

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

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

12

Overview

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

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

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

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

Human Malformations and Related Anomalies

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

1.2 Classification and Coding Classification

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

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

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

13

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

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

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

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

14

Overview

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

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

Percent Incidence

Genetic

15–25

Chromosome

10–15

Single gene

2–10

Multifactorial

20–25

Environmental

8–12

Maternal diseases

6–8

Uterine/placental

2–3

Drugs/chemicals

0.5–1

Twinning

0.5–1

Unknown

40–60

Coding

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

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

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

Chromosome Aberration

1959

Trisomy 21; 45,X; 47,XXY

1960

Trisomy 18; trisomy 13

1961

47,XYY

1963

Del 5p

1965

Del 4p

1969

Fragile X

1971

Trisomy 8

1973

Trisomy 9

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

Percent

All Chromosome Aberrations

40

Trisomies

20

T-16

8

T-13,15,21,22

2*

T-2,7,8,14,18

1*

T-4,9,10,20

0.5*

T-3,5,6,12,7

0.1*

T-1,11,19

<0.1*

Sex chromosome

<0.5

Monosomy X Autosomal monosomy

8 <0.1

Polyploidies

9

Triploidy

7

Tetraploidy Other Rearrangements Mosaicism Unbalanced rearrangement Balanced rearrangement

2 3 2 1 <0.5

*Approximate rate for each of the trisomies named.

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

15

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

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

16

Overview

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

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

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

Human Malformations and Related Anomalies

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

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

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

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

Prevalence

Trisomy 21

1/700

Trisomy 13

1/7000

Trisomy 18

1/8000

Trisomy 8*

<1/100,000

Trisomy 9

<1/100,000

Monosomy X

1/2500 (females)

47,XXX

1/1200 (females)

47,XXY

1/1000 (males)

47,XYY

1/1000 (males)

Fragile X

1/4000 (males)

48,XXYY

1/25,000 (males)

48,XXXX

<1/100,000 (females)

48,XXXY

<1/100,000 (males)

49,XXXXX

<1/100,000 (females)

49,XXXXY

<1/100,000 (males)

*Usually mosaic.

17

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

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

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

18

Overview

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

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

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

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

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

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

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

Human Malformations and Related Anomalies

19

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

Location

Findings

Alagille (JAG1)*

20p11.23-p12.2

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

Albright hereditary osteodystrophy-like syndrome

2q37

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

Alpha-thalassemia and mental retardation (ATR-16)

16p13.3

Dysmorphic facial features, alpha-thalassemia, mental retardation

Angelman (UBE3A)*

15q11-q13

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

Cat eye

22q11.2

Coloboma, choanal atresia, learning disabilities, mental retardation

Cri du chat

5p13-p15.2

Microcephaly, hypertelorism

DiGeorge 2

10p13

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

Greig cephalopolysyndactyly (GLI3)*

7p13

Craniosynostosis, polysyndactyly, mental retardation

Langer-Giedion

8q24.1

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

Miller-Dieker (LIS1)*

17p13.3

Type I lissencephaly, dysmorphic facies

NF1 microdeletion

17q11.2

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

Prader-Willi

15q11-q13

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

Rubinstein-Taybi (CBP)*

16p13.3

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

Smith-Magenis

17p11.2

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

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

22q11

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

WAGR (PAX6)*

11p13

Wilms tumor, aniridia, genitourinary anomalies, mental retardation

Williams (LIMK1)*

7q11.23

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

Wolf-Hirschhorn

4p16.3

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

1p36 Deletion

1p36

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

Distal 22q microdeletion (ProSAP2 ?)

22q13-qter

Mild facial dysmorphism, hypotonia, severe language delay

Xp22.3 Deletion

Xp22.3

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

Xp21 Deletion

Xp21

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

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

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

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

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

20

Overview

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

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

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

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

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

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

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

Human Malformations and Related Anomalies

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

21

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

Other Chromosome Aberrations

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

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

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

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

22

Overview

Uniparental Disomy

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

1.4 Gene Mutations and Malformations

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

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

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

Human Malformations and Related Anomalies

23

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

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

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

24

Overview

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

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

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

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

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

Gene/Locus/OMIM

Disorder

Gene/Locus/OMIM

ADULT (Acro-dermatoungual-lacrimal-tooth

p63, 3q27, 103285

Atrioventricular septal defect, partial, with heterotaxy

CRELD1, 3p25.3, 606217

Aarskog-Scott

FGD1, Xp11.21, 305400

Bamforth-Lazarus

FOXE1, 9q22, 241850

Acheiropody

C7orf2, 7q36, 205000

Bannayan-Riley-Ruvalcaba

PTEN, 10q23.31, 153480

Achondrogenesis

XLC26A2, 5q32-q33.1, 600972

Bardet-Biedl

209900

Achondrogenesishypochondrogenesis, type II

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

Type 1

11q13

Achondroplasia

FGFR3, 4p16.3, 100800

Type 2

16q21

Type 3

3p13-p12

Acrocallosal

GL13, 7p13, 200990

Acrocapitofemoral dysplasia

IHH, 2q33-q35, 607778

Type 4

15q22.3-q23

Acrofacial dysostosis, Nager type

9q32, 154400

Type 5

2q31

Acromesomelic dysplasia, HunterThompson type

CDMP1, 20q11.2, 201250

Type 6

20p12

Type 7

4q27

Acrorenalocular

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

Type 8

14q32.1

Agenesis of the corpus callosum with peripheral neuropathy

SLC12A6, 15q13-q14, 218000

Aicardi

Xp22, 304050

Barth

Xq28, 302060

Beare-Stevenson cutis gyrata

FGFR2, 10q26, 176943 KIP2, 11p15.5, 130650

Alagille

JAG1, 20p12, 118450

Beckwith-Wiedemann

Allan-Herndon

Xq21, 309600

9q34.3, 269700

Albright hereditary osteodystrophy

GNAS, 20q13.2, 174800

Berardinelli-Seip congenital lipodystrophy

FOXL2, 3q23, 110100

Alopecia universalis

8p21.2, 203655

Blepharophimosis, epicanthus inversus, and ptosis, type 1

Alpha-thalassemia/mental retardation

XNP, Xq13, 301040

Borjeson-Forssman-Lehmann

PHF6, Xq26.3, 301900

Amelogenesis imperfecta

Xp22.3-p22.1, 301200

Type A1

IHH, 2q33-q35, 112500

Brachydactyly

Angelman

UBE3A, 15q11-q13, 105830

Type B1

ROR2, 9q22, 113000

Aniridia, type II

PAX6, 11p13, 106210

Type C

CDMP1, 20q11.2, 113100

Anophthalmia 3

SOX2, 3q26.3-q27

Types D and E

HOXD13, 2q31-q32, 113200

Anophthalmos-1

Xq27-q28, 301590

Anterior segment anomalies and cataract

EYA1, 8q13.3, 601653

Anterior segment mesenchymal dysgenesis

FOXC1, 6p25, 601090

Anterior segment mesenchymal dysgenesis and cataract

FOXE3, 1p32, 107250

Antley-Bixler

Branchiooto

EYA1, 8q13.3, 601653

Branchiootorenal and branchiootorenal with cataract

EYA1, 8q13.3, 113650

Campomelic dysplasia

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

Camurati-Engelmann disease

TGFB1, 19q13.1, 131300

PITX3, 10q25, 107250

Cartilage–hair hypoplasia

9p21-p12, 250250

Apert

POR, 7q11.2, 124015

Cat eye

22q11, 115470

Arthrogryposis multiplex congenita, distal, type 1

FGFR2, 10q26, 101200

Cerebellar hypoplasia

OPHN1, Xq12

Cerebropalatocardiac

PQBP1, Xq11.2

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

9p13.2-p13.1, 108120

Arthrogryposis multiplex congenita, neurogenic

Char

TFAP2B, 6p12, 169100

CHARGE

CHD7, 8q12, 214800

5q35, 208100

Chondrodysplasia punctata, X-linked recessive

ARSE, Xp22.3, 302950

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

Xp11.3-q11.2, 301830

Chondrodysplasia, Grebe type

CDMP1, 20q11.2, 200700

Chondrodysplasia, HunterThompson type

CDMP1, 20q11.2, 201250

Asphyxiating thoracic dystrophy (Jeune)

15q13, 208500

Cleft lip/palate, nonsyndromic

MSX1, 4p16.1, 119530

Atelosteogenesis I, III

FLNB, 3p14.3, 108720

Cleft palate with ankyloglossia

TBX22, Xq12-q21, 303400

Atelosteogenesis II

SLC26A2, 5q32-q33.1, 256050

Atrial septal defect with atrioventricular conduction defects

NKX2E, 5q34, 108900

Cleidocranial dysplasia

CBFA1, 6p21, 119600

Coffin-Lowry

RSK2, Xp22.2-p22.1, 303600

Colonic aganglionosis, total, with small bowel involvement

RET, 10q11.2, 164761 (continued)

25

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

Gene/Locus/OMIM

Disorder

Gene/Locus/OMIM

Conotruncal anomaly face

TBX1, 22q11.2, 217095

Type 2

COL9A2, 1p33-p32.2, 600204

Contractural arachnodactyly, congenital

FBN2, 5q23-q31, 121050

Type 3

COL9A3, 20q13.3, 600969

COL9A1-related

COL9A1, 6q13, 120210

Myopathy-related

COL9A3, 20q13.3, 120270

Cornelia de Lange (see de Lange) Costello

22q13.1, 218040

Cowden disease

PTEN, 10q23.31, 601728

Craniofrontonasal dysplasia

EFNB1, Xq12, 304110

Craniometaphyseal dysplasia

5p15.2-p14.1, 123000

Craniosynostosis, nonspecific

FGFR2, 10q26, 176943

Crouzon

FGFR2, 10q26, 123500

Crouzon with acanthosis nigricans

FGFR3, 4p16.3, 134934

Currarino

HLXB9, 7q36, 176450

Cutis laxa, AD

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

Cutis laxa, neonatal

ATP7A, Xq12-q13, 300011

De Lange

NIPBL, 5p13.1, 122470

DiGeorge

TBX1, 22q11.2, 188400

Diastrophic dysplasia

SLC26A2, 5q32-q33.1, 222600

Duane-radial ray Dyggve-Melchior-Clausen

Exostoses, multiple, type 1

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

Exostoses, multiple, type 2

EXT2, 11p12-p11, 608210

FG syndrome

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

Fanconi anemia Complementation group A

227650 16q24.3, 227650

B

BRCA2, 13q12.3, 227660

C

9q22.3, 227645

D1

BRCA2, 13q12.3, 605724

D2

3p25.3, 227646

E

6p22-p21, 600901

F

11p15, 603467

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

G

FANCG, 9p13, 602956

FLJ90130, 18q12-q21.1, 223800

L

2p16.1, 608111

Dyschondrosteosis (see Leri-Weill) Dyskeratosis congenita

DKC1, Xq28, 305000

Dyssegmental dysplasia, Silverman-Handmaker type

HSPG2, 1p36.1, 224410

Fibrodysplasia ossificans progressiva

FOP, 4q27-q31, 135100

Fragile X syndrome

FMR1, Xq27.3, 309550

Frasier, pseudohermaphroditism

WT1, 11p13, 136680

Freeman-Sheldon

11p15.5, 191043

Frontometaphyseal dysplasia

FLNA, Xq28, 304120

EEC (Ectrodactyly-ectodermal dysplasia-clefting)

p63, 3q27, 129900

Ectodermal dysplasia, anhidrotic

ED1, Xq12-q13.1, 305100

GM1-gangliosidosis

GLB1, 3p21.33, 230500

Ectodermal dysplasia, hidrotic

GJB6, 13q12, 129500

Greig cephalopolysyndactyly

GLI3, 7p13, 175700

Ectodermal dysplasia, hypohidrotic with immune deficiency

NEMO, Xq28, 300291

Hand-foot-uterus

HOXA13, 7p15-p14.2, 140000

Ectopia pupillae

PAX6, 11p13, 129750

Hay-Wells

p63, 3q27, 106260

Heterotaxy, X-linked visceral

ZIC3, Xq26.3, 306955

COL1A1, 17q21.31-q22, 130000

Heterotopia, periventricular

FLNA, Xq28, 300049

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

Hirschsprung disease

RET, 10q11.2, 142623

Ehlers-Danlos syndrome Type I

COL5A2, 2q31, 130000 Type II

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

Type III

COL3A1, 2q31, 130020

Type IV

COL3A1, 2q31, 130050

Type VI

1p36.3-p36.2, 225400

Type VII

COL1A1, 17q21.31-q22, 130060

Type VIIA2

COL1A2, 7q22.1, 130060

Type VIIC

5q23, 225410

Type X

2q34, 225310

Holoprosencephaly 1

HPE1, 21q22.3, 236100

2

SIX3, 2p21, 157170

3

SHH, 7q36, 142945

4

TGIF, 18p11.3, 142946

5

ZIC2, 13q32, 603073

6

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

7

PTCH, 9q22.3, 601309

Holt-Oram

TBX5, 12q24.1, 142900

Ellis-van Creveld

4p16, 225500

Emery-Dreifuss muscular dystrophy

LMNA, 1q21.2, 181350

Epidermolysis bullosa dystrophica, AD

COL7A1, 3p21.3, 131750

Hydrolethalus

11q23-q25, 236680

Epiphyseal dysplasia, multiple

SLC26A2, 5q32-q33.1, 226900

Hyperostosis, endosteal

LRP5, 11q13.4, 144750

COMP, 19p13.1, 132400

Hypochondroplasia

FGFR3, 4p16.3, 146000

Type 1

Hutchinson-Gilford progeria

LMNA, 1q21.2, 176670

Hydrocephalus due to aqueductal stenosis

L1CAM, Xq28, 307000

(continued)

26

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

Gene/Locus/OMIM

Disorder

Gene/Locus/OMIM

Hypodontia

PAX9, 14q12-q13, 106600 MSX1, 4p16.1, 106600

Microcephaly, autosomal recessive, type 1

MCPH1, 8p23, 251200

Hypodontia with orofacial cleft Incontinentia pigmenti Type II

NEMO, Xq28, 308300

Type 2

19q13.1-q13.2

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

Type 3

9q34

FGFR2, 10q26, 123150

Type 4

15q15-q21

11q23, 147791

Type 5

1q31

Type 6

13q12.2

Jackson-Weiss Jacobsen Jeune (see asphyxiating thoracic dystrophy)

Miller-Dieker lissencephaly

LIS1, 17p13.3, 247200

Kallmann

Xp22.3, 308700

Milroy lymphedema

VEGFR3, 5q34, 153100

Kallmann 2

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

Morning glory disc anomaly

PAX6, 11p13, 607108

Klippel-Trenaunay

5q13.3, 149000

Mowat-Wilson

SMADIP1, 2q22, 235730

Kneist dysplasia

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

Mucolipidosis II

GNPTA, 4q21-q23, 252500

Mucopolysaccharidosis

Langer mesomelic dysplasia

SHOX, Xpter-p22.32, 249700

Langer-Giedion

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

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

IDUA, 4p16.3, 252800

Laron dwarfism

GHR, 5p13-p12, 262500

II (Hunter)

IDS, Xq28, 309900

Larsen, autosomal dominant

FLNB, 3p14.3, 150250

IIIA (Sanfilippo A)

SGSH, 17q25.3, 252900

Lenz microphthalmia

Xq27-q28, 309800

IIIB (Sanfilippo B)

NAGLU, 17q21, 252920

LEOPARD

PTPN11, 12q24.1, 151100

IIIC (Sanfilippo C)

MPS3C, Chr. 14, 252930

Leprechaunism

INSR, 19p13.2, 246200

IVA (Morquio)

GALNS, 16q24.3, 253000

Leri-Weill (dyschondrosteosis)

SHOX, Xpter-p22.32, 127300

IVB (Morquio B)

GLB1, 3p21.33, 230500

Limb-mammary

p63, 3q27, 603543

VI (Maroteaux-Lamy)

ARSM, 5q11-q13, 253200

Lipodystrophy, familial partial

LMNA, 1q21.2, 151660

VII (Sly)

GUSB, 7q21.11, 253220

Lissenephaly-1

LIS1, 17p13.3, 607432

Lissencephaly

Muenke

FGFR3, 4p16.3, 602849

MULIBREY nanism

17q22-q23, 253250

Norman-Roberts type

RELN, 7q22, 257320

Multiple endocrine neoplasia I

MEN1, 11q13, 131100

X-linked

DCX, Xq22.3-q23, 300067

Multiple endocrine neoplasia IIA

RET, 10q11.2, 171400

X-linked with ambiguous genitalia

ARX, Xp22.13, 300215

Multiple endocrine neoplasia IIB

RET, 10q11.2, 162300

Muscle-eye-brain disease

POMGNT1, 1p34-p33, 253280

Lowe

OCRL, Xq26.1, 309000

Nail-patella

LMX1B, 9q34.1, 161200

Lymphedema and ptosis

FOXC2, 16q24.3, 153000

Nance-Horan

NHS, Xp22.13, 302350

Lymphedema-distichiasis

FOXC2, 16q24.3

Neurofibromatosis, type 1

NF1, 17q11.2 162200

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

L1CAM, Xq28, 303350

Noonan

PTPN11, 12q24.1, 163950

Norrie disease

Xp11.4, 310600

FBN1, 15q21.1, 604308

Oculodentodigital dysplasia

GJA1, 6q21-q23.2, 164200

Mandibuloacral dysplasia

LMNA, 1q21.2, 248370

OSMED

COL11A2, 6p21.3, 215150

Marfan

FBN1, 15q21.1, 154700

Oligodontia

PAX9, 14q12-q13, 604625

Marshall

COL11A1, 1p21, 154780

Opitz BBB

CXorf5, Xp22.3-p22.2, 311200

McCune-Albright

GNAS, 20q13.2, 174800

Osteogenesis imperfecta

McKusick-Kaufman, polydactyly

20p12, 236700

MASS

Meckel Type 1

17q22-q23, 249000

Type 2

11q13, 603194

Type 3

8q24, 607361

Melnick-Needles

FLNA, Xq28, 309350

Menkes

ATP7A, Xq12-q13, 309400

Metaphyseal chondrodysplasia, Murk Jansen type

PTHR1, 3p22-p21.1, 156400

Metaphyseal chondrodysplasia, Schmid type

COL10A1, 6q21-q22.3, 120110

Type I

COL1A1, 17q21.31-q22, 166200

Type II

COL1A1, 17q21.31-q22, 166210

Type III

COL1A1, 17q21.31-q22, 259420

Type IV

COL1A1, 17q21.31-q22, 166220

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

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

27

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

Gene/Locus/OMIM

Otopalatodigital

Disorder

Gene/Locus/OMIM

Sjogren-Larsson

17p11.2, 270200

Type I

OPD1, Xq28, 311300

Smith-Fineman-Myers

XNP, Xq13, 309580

Type II

FLNA, Xq28, 311300

Smith-Lemli-Opitz, type I

11q12-q13, 270400

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

MECP2, Xq28, 300055

Smith-Lemli-Opitz, type II

11q12-q13, 268670

Smith-Magenis

17p11.2, 182290

Pallister-Hall

GLI3, 7p13, 146510

Smith-McCort dysplasia

18q12-q21.1, 607326

Parietal foramina 1

MSX2, 5q34-q35, 168500

Sotos

NSD1, 5q35, 117550

Peutz-Jeghers

19p13.3, 175200

Pfeiffer

FGFR1, 8p11.2-p11.1, 101600 FGFR2, 10q26, 101600

Piebaldism

KIT, 4q12, 164920

Polycystic kidney and hepatic disease

PKHD1, 6p21.1-p12, 263200

Polycystic kidney disease, adult type I

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

Polycystic kidney disease, adult type II

PKD2, 4q21-q23, 173910

Polydactyly, postaxial Type A3

19p13.2-p13.1, 607324

Types A1 and B

GLI3, 7p13, 174200

Polydactyly, preaxial Type II

7q26, 174500

Type IV

GLI3, 7p13, 174700

Prader-Willi

15q11, 176270

Progeria

LMNA, 1q21.2, 176670

Pseudoachondroplasia

COMP, 19p13.1, 177170

Pycnodysostosis

CTSK, 1q21, 265800

Refsum

PEX7, 6q22-q24, 266500

Robinow, autosomal recessive

ROR2, 9q22, 268310

Rubinstein-Taybi

CREBBP, 16p13.3, 180849

SED congenita (spondyloepiphyseal dysplasia)

Split hand/foot malformation Type 1 with deafness

7q21.2-q21.3, 605617

Type 1

7q21.2-q21.3, 183600

Type 2

Xq26, 313350

Type 3

10q24, 600095

Type 4

p63, 3q27, 605289

Type 5

2q31, 183600

Spondylocostal dysostosis, autosomal recessive, 1

19q13, 277300

Spondyloepiphyseal dysplasia tarda

Xp22.2-p22.1, 313400

Stickler Type I

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

Type II

COL11A1, 1p21, 604841

Type III

COL11A2, 6p21.3, 184840

Supravalvar aortic stenosis

ELN, 7q11.2, 185500

Sutherland-Haan

POBP1, Xp11.23, 309470

Symphalangism, proximal

NOG, 17q22, 185800

Synostoses, multiple, 1

NOG, 17q22, 186500

Synpolydactyly with foot anomalies

HOXD13, 2q31-q32, 186000 FBLN1, 22q13.3, 608180

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

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

HOXD13, 17q22, 186000

SEMD, Pakistani type (spondyloepimetaphyseal dysplasia)

10q22-q24, 603005

Tarsal-carpal coalition

NOG, 17q22, 186570

Tetralogy of Fallot

JAG1, 20p12, 187500

SMD (spondylometaphyseal dysplasia)

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

SMED, Strudwick type (spondyloepimetaphyseal dysplasia)

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

Saethre-Chotzen Schwartz-Jampel, type 1 Septooptic dysplasia

NKX2E, 5q34, 187500 Thanatophoric dysplasia, types I and II

FGFR3, 4p16.3, 187600

Townes-Brocks

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

FGFR2, 10q26, 101400

Treacher Collins mandibulofacial dysostosis

TWIST, 7p21, 101400

Trichorhinophalangeal

HSPG2, 1p36.1, 255800

Type I

8q24.12, 190350

3p21.2-p21.1, 182230

Type III

8q24.12, 190351

Shah-Waardenburg

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

Ulnar-mammary

Shprintzen-Goldberg

FBN1, 15q21.1, 182212

Van Buchem disease

17q11.2, 239100

Sialic acid storage disorder, infantile

6q13-q15, 269920

Van Buchem disease, type 2

LRP5, 11q13.4, 607636

Van der Woude, Type 1

IRF6, 1q32-q41, 119300

Silver-Russell

7p11.2, 180860

Van der Woude, Type 2

1p34, 606713

Simpson-Golabi-Behmel, type 1

GPC3, Xq26, 312870

Velocardiofacial

22q11.2, 192430

Situs ambiguous

NODAL, Chr. 10, 601265

28

TBX3, 12q24.1, 181450

(continued)

Human Malformations and Related Anomalies

29

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

Gene/Locus/OMIM

Disorder

Vohwinkel with ichthyosis

1q21, 604117

Williams-Beuren

ELN, 7q11.2, 194050

WAGR (Wilms tumoraniridia-genitourinary anomalies-mental retardation)

WT1, 11p13, 194072

Wolf-Hirschhorn

4p16.3, 194190

X-linked hydrocephalus spectrum

L1CAM, Xq28, 303350

Zellweger

PEX1, 7q21-q22, 214100

Waardenburg

Gene/Locus/OMIM

PEX2, 8q21.1, 170993

Type I

PAX3, 2q35, 193500

Type IIA

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

Type III

PAX3, 2q35, 148820

PEX5, 12p13.3, 214100

Waardenburg-Shah

SOX10, 22q13, 277580

PEX10, Chr. 1, 214100

Walker-Warburg

9q31, 236670

PEX13, 2p15, 214100

Weaver

NSD1, 5q35, 277590

PEX16, 11p12-p11.2, 603360

Weill-Marchesani

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

PEX19, 1q22, 214100

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

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

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

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

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

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

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

30

Overview

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

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

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

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

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

Human Malformations and Related Anomalies

31

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

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

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

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

Mosaicism

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

32

Overview

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

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

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

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

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

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

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

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

Incidence per 10,000 births

Neural tube defects Anencephaly

5

Spina bifida

5

Encephalocele Cleft lip/palate

1 10

Congenital dislocation of the hip

10

Club foot

12

Pyloric stenosis

30

Cardiac defects

70

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

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

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

33

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

34

Overview

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

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

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

Human Malformations and Related Anomalies

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

Examination

Estimated Ovarian Radiation Dose (millirads)

Barium Enema Total

805

Radiography

439

Fluoroscopy

366

Upper Gastrointestinal Series Total

558

Radiography

360

Fluoroscopy

198

Intravenous or retrograde pyelography

407

Hip

309

Abdomen

289

Lumbar spine

275

Cholecystography

193

Pelvis Thoracic spine

41 9

Chest Radiography Photofluorography Fluoroscopy Skull

8 8 71 4

Cervical spine

2

Upper extremity (excluding shoulder)

1

Shoulder

<1

Lower extremity (excluding hip)

<1

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

35

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

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

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

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

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

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

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

36

Overview

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

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

Prenatal Infections

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

Cytomegalovirus

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

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

Human Malformations and Related Anomalies

37

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

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

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

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

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

Mumps Virus

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

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

38

Overview

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

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

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

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

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

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

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

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

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

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

Human Malformations and Related Anomalies

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

39

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

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

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

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

40

Overview

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

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

Malaria

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

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

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

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

Human Malformations and Related Anomalies

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

ACE inhibitors

Lithium

Alcohol (ethyl)

Methimazole

Aminopterin, methotrexate

Methyl mercury

Androgens

Methylene blue

Busulfan

Misoprostol

Carbamazepine

Penicillamine

Carbimazole

Propylthiouracil

Chlorobiphenyls

Tetracycline

Cocaine

Thalidomide

Coumarin

Toluene

Cyclophosphamide Diethylstilbestrol

Trimethadione, paramethadione

Diphenylhydantoin

Valproic acid

Fluconazole

Vitamin A

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

Iodides Isotretinoin, etretinate Teratogenicity Controversial/Doubtful

Agent Orange

41

Metronidazole

Aspartame

Oral contraceptives

Aspirin

Retinoids (topical)

Bendectin

Rubella vaccine

Cigarette smoking

Spermicides

Corticosteroids

Streptomycin

Lead

Vitamin D

Marijuana

Zinc deficiency

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

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

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

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

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

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Overview

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

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

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

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

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

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

Human Malformations and Related Anomalies

43

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

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

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

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

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

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

44

Overview

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

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

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

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

Human Malformations and Related Anomalies

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

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

45

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

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

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

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

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

46

Overview

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

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

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

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

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

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

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

Human Malformations and Related Anomalies

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

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

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

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

Mercury

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

Lithium

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

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

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

48

Overview

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

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

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

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

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

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

Human Malformations and Related Anomalies

Fluconazole

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

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

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

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

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

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

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

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

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

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

Human Malformations and Related Anomalies

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Hyperparathyroidism

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

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

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

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

Hypoparathyroidism

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

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

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Overview

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

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

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

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

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

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

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

Human Malformations and Related Anomalies

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

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

Vitamin D

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

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

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

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

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

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

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

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

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

Malformations of the Uterus

Vascular Compromise

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

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

Fibroids

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

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

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

Amnion Disruption and Amniotic Bands

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

Human Malformations and Related Anomalies

55

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

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

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

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

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Overview

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

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

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

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

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

Human Malformations and Related Anomalies

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Platelet Isoimmunization

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

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

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

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

ABO Incompatibility

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

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

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

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Overview

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

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

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

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

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

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

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

Human Malformations and Related Anomalies

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

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

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

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Assessment of Embryonic and Fetal Growth

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

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

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Overview

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

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

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

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

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

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

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

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

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

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

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

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

Human Malformations and Related Anomalies

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

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

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

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

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Overview

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

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

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

Human Malformations and Related Anomalies

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

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

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

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

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

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

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Overview

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

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

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

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

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

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Overview Table 1-15. Conditions for which growth curves are available Achondroplasia Amyoplasia de Lange syndrome Diastrophic dysplasia Distal arthrogryposis

Table 1-16. Indications for chromosome analysis Individual with

Features of recognizable chromosomal syndrome Mental retardation of unknown cause Unexplained major and minor anomalies Multiple congenital anomalies

Fragile X syndrome

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

Marfan syndrome

Unexplained abnormalities of growth

Multiple pterygium syndrome

Certain malignancies

Noonan syndrome

Unexplained failure of neonatal adaptation

Prader-Willi syndrome

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

Pseudoachondroplasia Rubinstein-Taybi syndrome Sickle cell disease

Couples with

Spondyloepiphyseal dysplasia

Repeated spontaneous abortions

Trisomy 13

Infertility

Trisomy 18

Offspring with a chromosomal duplication, deletion, or other rearrangement

Trisomy 21 (Down syndrome) Williams syndrome From Saul et al. 1998.496

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

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

Family Members of

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

Abortions Unexplained stillborns Hydropic placentas

Biochemical Tests

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

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

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

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Molecular Analysis

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

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

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

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

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

Lissencephaly/ Pachygyria

Polymicrogyria

Cortical Heterotopias

Dysgenesis of Corpus Callosum

Cerebellar Malformation/ Dysplasias

Holoprosencephaly

þ

þ

þ

þ

þ

þ

þ

Dysplasia of Olivary Nuclei

Hypoplasia of Temporal Lobes

Amino Acids Nonketotic hyperglycinemia

þ

þ

Cholesterol Smith-Lemli-Opitz

þ

þ

þ

Fatty Acid Oxidation þ

Carnitine palmitoyl transferase 2 Glutaric acidemia 2

þ

þ

þ

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

þ

þ

Mitochondrial þ

Fumarase deficiency Pyruvate dehydrogenase deficiency

þ

þ

þ

þ

þ

þ þ

þ

þ

Respiratory chain enzyme deficiency Organic Acidurias Ethylmalonic acidemia*

þ

Glutaric acidemia 1 Peroxisomal Zellweger

þ

þ

þ

Infantile Refsum

þ

þ

þ

þ

Infantile adrenoleukodystrophy Functional enzyme deficiency

þ

þ

þ

þ

þ

þ

þ

þ þ

Chondrodysplasia punctata Others þ

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

þ

þ

þ

þ þ

Human Malformations and Related Anomalies

71

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

Structural Anomalies

Biochemical Findings

Adenylate Succinate Lyase Deficiency

Lissencephaly, hypoplasia of cerebellar vermis

ADSL deficiency (urinary metabolites)

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

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

Abnormal sialidation of serum transferrin (detected by isoelectric focusing)

CDG II (a–d Subtypes)

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

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

Walker-Warburg Syndrome

Lissencephaly, encephalocele, microphthalmia

–

Muscle-Eye-Brain Disease

Hydrocephaly, cerebellar hypoplasia, glaucoma, muscle dystrophy

–

Progeroid Type of Ehlers-Danlos Syndrome

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

–

Hereditary Multiple Exostoses

Congenital Disorders of N-Glycosylation

Disorders of O-Glycosylation

Short stature, exostoses

–

DOOR (deafness, onychodystrophy, onycholysis, mental retardation)

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

Elevated a-ketoglutarate

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

Craniofacial, brain, skeletal and genital anomalies

Low cholesterol with elevated precursors

Glutaric Aciduria 2

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

Acidosis, hypoglycemia, elevations of glutaric acid

Lysosomal Disorders (mucopolysaccharidoses, mucolipidoses, gangliosidoses, sialidoses)

Coarse facies, hernias, hepatosplenomegaly, dysostosis multiplex

Elevated urinary mucopolysaccharides, abnormal oligosaccharides

Menkes

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

Low serum copper and ceruloplasmin

Peroxisomal Disorders (Zellweger, infantile adrenoleukodystrophy, infantile Refsum)

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

Elevated very long chain fatty acids, plasmalogens

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

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

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

72

Overview

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

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

6. Kalousek DK, Pantzar T, Tsai M, et al.: Early spontanous abortion: morphologic and karyotypic findings in 3912 cases. Birth Defects Orig Artic Ser 29:43, 1993. 7. Shepard TH, Fantel AG, Fitzimmons J: Congenital defect rates among spontaneous abortuses: twenty years of monitoring. Teratology 39:325, 1989. 8. Whitaker PG, Taylor A, Lind T: Unsuspected pregnancy loss in healthy women. Lancet 1:1126, 1983. 9. Shiota K, Uwabe C, Nishimura H: High prevalence of defective human embryos at the early postimplantation period. Teratology 35:309, 1987. 10. Miller JF, Williamson E, Glue J, et al.: Fetal loss after implantation. Lancet 2:554, 1980. 11. Rushton DI: Examination of products of conception from previable human pregnancies. J Clin Pathol 34:819, 1981. 12. Harlap S, Shiono PH, Ramcharan S: A life table of spontaneous abortions and the effects of age, parity, and other variables. In: Human Embryonic and Fetal Death. IH Porter, EB Hook, eds. Academic Press, New York, 1980, p 145. 13. Warburton D, Stein Z, Kline J, et al.: Chromosome abnormalities in spontaneous abortion: data from the New York City study. In: Human Embryonic and Fetal Death. IH Porter, EB Hook, eds. Academic Press, New York, 1980, p 261. 14. Eiben B, Bartels I, Bahr-Ponsch S, et al.: Cytogenetic analysis of 750 spontaneous abortions with the direct preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage. Am J Hum Genet 47:656, 1990. 15. Hassold T, Chen N, Funkhouser J, et al.: A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet 44:151, 1980. 16. Tabet AC, Aboura A, Dauge MC, et al.: Cytogenetic analysis of trophoblasts by comparative genomic hybridization in embryo-fetal development anomalies. Prenat Diagn 21:613, 2001. 17. Kajii T, Ferrier A, Niikawa N, et al.: Anatomic and chromosomal anomalies in 639 spontaneous abortuses. Hum Genet 55:87, 1980. 18. Marden PM, Smith DW, McDonald MJ: Congenital anomalies in the newborn infant, including minor variations. J Pediatr 64:357, 1964. 19. Van Regemorter N, Dodion J, Druart C: Congenital malformations in 10,000 consecutive births in a university hospital: need for genetic counseling and prenatal diagnosis. J Pediatr 104:386, 1984. 20. Myrianthopoulos NC, Chung CS: Congenital malformation in singletons: epidemiologic survey. BDOAS X(11):1, 1974. 21. Chung CS, Myrianthopoulos NC: Congenital anomalies: mortality and morbidity, burden and classification. Am J Med Genet 27:505, 1987. 22. National Birth Defects Prevention Network: Birth defects surveillance data from selected states, 1996–2000. Birth Def Res (Part A) Clin Mol Teratol 67:729, 2003. 23. Johnson KC, Rouleau J: Temporal trends in Canadian birth defects prevalences, 1979–1993. Can J Public Health 88:169, 1997. 24. Queisser-Luft A, Stolz G, Wiesel A, et al.: Malformations in newborn: results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990–1998). Arch Gynecol Obstet 266:163, 2002. 25. Stoll C, Eurocat Working Group: Distribution of single organ malformations in European populations. Ann Genet 38:32, 1995. 26. California Birth Defects Monitoring Program: Birth Defects in California: 1983–1990. California Birth Defects Monitoring Program, 1994. 27. Cha´vez GF, Cordero JF, Becerra JE: Leading major congenital malformations among minority groups in the United States, 1981–1986. CDC Surveil Sum 37:17, 1988. 28. Ka¨lle´n B: Population surveillance of multimalformed infants: experience with the Swedish registry of congenital malformations. J Hum Genet 35:205, 1987. 29. Merlob P, Papier CM, Klingberg MA, et al.: Incidence of congenital malformations in the newborn, particularly minor abnormalities. Prog Clin Biol Res 163(C):51, 1985. 30. Graham JM: Clinical approach to human structural defects. Semin Perinatol 15(Suppl 1): 2, 1991.

Human Malformations and Related Anomalies 31. Angell RR, Sandison A, Brain AD: Chromosome variation in perinatal mortality: a survey of 500 cases. J Med Genet 21:39, 1984. 32. Pitkin RM: Fetal death: diagnosis and management. Am J Obstet Gynecol 157:583, 1987. 33. Curry CJR: Pregnancy loss, stillbirth, and neonatal death. A guide for the pediatrician. Pediatr Clin N Am 39:157, 1992. 34. Pauli RM, Reiser CA, Lebovitz RM, et al.: Wisconsin Stillbirth Service Program: I. Establishment and assessment of a community-based program for etiologic investigation of intrauterine deaths. Am J Med Genet 50:116, 1994. 35. International Clearinghouse for Birth Defects Monitoring Systems: Annual Report 1999, with data for 1997. International Centre for Birth Defects, Rome, 1999. 36. Centers for Disease Control and Prevention: Infant mortality statistics from the 2001 period linked birth/infant death data set. Nat Vital Stat Rep 52:1, 2003. 37. Muhuri PK, MacDorman MF, Ezzati-Rice TM: Racial differences in leading causes of infant death in the United States. Paediatr Perinat Epidemiol 18:51, 2004. 38. Serenius F, Winbo I, Dahlquist G, et al.: Cause-specific stillbirth and neonatal death in Sweden: a catchment area-based analysis. Acta Paediatr 90:1054, 2001. 39. Mattos TC, Giugliani R, Haase HB: Congenital malformations detected in 731 autopsies of children aged 0 to 14 years. Teratology 35:305, 1987. 40. Blackburn W, Cooley NR Jr: The delineation of birth defects by fetal autopsy. Proc Greenwood Genet Center 16:15, 1997. 41. Wilson JG: Environment and Birth Defects. Academic Press, New York, 1973. 42. Nelson K, Holmes LB: Malformations due to presumed spontaneous mutations in newborn infants. N Engl J Med 320:19, 1989. 43. Jones KL: Smith’s Recognizable Patterns of Human Malformations, eds 4, 5. WB Saunders, Philadelphia, 1988, 1997. 44. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451, 1986. 45. Biesecker LG: The multifaceted challenges of Proteus syndrome. JAMA 285:2240, 2001. 46. Kurnit DM, Layton WM, Matthysse S: Genetics, chance, and morphogenesis. Am J Hum Genet 41:979, 1987. 47. International Anatomical Nomenclature Committee: Nomina Anatomica, ed 6. Churchill Livingstone, Edinburgh, 1989. 48. Malacarne V: Memoires della societes itali, vol IX. 1798, p 49. 49. Spranger J, Benirschke K, Hall JG, et al.: Errors of morphogenesis: concepts and terms. J Pediatr 100:160, 1982. 50. Me´hes K, Stalder G: Minor Malformations in the Neonate. Akade´miae Kiado´, Budapest, 1983. 51. Leppig KA, Werler MM, Cann CI, et al.: Predictive value of minor anomalies. I. Association with major malformations. J Pediatr 110:531, 1987. 52. Holmes LB: Congenital malformations. N Engl J Med 295:204, 1976. 53. Smith DW: Classification, nomenclature, and naming of morphologic defects. J Pediatr 87:162, 1975. 54. Opitz JM, Herrmann J, Pettersen JC, et al.: Terminological, diagnostic, nosological, and anatomical-developmental aspects of developmental defects in man. Adv Hum Genet 9:71, 1979. 55. Pinsky L: The polythetic (phenotypic community) system of classifying human malformation syndromes. BDOAS XIII(3A):13, 1977. 56. Gilbert-Barness E, Opitz JM, Barness LA: The pathologist’s perspective of genetic disease: malformations and dysmorphology. Pediatr Clin North Am 36:163, 1989. 57. McKusick VA: On lumpers and splitters, or the nosology of genetic disease. BDOAS V(1):23, 1969. 58. Merks JH, Karnebeek CD, Caron HN, et al.: Phenotypic abnormalities: terminology and classification. Am J Med Genet 123A:211, 2003. 59. Spranger J, Smith DW: Pro and con the term ‘‘anomalad.’’ J Pediatr 93:159, 1978. 60. Bartsocas CS, Smith DW, Fraser FC: ‘‘Anomalad’’ versus ‘‘polyanomaly.’’ J Pediatr 88:899, 1976.

73

61. Benirschke K, Lowry RB, Opitz JM, et al.: Developmental terms—some proposals: first report of an international working group. Am J Med Genet 3:297, 1979. 62. Fiedler L: Freaks, Myths and Images of the Secret Self. Simon and Schuster, New York, 1978, p 15. 63. Johannsen W: Elemente der exakten Erblichkeitslehre. Jena: Fischer, 1909, p 143. 64. Comi AM: Pathophysiology of Sturge-Weber syndrome. J Child Neurol 18:509, 2003. 65. Opitz JM, Reynolds JF, Spano LM: The Developmental Field Concept. Alan R Liss, New York, 1986. 66. Opitz JM, Gilbert EF: Editorial Comment: CNS anomalies and the midline as a ‘‘developmental field.’’ Am J Med Genet 12:443, 1982. 67. Mall FP: On stages in the development of human embryos from 2 to 25 mm long. Anat Anz 46:78, 1914. 68. Streeter GL: Developmental horizons in human embryos: description of age group XI, 13 to 20 somites, and age group XII, 21 to 29 somites. Contrib Embryol 30:211, 1942. 69. Streeter GL: Developmental horizons in human embryos: description of age groups XIX, XX, XXI, XXII, and XXIII, being the fifth issue of a survey of the Carnegie Collection. Contrib Embryol 34:165, 1951. 70. O’Rahilly R: Developmental Stages in Human Embryos, Part A: Embryos of the First Three Weeks (Stages 1 to 9). Carnegie Institute, Washington, DC, Publication 631, 1973. 71. O’Rahilly R, Muller F: Human Embryology and Teratology, ed 3. Wiley-Liss, New York, 2001. 71a. Barker DJP, Forse´n T, Eriksson JG, et al.: Growth and living conditions in childhood and hypertension in adult life: longitudinal study. J Hypertens 20:1951, 2002. 72. Gilbert SF: Developmental Biology, ed 7. Sinauer Associates, Sunderland, MA, 2003. 73. Friedman JM: Teratogens and growth. Growth Gen Horm 3(4):6, 1987. 74. Smithells RW: The demonstration of teratogenic effects of drugs in humans. In: Drugs and Pregnancy: Human Teratogenesis and Related Problems. DF Hawkins, ed. Churchill Livingstone, Edinburgh, 1983. 75. Robbins SL, Cotran RS: Pathologic Basis of Disease, ed 7. WB Saunders, Philadelphia, 2004. 76. Rimoin DL, Hall J, Maroteaux P: International nomenclature of constitutional diseases of bone with bibliography. BDOAS XV(10):1, 1979. 77. Hall CM: International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 113:65, 2002. 78. Horton WA: Histochemistry, a valuable tool in connective tissue research. Coll Rel Res 4:231, 1984. 79. van Etten AM: Dwarfs Don’t Live in Doll Houses. Adaptive Living, Rochester, 1988, p 216. 80. Smith DW: Recognizable Patterns of Human Malformations, eds 1–3. WB Saunders, Philadelphia, 1970, 1976, 1982. 81. Allen G, Benda CE, Book JA, et al.: Mongolism. Lancet 1:775, 1961. 82. Empedocles: The Fragments of Empedocles. Translated by WE Leonard. Open Court Publishing, Chicago, 1908. 83. Pare A: On Monsters and Marvels. Translated by JL Pallister. University of Chicago Press, Chicago, 1982. 84. Cleland J: Memoirs and Memoranda in Anatomy, vol l. Williams & Norgate, London, 1899. 85. St. Isidore: Etymologies. Wolff and Kerver, Paris, 1499. 86. Huber JJ: Observationes atque cogitationes non nullae de monstris. Hu¨teri and Harmes, Cassellis, 1748. 87. Geoffroy Saint-Hilaire I: Historie des Anomalies. vols. 1–3. JB Baillie`re, Paris. 1832–1837. 88. Schenck J: Observationum Medicarum, Rararum, Novarum, Admirabilium, et Monstrosarum Volumen. N Hoffmannum, Frankfurt, 1609. 89. Aldrovandus U: Monstrorum Historia. N Tebaldinus, Bononiae, 1642. 90. Taruffi: Storia della teratologia, vols. l-VIII. Regia Tipografia, Bologna,1881–1894.

74

Overview

91. Lowne BT: Descriptive Catalogue of the Teratological Series in the Museum of the Royal College of Surgeons of England. Taylor and Francis, London, 1893. 92. Ballantyne JW: Manual of Antenatal Pathology and Hygiene. The Embryo. William Green and Sons, Edinburgh, 1904. 93. Warkany J: Congenital Malformations: Notes and Comments. Year Book, Chicago, 1971. 94. International Classification of Diseases, Rev 9, Clinical Modification (ICD.9.CM), ed 3. U .S. Department of Health and Human Services, Washington, DC, Publication 1:639, 1989. 95. British Paediatric Association: Classification of Diseases, ed 2. British Paediatric Association, London, 1987. 96. Centers for Disease Control: 6-Digit Code for Reportable Congenital Anomalies, Version 6/89. U.S. Department of Health and Human Services, Atlanta, 1989. 97. Cote R, Rothwell D, Palotay J, et al.: The Systematized Nomenclature of Human and Veterinary Medicine: SNOMED International College of American Pathologists, Northfield, IL, 1993. 98. Leichty E: The Omen Series Summa Izbu, JJ Augustin Publisher, Locust Valley, New York, 1970. 99. Billard CM: A Treatise on the Disease of Infants, ed 3. (translated by J Stewart) G Adlard, New York, 1839. 100. Forster A: Handbuch der Pathologischen Anatomie, vol II, Leipzig, 1862–1865. 101. McKusick VA: Mendelian Inheritance in Man. A Catalog of Human Genes and Genetic Disorders, ed 12. Johns Hopkins University Press, Baltimore, 1998. 102. Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD). World Wide Web URL: http:// www.ncbi.nlm.nih.gov/omim, 2000. 103. Shepard TH: Catalog of Teratogenic Agents, ed 10. Johns Hopkins University Press, Baltimore, 2001. 104. Winter RM, Baraitser M: London Dysmorphology Database, version 3.0.3. Oxford University Press, Oxford, 2003. 105. Bankier A, Rose CM, Chemke J, et al.: ‘‘P.O.S.S.U.M.: Pictures of Standard Syndromes and Undiagnosed Malformations,’’ version 5.5. Computer Power Pty Ltd and Murdock Institute, Melbourne, 2004. 106. Flemming W: Beitrage zur Kenntniss der Zelle und ihrer Lebenserscheinungen. Arch Mikrosk Anat Entwickl 20:1, 1882. 107. Lejeune J: Le mongolisme. Premier example d’aberration autosomique humaine. Ann Genet Semaine Hop 1:41, 1959. 108. Waardenburg PJ: Das menschliche Auge und seine Erbanlagen. Martinus Nijhoff, Haag, 1932. 109. Bleyer A: Indications that mongoloid imbecility is a gametic mutation of degressive type. Am J Dis Child 47:342, 1934. 110. Tjio JH, Leyan A: The chromosome number of man. Hereditas 42:1, 1956. 111. Carr DH: Chromosome studies in abortuses and stillborn infants. Lancet 2:603, 1963. 112. Penrose LS, Delhanty JDA: Triploid cell cultures from a macerated fetus. Lancet 1:1261, 1961. 113. Hall B, Kallen B: Chromosome studies in abortuses and stillborn infants. Lancet 1:110, 1964. 114. Aula P, Hjeh L: A structural chromosome anomaly in a human fetus. Ann Paediatr Fenn 8:297, 1962. 115. Steele MW, Breg WR: Chromosome analysis of human amniotic fluid cells. Lancet 1:383, 1966. 116. Caspersson T, Lomakka G, Zech L: The 24 fluorescence patterns of human metaphase chromosomes—distinguishing characters and variability. Hereditas 67:89, 1971. 117. Sutherland GR: Heritable fragile sites on human chromosomes. I. Factors affecting expression in lymphocyte culture. Am J Hum Genet 31:125, 1979. 118. Yunis JJ: High resolution of human chromosomes. Science 191:1268, 1976.

119. Biesecker LG: The end of the beginning of chromosome ends. Am J Med Genet 107:263, 2002. 120. Pinkel D, Seagraves R, Sudar D, et al.: High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20:207, 1998. 121. Hassold TJ: The origin of aneuploidy in humans. In: Aneuploidy, Etiology and Mechanisms. VL Dellarco, PE Voytek, A Hollaender, eds. Plenum Press, New York, 1985, p 103. 122. Therman E: Human Chromosomes, Structure, Behavior, Effects, ed 2. Springer-Verlag, New York, 1986. 123. Pai GS, Lewandowski RC, Borgaonkar DS: Handbook of Chromosomal Syndromes. John Wiley & Sons, Hoboken, 2003. 124. Plenge RM, Stevenson RE, Lubs HA, et al.: Skewed X-inactivation is a common feature of X-linked mental retardation disorders. Am J Hum Genet 71:168, 2002. 125. Rappold GA: The pseudoautosomal regions of the human sex chromosomes. Hum Genet 92:315, 1993. 126. Hall JG: Genomic imprinting: review and relevance to human diseases. Am J Hum Genet 46:857, 1990. 127. Lyon MF: Mechanisms and evolutionary origins of variable X-chromosome activity in mammals. Proc R Soc Lond [Biol] 187:243, 1974. 128. Nicholls RD, Knoll JHM, Butler MG, et al.: Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome. Nature 342:281, 1989. 129. Hashimshony T, Zhang J, Keshet I, et al.: The role of DNA methylation in setting up chromatin structure during development. Nat Genet 34:187, 2003. 130. Pembrey ME: Time to take epigenetic inheritance seriously. Eur J Hum Genet 10:669, 2002. 131. Jiang Y-H, Bressler J, Beaudet AL: Epigenetics and human disease. Ann Rev Genomics Hum Genet 5:479, 2004. 132. Burmeister M, Monaco AP, Gillard EF, et al.: A 10-megabase physical map of human Xp21, including the Duchenne muscular dystrophy gene. Genomics 2:189, 1988. 133. Warburton D: Chromosomal causes of fetal death. Clin Obstet Gynecol 30:268, 1987. 134. Porter IH, Hook EB: Human Embryonic and Fetal Death. Academic Press, New York, 1980. 135. de Grouchy J, Turleau C: Clinical Atlas of Human Chromosomes, ed 2. John Wiley & Sons, New York, 1984. 136. Schinzel A: Catalogue of Unbalanced Chromosome Aberrations in Man, ed 2. Walter de Gruyter, Berlin, 2001. 137. Hsu LYF: Prenatal diagnosis of chromosomal abnormalities through amniocentesis. In: Genetic Disorders of the Fetus. Diagnosis, Prevention and Treatment, ed 4. Milunsky A, ed. John Hopkins Univ Press, Baltimore, 1998, p 179. 138. Alberman ED, Creasy MR: Frequency of chromosomal abnormalities in miscarriages and perinatal deaths. J Med Genet 14:313, 1977. 139. Hanna JS, Shires P, Matile G: Trisomy 1 in a clinically recognized pregnancy. Am J Med Genet 68:98, 1997. 140. Dunn TM, Grunfeld L, Kardon NB: Trisomy 1 in a clinically recognized IVF pregnancy. Am J Med Genet 99:152, 2001. 141. Rosenfeld RG, Grumbach MM: Turner Syndrome. Marcel Dekker, New York, 1990. 142. Stern C: Genetic mosaics in animals and man. In: Genetic Mosaics and Other Essays. C Stern, ed. Harvard University Press, Cambridge, 1968. 143. Happle R: Lyonization and the lines of Blaschko. Hum Genet 70:200, 1985. 144. Pagon RA, Hall JG, Davenport SLH, et al.: Abnormal skin fibroblast cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes. Am J Hum Genet 31:54, 1979. 145. Donnai D, McKeown C, Andrews T, et al.: Diploid/triploid mixoploidy and hypomelanosis of Ito. Lancet 1:1443, 1986. 146. Thomas IT, Frias JL, Cantu ES, et al.: Association of pigmentary anomalies with chromosomal and genetic mosaicism and chimerism. Am J Hum Genet 45:193, 1989.

Human Malformations and Related Anomalies 147. Juberg RC, Holliday DJ, Hennesy VS: Familial sex chromosomal mosaicism. Pediatr Res 23:330A, 1988. 148. Kalousek DK, Barrett IJ, McGillivray BC: Placental mosaicism and intrauterine survival of trisomies 13 and 18. Am J Hum Genet 44:338, 1989. 149. Gartner AB, Barrett IJ, Kalousek DK: Confined placental mosaicism in spontaneous abortions. Am J Hum Genet 43:A130, 1988. 150. Kalousek DK, Dill FJ: Chromosomal mosaicism confined to the placenta in human conceptions. Science 221:665, 1983. 151. Lestou VS, Desilets V, Lomax BL, et al.: Comparative genomic hybridization: a new approach to screening for intrauterine complete or mosaic aneuploidy. Am J Med Genet 92:281, 2000. 152. Murachi S, Nogami H, Oki T, et al.: The tricho-rhino-phalangeal syndrome with exostoses: four additional patients without mental retardation, and review of the literature. Am J Med Genet 19:111, 1984. 153. Schmickel RD: Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr 109:231, 1986. 154. Brewer C, Holloway S, Zawalnyski P, et al.: A chromosomal deletion map of human malformations. Am J Hum Genet 63:1153, 1998. 155. Koolen DA, Nillesen WM, Versteeg MHA, et al.: Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA). J Med Genet 41:892, 2004. 156. Schwartz S, Graf MD: Microdeletion syndromes: characteristics and diagnosis. In: Molecular Cytogenetics. Protocols and Applications. Fan Y-S, ed. Humana Press, Totowa NJ, 2002, p 275. 157. Schinzel A: Microdeletion syndromes, balanced translocations, and gene mapping. J Med Genet 25:454, 1988. 158. Wyandt HE: Ring autosomes: identification, familial transmission, causes of phenotypic effects and in vitro mosaicism. In: The Cytogenetics of Mammalian Autosomal Rearrangements. A Daniel, ed. AR Liss, New York, 1988, p 667. 159. van Dyke DL: Isochromosomes and interstitial tandem direct and inverted duplications. In: The Cytogenetics of Mammalian Autosomal Rearrangements. A Daniel, ed. AR Liss, New York, 1988, p 635. 160. Schwartz S, Palmer CG, Yu P-L, et al.: Analysis of translocations observed in three different populations. II. Robertsonian translocations. Cytogenet Cell Genet 42:53, 1986. 161. Schwartz S, Palmer CG, Yu P-L, et al.: Analysis of translocations observed in three different populations. I. Reciprocal translocations. Cytogenet Cell Genet 42:42, 1986. 162. Abuelo DN, Barsel-Bowers G, Richardson A: Insertional translocations: report of two new families and review of the literature. Am J Med Genet 31:319, 1988. 163. Davis JR, Rogers BB, Hagaman RM, et al.: Balanced reciprocal translocations: risk factors for aneuploid segregant viability. Clin Genet 27:1, 1985. 164. Stene J, Stengel-Rutkowski S: Genetic risks of familial reciprocal and robertsonian translocation carriers. In: The Cytogenetics of Mammalian Autosomal Rearrangements. A Daniel, ed. AR Liss, New York, 1988, p 3. 165. Groupe de Cytoge´ne´ticiens Francais: Pericentric inversions in man: a French collaborative study. Am Genet 29:129, 1986. 166. Kleczkowska A, Fryns JP, Van den Berghe H: Pericentric inversions in man: personal experience and review of the literature. Hum Genet 75:333, 1987. 167. Groupe de Cytoge´ne´ticiens Francais: Paracentric inversions in man: a French collaborative study. Ann Genet 29:169, 1986. 168. Madan K, Seabright M, Lindenbaum RH, et al.: Paracentric inversions in man. J Med Genet 21:407, 1984. 169. Harbison M, Hassold T, Kobryn C, et al.: Molecular studies of the parental origin and nature of human X isochromosomes. Cytogenet Cell Genet 47:217, 1988. 170. Schmutz SM, Pinno E: Morphology alone does not make an isochromosome. Hum Genet 72:253, 1986. 171. Tedeschi B, Porfirio B, Vernole P, et al.: Common fragile sites: their prevalence in subjects with constitutional and acquired chromosomal instability. Am J Med Genet 27:471, 1987.

75

172. Sutherland GR, Baker E, Richards RI: Fragile sites still breaking. Trends Genet 14:501, 1998. 173. German J: Chromosome Mutations and Neoplasia. AR Liss, New York, 1983. 174. Auerbach AD, Alder B, Chaganti RSK: Prenatal and postnatal diagnosis and carrier detection of Fanconi anemia by a cytogenetic method. Pediatrics 67:128, 1981. 175. Parry DM, Mulvihill JJ, Tsai S, et al.: SC phocomelia syndrome, premature centromere separation, and congenital cranial nerve paralysis in two sisters, one with malignant melanoma. Am J Med Genet 24:653, 1986. 176. Kawame H, Sugio Y, Fuyama Y, et al.: Syndrome of microcephaly, Dandy-Walker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD): report of a new case and review of the literature. J Hum Genet 44:219, 1999. 177. Gabriel JM, Higgins MJ, Gebuhr TC, et al.: A model system to study genomic imprinting of human genes. Proc Natl Acad Sci USA 95: 14857, 1998. 178. Fre´zal J, Schinzel A: Report of the committee on clinical disorders, chromosome aberrations and uniparental disomy. Cytogenet Cell Genet 58:986, 1991. 179. Reish O, Lerer I, Amiel A, et al.: Wiedemann-Beckwith syndrome: further prenatal characterization of the condition. Am J Med Genet 107:209, 2002. 180. Preece MA, Price SM, Davies V et al.: Maternal uniparental disomy 7 in Silver-Russell syndrome. J Med Genet 70:328, 1997. 181. Engel E, Antonarakis SE: Genomic Imprinting and Uniparental Disomy in Medicine: Clinical and Molecular Aspects. Wiley-Liss, New York, 2002. 182. Mendel G: Experiments in Plant Hybridisation. Translated by The Royal Horticultural Society of London. Harvard University Press, Cambridge, 1965. 183. Corcos AF, Monaghan FV: Role of DeVries in the recovery of Mendel’s work. J Hered 76:187, 1985; 78:275, 1987. 184. Corcos AF, Monaghan FV: Tschermak, a non-discoverer of mendelism. J Hered 77:468, 1986; 78:208, 1987. 185. Corcos AF, Monaghan FV: Correns, an independent discoverer of Mendelism? J Hered 78:330, 1987; 78:404, 1987. 186. Farabee WC: Inheritance of digital malformations in man. In: Papers of the Peabody Museum of American Archaeology and Ethnology, vol 3. Harvard University Press, Cambridge, 1905, p 69. 187. Garrod AE: Inborn errors of metabolism. Lancet 2:1, 73, 142, 214, 1908. 188. Garrod AE: The incidence of alkaptonuria: a study in chemical individuality. Lancet 2:1616, 1902. 189. Johannsen W: The genotype conception of heredity. Am Nat 45:129, 1911. 190. Strachan T, Read AP: Human Molecular Biology, ed 2. Wiley-Liss, New York, 1999. 191. Watson JD: Molecular Biology of the Gene, ed 5. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2004. 192. Padgett RA, Grabowski PJ, Konarska MM, et al.: Splicing of messenger RNA precursors. Annu Rev Biochem 55:1119, 1986. 193. Gilbert W: Genes-in-pieces revisited. Science 228:823, 1985. 194. Cao A, Moi P: Regulation of the globin genes. Ped Res 51:415, 2002. 195. Kornak U, Mundlos S: Genetic disorders of the skeleton: a developmental approach. Am J Hum Genet 73:447, 2003. 196. Epstein CJ, Erickson RP, Wynshaw-Brois A: Inborn Errors of Development. The Molecular Basis of Clinical Disorders of Morphogenesis. Oxford University Press, New York, 2004. 197. Watson JD, Jordan E: The human genome program at the National Institutes of Health. Genomics 5:654, 1989. 198. Barnhardt BJ: The Department of Energy (DOE) human genome initiative. Genomics 5:657, 1989. 199. International Human Genome Sequencing Consortium: Initial sequencing and analysis of the human genome. Nature 409:860, 2001. 200. Venter JC, Adams MD, Myers EW, et al.: The sequence of the human genome. Science 291:1304, 2001.

76

Overview

201. Cuticchia AJ: Human Gene Mapping: A Compendium. Johns Hopkins Univ Press, 1995. 202. Tsipouras P, Ramirez F: Genetic disorders of collagen. J Med Genet 24:2, 1987. 203. Knowlton RG, Weaver EJ, Struyk AF, et al.: Genetic linkage analysis of hereditary arthro-ophthalmopathy (Stickler syndrome) and the type II procollagen gene. Am J Hum Genet 45:681, 1989. 204. Hall JG: Review and hypothesis: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet 43:355, 1988. 205. Cohn DH, Starman BJ, Blumberg B, et al.: Recurrence of lethal osteogenesis imperfecta due to parental mosaicism in a human type I collagen gene (Col 1Al). Am J Hum Genet 46:591, 1990. 206. Carter CO: Principles of polygenic inheritance. BDOAS XIII(3A):69, 1977. 207. Holt SB: Quantitative genetics of fingerprint patterns. Br Med Bull 17:247, 1961. 208. Carter CO: Genetics of common disorders. Br Med Bull 25:52, 1969. 209. Roberts JAF: Multifactorial inheritance in relation to normal and abnormal human traits. Br Med Bull 17:241, 1961. 210. Chinn S, Price CE, Rona RJ: Need for new reference curves for height. Arch Dis Child 64: 1545, 1989. 211. Edwards JG: The simulation of Mendelism. Acta Genet (Basel) 10:63, 1960. 212. Stevenson RE: The Fetus and Newly Born Infant, ed 2. CV Mosby, St. Louis, 1977. 213. Kalter H: Teratology in the 20th century. Environmental causes of congenital malformations in humans and how they were established. Neurotoxicol Teratol 25:131, 2003. 214. Kalter H, Warkany J: Congenital malformations: etiologic factors and their role in prevention. N Engl J Med 308:424, 491, 1983. 215. Brent R, Weitzman M, Balk S, et al.: The vulnerability, sensitivity and resiliency of the developing embryo, infant, child, and adolescent to the effects of environmental chemicals, drugs, and physical agents as compared to the adult. Pediatrics 113 (suppl):933, 2004. 216. Brent RL: Environmental causes of human congenital malformations: The pediatrician’s role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. Pediatrics 113(suppl):957, 2004. 217. Wilson JG: Current status of teratology: general principles and mechanisms derived from animal studies. In Handbook of Teratology, vol l. JG Wilson, FC Fraser, eds. Plenum, New York, 1977, p 47. 218. Trasler DG: Strain differences in susceptibility to teratogenesis: survey of spontaneously occurring malformations in mice. In: Teratology. JG Wilson, J Warkany, eds. University of Chicago Press, Chicago, 1965, p 38. 219. Fraser FC: The genetics of cleft lip and cleft palate. Am J Hum Genet 22:336, 1970. 220. Brent RL: Radiation teratogenesis. Teratology 21:281, 1980. 221. Penfil RL, Brown ML: Genetically significant dose to the United States population from diagnostic medical roentgenology, 1964. Radiology 90:209, 1968. 221a. Hujoel PP, Bollen AM, Noonan CJ, et al.: Antepartum dental radiography and infant low birth weight. JAMA. 291:1987, 2004. 222. Neel JV, Satoh C, Goriki K, et al.: Search for mutations altering protein charge and/or function in children of atomic bomb survivors: final report. Am J Hum Genet 42:663, 1988. 223. Mayer MD, Harris W, Wimpfheimer S: Therapeutic abortion by means of X-ray. Am J Obstet Gynecol 32:945, 1936. 224. Goldstein L, Murphy DP: Etiology of the ill-health in children born after maternal pelvic irradiation. Part II. Defective children born after postconception pelvic radiation. Am J Roentgenol 22:322, 1929. 225. Dekaban A: Abnormalities in children exposed to X-radiation injury to the human fetus. Part I. J Nucl Med 9:471, 1968. 226. Murphy DP: The outcome of 625 pregnancies in women subjected to pelvic radium or roentgen irradiation. Am J Obstet Gynecol 18:179, 1929. 227. Graham JM Jr, Jones KL, Brent RL: Contribution of clinical teratologists and geneticists to the evaluation of the etiology of congenital

228.

229. 230. 231.

232.

233.

234. 235.

236. 237.

238.

239.

240.

241.

242. 243. 244. 245. 246. 247. 248. 249.

250. 251.

252.

malformations alleged to be caused by environmental agents: ionizing radiation, electromagnetic fields, microwaves, radionuclides, and ultrasound. Teratology 59:307, 1999. Sankaranarayanan K: Ionizing radiation and genetic risks X. The potential ‘‘disease phenotypes’’ of radiation-induced genetic damage in humans: perspectives from human molecular biology and radiation genetics. Mutat Res 429:45, 1999. Russell KP, Rose H, Starr P: Maternal and fetal thyroid function during pregnancy. Surg Obstet Gynecol 104:560, 1957. Fisher WD, Voorhess ML, Gardner LI: Congenital hypothyroidism in infant following maternal I-131 therapy. J Pediatr 62:132, 1963. Brent RL: The effect of embryonic and fetal exposure to X-ray, microwaves, and ultrasound: counseling the pregnant and nonpregnant patient about these risks. Semin Onco1 16:347, 1989. Brent RL: Radiations and other physical agents. In Handbook of Teratology, vol l. JG Wilson, FC Fraser, eds. Plenum Press, New York, 1977, p 153. Goldhaber MK, Polen MR, Hiatt RA: The risk of miscarriage and birth defects among women who use video display terminals during pregnancy. Am J Indust Med 13:695, 1988. Carstensen EL, Gates AH: The effects of pulsed ultrasound on the fetus. J Ultrasound Med 3:145, 1984. McLeod DR, Fowlow SB: Multiple malformations and exposure to therapeutic ultrasound during organogenesis. Am J Med Genet 34:317, 1989. Miller P, Smith DW, Shepard TH: Maternal hyperthermia as a possible cause of anencephaly. Lancet 1:519, 1978. Clarren SK, Smith DW, Harvey MAS, et al.: Hyperthermia— a prospective evaluation of a possible teratogenic agent in man. J Pediatr 95:81, 1979. Pleet H, Graham JMJ, Smith DW: Central nervous system and facial defects associated with maternal hyperthermia at four to 14 weeks’ gestation. Pediatrics 67:785, 1981. Edwards MJ: Congenital defects in guinea pigs: fetal resorptions, abortions, and malformations following induced hyperthermia during early gestation. Teratology 2:313, 1969. Supernau DW, Wertelecki W: Brief clinical report: similarity of effects—experimental hyperthermia as a teratogen and maternal febrile illness associated with oromandibular and limb defects. Am J Med Genet 21:575, 1985. Lipson AH, Webster WS, Brown-Woodman PDC, et al.: Mobius syndrome: animal model-human correlations and evidence for a brainstem vascular etiology. Teratology 40:339, 1989. Gibbs RS: The origins of stillbirth: infectious diseases. Semin Perinatol 26:75, 2002. Behrman RE, Kliegman RM, Jenson HB: Nelson Textbook of Pediatrics, ed 17. WB Saunders, Philadelphia, 2004. Gershon AA, Hotez PJ, Katz SL: Krugman’s Infectious Diseases of Children, ed 11. CV Mosby, Philadelphia, 2004. Monif GRG: Viral Infections of the Human Fetus. Macmillan, London, 1969. Hanshaw JB, Dudgeon JA, Marshall WC: Viral Diseases of the Fetus and Newborn, ed 2. WB Saunders, Philadelphia, 1985. Remington JS, Klein JO: Infectious Diseases of the Fetus and Newborn Infant, ed 5. WB Saunders, Philadelphia, 2001. Medearis DN: Observations concerning human cytomegalovirus infection and disease. Bull Johns Hopkins Hosp 114:181, 1964. Reynolds DW, Stagno S, Stubbs KG: Inapparent congenital cytomegalovirus infection with elevated cord IgM levels. N Engl J Med 290:291, 1974. Stern H, Tucker SM: Prospective study of cytomegalovirus infection in pregnancy. Br Med J 1:268, 1973. Enders G, Bader U, Lindemann L, et al.: Prenatal diagnosis of congenital cytomegalovirus infection in 189 pregnancies with known outcome. Prenat Diagn 21:362, 2001. Jarvis MA., Nelson JA: Mechanisms of human cytomegalovirus persistence and latency. Front in Biosci 7:d1575, 2002.

Human Malformations and Related Anomalies 253. Schaffer AJ: Diseases of the Newborn, ed 2. WB Saunders, Philadelphia, 1966. 254. South MA, Thompkins WAF, Morris CR, et al.: Congenital malformation of the central nervous system associated with genital type (type 2) herpes virus. J Pediatr 75:13, 1969. 255. Alkalay AL, Pomerance JJ, Rimoin DL: Fetal varicella syndrome. J Pediatr 111:320, 1987. 256. Paryani SG, Arvin AM: Intrauterine infection with varicella-zoster virus after maternal varicella. N Engl J Med 314:1542, 1986. 257. Huang C-S, Lin S-P, Chiu N-C, et al.: Congenital varicella syndrome as an unusual cause of congenital malformation: report of one case. Acta Paediatr Tw 42:239, 2001. 258. Coffey VP, Jessop WJE: Maternal influenza and congenital deformities: a prospective study. Lancet 2:935, 1959. 259. Shone JD, Armas SM, Manning JA: The mumps antigen test in endocardial fibroelastosis. Pediatrics 37:423, 1966. 260. Gregg NM: Congenital cataract following German measles in the mother. Trans Ophthalmol Soc Aust 3:35, 1941. 261. Monif GRG, Hardy JB, Sever JL: Studies in congenital rubella, Baltimore 1964–65. Bull Johns Hopkins Hosp 118:85, 97, 1966. 262. Desmond MM, Wilson GS, Melnick JL, et al.: Congenital rubella encephalitis. J Pediatr 71:311, 1967. 263. Chiriboga-Klein S, Oberfield SE, Casullo AM, et al.: Growth in congenital rubella syndrome and correlation with chemical manifestations. J Pediatr 115:251, 1989. 264. Cooper LZ, Ziring PR, Ockerse AB, et al.: Rubella: clinical manifestations and management. Am J Dis Child 118:18, 1969. 265. Rodis JF, Hovick TJJ, Quinn DL, et al.: Human parvovirus infection in pregnancy. Obstet Gynecol 72:733, 1988. 266. Oleske J, Minnefor A, Cooper RJ, et al.: Immune deficiency syndrome in children. JAMA 249:2345, 1983. 267. Rubinstein A, Sicklick M, Gupta A, et al.: Acquired immunodeficiency with reversed T4-T8 ratios in infants born to promiscuous and drugaddicted mothers. JAMA 249:2350, 1983. 268. Scott GB, Buck BE, Leterman JG, et al.: Acquired immunodeficiency syndrome in infants. N Engl J Med 310:76, 1984. 269. Marion RW, Wiznia AA, Hutcheon RG, et al.: Human T-cell lymphotropic virus type III (HTLV-III) embryopathy. Am J Dis Child 140:638, 1986. 270. Iosub S, Bamji M, Stone RK, et al.: More on human immunodeficiency virus embryopathy. Pediatrics 80:512, 1987. 271. Brown GC, Evans TN: Serologic evidence of coxsackievirus etiology of congenital heart disease. JAMA 199:183, 1967. 272. Gauntt CG, Gudvangen RJ, Brans YW, et al.: Coxsackievirus group B antibodies in the ventricular fluid of infants with severe anatomic defects in the central nervous system. Pediatrics 76:64, 1985. 273. Gear J: Coxsackie virus infections in Southern Africa. Yale J Biol Med 34:289, 1961. 274. Manson MM, Logan WPD, Loy RM: Rubella and other virus infections during pregnancy. In Ministry of Health: Reports on Public Health and Medical Subjects. No.101. Her Majesty’s Stationery Office, London, 1960. 275. Green DM, Reid SM, Rhaney K: Generalized vaccinia in the human fetus. Lancet 1:1296, 1966. 276. Moss PD, Heffernan CK, Thurston JG: Enteroviruses and congenital abnormalities. Br Med J 1:110, 1967. 277. Siegel M, Greenberg M: Poliomyelitis in pregnancy. Effect on fetus and newborn infant. J Pediatr 49:280, 1956. 278. Lin HH, Lee TY, Chen DS, et al.: Transplacental leakage of HBeAgpositive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus. J Pediatr 111:877, 1987. 279. Ryan GMJ, Abdella TN, McNeeley SG, et al.: Chlamydia trachomatis infection in pregnancy and effect of treatment on outcome. Am J Obstet Gyneco1 162:34, 1990. 280. Naessens A, Foulon W, Breynaert J, et al.: Postpartum bacteremia and placental colonization with genital mycoplasmas and pregnancy outcome. Am J Obstet Gynecol 160:647, 1989.

77

281. Braun P, Lee Y-H, Klein JO, et al.: Birth weight and genital mycoplasmas in pregnancy. N Engl J Med 284:167, 1971. 282. Monif GRG: Infectious Diseases in Obstetrics and Gynecology. Harper & Row, Hagerstown, MD, 1974. 283. Ewing CI, Roberts C, Davidson DC, et al.: Early congenital syphilis still occurs. Arch Dis Child 60:1128, 1985. 284. Groseclose SL, Brathwaite WS, Hall PA, et al.: Summary of notifiable diseases—United States, 2002. MMWR 51:1, 2004. 285. Harter CA, Benirschke K: Fetal syphilis in the first trimester. Am J Obstet Gynecol 124:705, 1976. 286. Putkonen T: Does early treatment prevent dental changes in congenital syphilis? Acta Derm Venereol (Stockh) 43:240, 1963. 287. Bulova SI, Schwartz E, Harrer WV: Hydrops fetalis and congenital syphilis. Pediatr 49:285, 1972. 288. Murphy FK, Patamasucon P: Congenital syphilis. In Sexually Transmitted Diseases. KK Holmes, P-A Mardh, PF Sparling, PJ Wiesner, eds. McGraw-Hill, New York, 1984, p 352. 289. Lindsay S, Luke IW: Fatal leptospirosis (Weil’s disease) in a newborn infant. J Pediatr 34:90, 1949. 290. MacDonald AB: Gestational Lyme borreliosis. Rheum Dis Clin North Am 15:657, 1989. 291. Bruner JP, Elliott JP, Kilbride HW, et al.: Candida chorioamnionitis diagnosed at amniocentesis with subsequent fetal infection. Am J Perinatol 3:213, 1986. 292. Sever JL, Ellenberg JH, Ley AC, et al.: Toxoplasmosis: maternal and pediatric findings in 23,000 pregnancies. Pediatrics 82:181, 1988. 293. Eichenwald HF: A study of congenital toxoplasmosis. In Human Toxoplasmosis. Ejnar Munksgaards Forlag, Copenhagen, 1960, p 41. 294. Saxon SA, Knight W, Reynolds DW, et al.: Intellectual deficits in children born with subclinical congenital toxoplasmosis: a preliminary report. J Pediatr 82:792, 1973. 295. Covell G: Congenital malaria. Trop Dis Bull 47:1147, 1950. 296. Jones KL, Smith DW, Ulleland CN, et al.: Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1:1267, 1973. 297. Warner RH, Rossett HL: The effects of drinking on offspring: an historical survey of the American and British literature. J Stud Alcohol 36:1395, 1975. 298. Lemoine P, Harousseau H, Borteyru J, et al.: Children of alcoholic parents: abnormalities observed in 127 cases. Quest Med 21:476, 1968. 299. Jones KL: The fetal alcohol syndrome. Growth Gen Horm 4:1, 1988. 300. Hadeed AJ, Siegel SR: Maternal cocaine use during pregnancy: effect on the newborn infant. Pediatrics 84:205, 1989. 301. Chasnoff IJ, Chisom GM, Kaplan WE: Maternal cocaine use and genitourinary tract malformations. Teratology 37:201, 1988. 302. Fulroth R, Phillips B, Durand DJ: Perinatal outcome of infants exposed to cocaine and/or heroin in utero. Am J Dis Child 143:905, 1989. 303. Bingol N, Fuchs M, Diaz V, et al.: Teratogenicity of cocaine in humans. J Pediatr 110:93, 1987. 304. Werler MM, Pober BR, Holmes LB: Smoking and pregnancy. In: Teratogen Update: Environmentally Induced Birth Defect Risks. JL Sever, RL Brent, eds. AR Liss, New York, 1986, p 131. 305. Naeye R, Harkness W, Utts J: The duration of maternal cigarette smoking, fetal and placental disorders. Early Hum Dev 3:229, 1979. 306. MacMahon B, Alpert M, Salber EJ: Infant weight and parental smoking habits. Am J Epidemiol 82:247, 1966. 307. Underwood P, Hester LL, Lafitte TJ, et al.: The relationship of smoking to the outcome of pregnancy. Am J Obstet Gynecol 91:270, 1965. 308. Hingson R, Alpert JJ, Day N, et al.: Effects of maternal drinking and marijuana use on fetal growth and development. Pediatrics 70:539, 1982. 309. Long SY: Does LSD induce chromosomal damage and malformations? A review of the literature. Teratology 6:75, 1972. 310. Meadow WR: Congenital abnormalities and anticonvulsant drugs. Proc R Soc Med 63:48, 1970. 311. Melchior JD, Svensmark O, Trolle D: Placental transfer of phenobarbitone in epileptic women, and elimination in newborns. Lancet 2:860, 1967.

78

Overview

312. Kelly TE: Teratogenicity of anticonvulsant drugs. Am J Med Genet 19:413, 435, 445, 451, 1984. 313. Hill RM, Verniaud WM, Homing MG, et al.: Infants exposed in utero to antiepileptic drugs: a prospective study. Am J Dis Child 127:645, 1974. 314. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 87:285, 1975. 315. Hanson JW, Myrianthoupoulos NC, Harvey MAS, et al.: Risks to offspring of women treated with hydantoin anticonvulsants with emphasis on the fetal hydantoin syndrome. J Pediatr 89:662, 1976. 316. Zackai EH, Mellman WJ, Neiderer B, et al.: The fetal trimethadione syndrome. J Pediatr 87:280, 1975. 317. Robert E: Valproic acid and spina bifida: a preliminary report— France. MMWR 31:565, 1982. 318. DiLiberti JH, Farnon PA, Dennis NR, et al.: The fetal valproate syndrome. Am J Med Genet 19:473, 1984. 319. Hardinger HH, Atkin JF, Blackston RD, et al.: Verification of the fetal valproate syndrome phenotype. Am J Med Genet 29:171, 1988. 320. Jones KL, Lacro RV, Johnson KA, et al.: Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 320:1661, 1989. 321. Thiersch JB: Therapeutic abortions with a folic acid antagonist, 4-amino pteroylglutamic acid, administered by the oral route. Am J Obstet Gynecol 63:1298, 1952. 322. Shaw EB, Steinbach HL: Aminopterin-induced fetal malformation. Am J Dis Child 115:477, 1968. 323. Milunsky A, Fraef JW, Gaynor MF: Methotrexate-induced congenital malformations. J Pediatr 72:790, 1968. 324. Shaw EB, Rees EL: Fetal damage due to aminopterin ingestion: followup at 17½ years of age. Am J Dis Child 134:1172, 1980. 325. Coelho KE, Sarmento MF, Veiga CM, et al.: Misoprostol embryotoxicity: clinical evaluation of fifteen patients with arthrogryposis. Am J Med Genet 95:297, 2000. 326. Gonzalez CH, Marques-Dias MJ, Kim CE, et al.: Congenital abnormalities in Brazilian children associated with misoprostol misuse in first trimester of pregnancy. Lancet 351:1624, 1998. 327. Pastuszak AL, Schu¨ler L, Speck-Martins CE, et al.: Use of misoprostol during pregnancy and Mo¨bius syndrome in infants. New Engl J Med 338:1881, 1998. 328. Schu¨ler L, Pastuszak A, Sanseverino MTV, et al.: Pregnancy outcome after exposure to misoprostol in Brazil: a prospective, controlled study. Reprod Toxicol 13:147, 1999. 329. Wheeler M, O’Meara P, Stanford M: Fetal methotrexate and misoprostol exposure: the past revisited. Teratology 66:73, 2002. 330. Lenz W: A short history of thalidomide embryopathy. Teratology 38:203, 1988. 331. Quibell EP: The thalidomide embryopathy: an analysis from the UK. Practitioner 225:721, 1981. 332. Taussig HB: A study of the German outbreak of phocomelia: the thalidomide syndrome. JAMA 180:1106, 1962. 333. Yang Q, Khoury MJ, James LV, et al.: The return of thalidomide: are birth defects surveillance systems ready? Am J Med Genet 73:251, 1997. 334. Rosa FW: Teratogenicity of isotretinoin. Lancet 2:513, 1983. 335. Rosa FW, Wilk AL, Kelsey FO: Teratogen update: vitamin A congeners. Teratology 33:355, 1986. 336. Fernhoff PM, Lammer EJ: Craniofacial features of isotretinoin embryopathy. J Pediatr 105:595, 1984. 337. Lammer EJ, Chen DT, Hoar RM, et al.: Retinoic acid embryopathy. N Engl J Med 313:837, 1985. 338. Lammer EJ, Schunior A, Holmes LB: Retinoic acid fetopathy. Proc Greenwood Genet Center 9:68, 1990. 339. Rothman KJ, Moore LL, Singer MR, et al.: Teratogenicity of high vitamin A intake. N Engl J Med 333:1369, 1995. 340. Mastroiacovo P, Mazzone T, Addis A, et al.: High vitamin A intake in early pregnancy and major malformations: a multicenter prospective controlled study. Teratology 59:7, 1999.

341. Grote W, Harms D, Janig U, et al.: Malformation of a fetus conceived 4 months after termination of maternal etretinate treatment. Lancet 1:1276, 1985. 342. Grumbach MM, Ducharme JR: The effects of androgens on fetal sexual development: androgen-induced female pseudohermaph-rodism. Fertil Steril 11:157, 1960. 343. Wilkins L: Masculinization of female fetus due to the use of oral1y given progestins. JAMA 172:1028, 1960. 344. Burnstein R, Wasserman HC: The effect of Provera on the fetus. Obstet Gynecol 23:931, 1964. 345. Jewelewicz R, Perkins RP, Dyrenfurth I, et al.: Luteomas of pregnancy, a cause of maternal virilization. Am J Obstet Gynecol 109:24, 1971. 346. Verhoeven AT, Mastboom JL, van Levsden HA: Virilization in pregnancy coexisting with an (ovarian) mucinous cystadenoma-a case report and review of virilizing ovarian tumors in pregnancy. Obstet Gynecol Surv 28:597, 1973. 347. Bongiovanni AM, McPadden AJ: Steroids during pregnancy and possible fetal consequences. Fertil Steril 11:181, 1960. 348. Grajwer LA, Lilien LD, Pi1des RS: Neonatal subclinical adrenal insufficiency: result of maternal steroid therapy. JAMA 238:1279, 1977. 349. Janerich DT, Piper JM, Glebatis DM: Oral contraceptives and congenital limb-reduction defects. N Engl J Med 291:697, 1974. 350. Heinonen OP, Slone D, Monson RR, et al.: Cardiovascular birth defects and antenatal exposure to female sex hormones. N Engl J Med 296:67, 1977. 351. Kricker A, Elliott JW, Forrest JM, et al.: Congenital limb reduction deformities and use of oral contraceptives. Am J Obstet Gynecol 155: 1072, 1986. 352. Nora JJ, Nora AH, Wexler PL: Exogenous sex hormones and birth defects: continuing the dialogue. Am J Obstet Gynecol 144:860, 1982. 353. Nora JJ, Nora AH: Birth defects and oral contraceptives. Lancet 1:941, 1973. 354. Lammer EJ, Cordero JF: Exogenous sex hormone exposure and the risk for major malformations. JAMA 255:3128, 1986. 355. Gal I, Kirman B, Stern J: Hormonal pregnancy tests and congenital malformation. Nature 216:83, 1967. 356. Czeizel A, Keller S, Bod M: An etiological evaluation of increased occurrence of congenital limb reduction abnormalities in Hungary, 1975–1978. Int J Epidemiol 12:445, 1983. 357. Oakley GP, F1ynt JW, Falek A: Hormonal pregnancy tests and congenital malformations. Lancet 2:256, 1973. 358. Mulvihill JJ, Mulvihill CG, Neill CA: Congenital heart defects and prenatal sex hormones. Lancet 1:1168, 1974. 359. Harlap S, Prywes R, Davies AM: Birth defects and oestrogens and progesterones in pregnancy. Lancet 1:682, 1975. 360. Stillman RJ: In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance in male and female offspring. Am J Obstet Gynecol 142:905, 1982. 361. Herbst AL, Scully RE: Adenocarcinoma of the vagina in adolescence: a report of seven cases including clear cell carcinomas (so-called mesonephromas). Ca 25:745, 1970. 362. Mills JL, Bongiovanni AM: Effect of prenatal estrogen exposure on male genitalia. Pediatrics 62(Suppl):1160, 1978. 363. Burrows RF, Burrows EA: Assessing the teratogenic potential of antiotensin-converting enzyme inhibitors in pregnancy. Aust NZ J Obstet Gynaecol 38:306, 1998. 364. Barr M, Cohen MM: Ace inhibitor fetopathy and hypocalvaria: the kidney-skull connection. Teratology 44:485, 1991. 365. Niswander KR, Gordon M: The Women and Their Pregnancies. WB Saunders, Philadelphia, 1972, p 246. 366. Refetoff S, Ochi Y, Selenkow HA, et al.: Neonatal hypothyroidism and goiter in one infant of each of two sets of twins due to maternal therapy with antithyroid drugs. J Pediatr 85:240, 1974. 367. Burrow GN, Bartsocas C, Klatskin EH, et al.: Children exposed in utero to propylthiouracil: subsequent intellectual and physical development. Am J Dis Child 116:161, 1968.

Human Malformations and Related Anomalies 368. Foulds N, Walpole I, Elmslie F, et al.: Carbimazole embryopathy: an emerging phenotype. Am J Med Genet 132A:130, 2005. 369. Wilson LC, Kerr BA, Wilkinson R, et al.: Choanal atresia and hypothelia following methimazole exposure in utero: a second report. Am J Med Genet 75:220, 1998. 370. Diav-Citrin O, Ornoy A: Teratogen update: antithyroid drugsmethimazole, carbimazole, and propylthiouracil. Teratology 65:38, 2002. 371. Senior B, Chernoff HL: Iodide goiter in the newborn. Pediatrics 47:510, 1971. 372. Weinstein MR: The international registry of lithium babies. Drug Infect J 10:94, 1976. 373. Cohen LS, Friedman JM, Jefferson JW: A reevaluation of risk of in utero exposure to lithium. JAMA 271:146, 1994. 374. Murakami U: The effect of organic mercury on intrauterine life. Adv Exp Med Biol 27:301, 1971. 375. Amin-zaki L, Majeed MA, Elhassani SB, et al.: Prenatal methylmercury poisoning: clinical observations over five years. Am J Dis Child 133:172, 1979. 376. Hall JG: Embryopathy associated with oral anticoagulant therapy. BDOAS XII(5):33, 1976. 377. Stevenson RE, Burton M, Ferlauto GJ, et al.: Hazards of oral anticoagulants during pregnancy. JAMA 243:1549, 1980. 378. Hall JG, Pauli RM, Wilson KM: Maternal and fetal sequelae of anticoagulants during pregnancy. Am J Med 68:122, 1980. 379. Rogan WJ, Gladen BC, Hung K-L, et al.: Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 241:334, 1988. 380. Miller RW: Cola-colored babies: chlorobiphenyl poisoning in Japan. Teratology 4:211, 1971. 381. Lee BE, Feinberg M, Abraham JJ, et al.: Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J 11:1062, 1992. 382. Mastroiacovo P, Mazzone T, Botto LD, et al.: Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol 175:1645, 1996. 383. Pursley TJ, Blomquist IK, Abraham J, et al.: Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 22:336, 1996. 384. Aleck KA: Long-term follow-up of fluconazole embryopathy—a disorder caused by inhibition of normal sterol metabolism. Proc Greenwood Genet Center 22:60, 2003. 385. Friedman JM, Little BB, Brent RL, et al.: Potential human teratogenicity of frequently prescribed drugs. Obstet Gynecol 75:594, 990. 386. Wilson JG; Embryotoxicity of drugs in man. In: Handbook or Teratology, vol 1. JG Wilson, FC Fraser, eds. Plenum Press, New York, 1977, p 309. 387. Holmes LB: Teratogen update: bendectin. Teratology 27:277, 1983. 388. Carter MP, Wilson F: Antibiotics in early pregnancy and congenital malformations. Dev Med Child Neurol 7:353, 1965. 389. Mjolnerod OK, Rasmussen K, Dommerud SA, et al.: Congenital connective-tissue defect probably due to D-penicillamine treatment in pregnancy. Lancet 1:673, 1971. 390. Doll DC, Ringerberg S, Yarbro JW: Antineoplastic agents and pregnancy. Semin Oncol 16:337, 1989. 391. Farquhar JW: The child of the diabetic woman. Arch Dis Child 34:76, 1959. 392. North AFJ, Mazumdar S, Logrillo VM: Birthweight, gestational age, and perinatal deaths in 5,471 infants of diabetic mothers. J Pediatr 90:444, 1977. 393. Naeye RL: Infants of diabetic mothers: a quantitative, morphologic study. Pediatrics 35:1980, 1965. 394. Farquhar JW: Prognosis for babies born to diabetic mothers in Edinburgh. Arch Dis Child 44:36, 1969. 395. Pedersen LM, Tygstrup I, Pederson J: Congenital malformations in newborn infants of diabetic women: correlation with maternal diabetic vascular complications. Lancet 1:1124, 1964. 396. Lucas MJ, Leveno KJ, Williams ML: Early pregnancy glycosylated hemoglobin, severity of diabetes, and fetal malformations. Am J Obstet Gynecol 161:426, 1989.

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397. Mills JL: Malformations in infants of diabetic mothers. In: Teratogen Update: Environmentally Induced Birth Defect Risks. JL Sever, RL Brent, eds. AR Liss, New York, 1986, p 165. 398. Janssen PA, Rothman I, Schwartz SM: Congenital malformations in newborns of women with established and gestational diabetes in Washington State, 1984–91. Pediatr Perinat Epidemiol 10:52, 1996. 399. Becerra JE, Khoury MJ, Cordero JF, et al.: Diabetes mellitus during pregnancy and the risks for specific birth defects: a population based case-control study. Pediatrics 85:1, 1990. 400. Reece EA, Quintela PA, Homko CJ, Sivan E: Early fetal growth delay: is it really predictive of congenital anomalies in infants of diabetic women? J Mat-Fet Med 6:168, 1997. 401. Roberts AB, Pattison NS: Pregnancy in women with diabetes mellitus, twenty years experience: 1968–1987. New Zealand Med J 103:211, 1990. 402. Siegler AM: Pregnancy and cretinism: report of a case and review of the literature. Obstet Gynecol 8:639, 1956. 403. Jones WS, Man EB: Thyroid function in human pregnancy. VI. Premature deliveries and reproductive failures of pregnant women with low serum butanol-extractable iodines. Maternal serum TBG and TBPA capacities. Am J Obstet Gynecol 104:909, 1969. 404. Sutherland JM, Esselborn VM, Burket RL, et al.: Familial non-goitrous cretinism apparently due to maternal antithyroid antibody. N Engl J Med 263:336, 1960. 405. Green WL: Humoral and genetic factors in thyrotoxic Graves disease and neonatal thyrotoxicosis. JAMA 235:1449, 1976. 406. Burrow GN: The management of thyrotoxicosis in pregnancy. N Engl J Med 313:562, 1985. 407. Davis LE, Lucas MJ, Hankins GDV, et al.: Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 160:63, 1989. 408. Sunshine P, Kusumoto H, Kriss JP: Survival time of circulating longacting thyroid stimulator in neonatal thyrotoxicosis: implications for diagnosis and therapy of the disorder. Pediatrics 36:869, 1965. 409. Nutt J, Clark F, Welch RG, et al.: Neonatal hyperthyroidism and longacting thyroid stimulator protector. Br Med J 2:695, 1974. 410. Stevenson RE, Trent HW III: Maternal hyperthyroidism and congenital craniosynostosis. Proc Greenwood Genet Center 9:3, 1990. 411. Hollingsworth DR, Mabry CC, Eckerd JM: Hereditary aspects of Graves’ disease in infancy and childhood. J Pediatr 81:446, 1972. 412. Landing BH, Kamoshita S: Congenital hyperparathyroidism secondary to maternal hypoparathyroidism. J Pediatr 77:842, 1970. 413. Jacobson BB, Terslev E, Lund B, et al.: Neonatal hypocalcemia associated with maternal hyperparathyroidism. Arch Dis Child 53:308, 1978. 414. Koerten JM, Morales WJ, Washington SR III, et al.: Cushing’s syndrome in pregnancy: a case report and literature review. Am J Obstet Gynecol 154:626, 1986. 415. Kolodny RC: Herpes gestationis. Am J Obstet Gynecol 104:39, 1969. 415a. Nelson JL: Microchimerism in human health and disease. Autoimmun 36:5, 2003. 416. Mabry CC, Denniston JC, Coldwell JG: Mental retardation in children of phenylketonuric mothers. N Engl J Med 275:1331, 1966. 417. Stevenson RE, Huntley CC: Congenital malformations in off-spring of phenylketonuric mothers. Pediatr 40:33, 1967. 418. Lenke RR, Levy HL: Maternal phenylketonuria and hyperphenylalaninemia. N Engl J Med 303:1202, 1980. 419. Platt LD, Koch R, Hanley WB, et al.: The international study of pregnancy outcome in women with maternal phenylketonuria: report of a 12-year study. Am J Obstet Gynecol 182:326, 2000. 420. Mahon BE, Levy HL: Maternal Hartnup disorder. Am J Med Genet 24:513, 1986. 421. Stevenson RE, Taylor HA: Pregnancy and pyridoxine-responsive homocystinuria. Proc Greenwood Genet Center 3:47, 1984. 422. Scriver CR, Beaudet AL, Sly WS, et al.: The Metabolic & Molecular Bases of Inherited Disease, 8 ed. McGraw-Hill, New York, 2001. 423. Smithells RW, Sheppard S, Schorah CJ: Vitamin levels and neural tube defects. Arch Dis Child 51:944, 1959.

80

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

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

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

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

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

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

Part II Cardiorespiratory Organs

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

I

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

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

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

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

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

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

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

Commitment of Precardiac Mesoderm

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

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

Heart

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

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

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

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

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

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Cardiorespiratory Organs

Left Atrium and Pulmonary Veins

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

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

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

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

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

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

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

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

Heart

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

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

Table 2-2. Prevalence of cardiovascular malformations: Baltimore–Washington Infant Study (BWIS) and the Metropolitan Atlanta Congenital Defect Program (MACDP) Prevalence per 10,000* BWIS 1981–1989

MACDP 1968–1997

MACDP 1995–1997

11.2

16.6

24.0

Pulmonary valve stenosis

5.4

3.8

6.0

Peripheral pulmonic stenosis

NA

3.6

7.0

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

3.3

2.7

3.4

With Down syndrome

2.3

1.5

2.4

Without Down syndrome

1.0

1.2

1.0

Tetralogy of Fallot

3.3

3.8

4.7

Atrial septal defect, secundum

3.2

10.0

4.6

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

2.6

1.1

2.2

Hypoplastic left heart syndrome

1.8

2.1

2.1

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

1.4

1.3

1.6

Cardiovascular Malformation

Ventricular septal defect (includes membranous, muscular, unspecified)

Coarctation of the aorta

1.4

2.9

3.5

Patent ductus arteriosus

0.9

6.6

8.1

Aortic valve stenosis

0.8

1.0

0.8

Bicuspid aortic valve

0.7

NA

NA

Double-outlet right ventricle

0.7

1.1

2.2

Total anomalous pulmonary venous return

0.6

0.7

0.7

Pulmonary atresia with intact ventricular septum

0.6

0.6

0.6

Interrupted aortic arch

0.6

NA

NA

Ebstein anomaly

0.6

0.4

0.6

Common arterial trunk (truncus)

0.5

0.5

0.6

Tricuspid atresia Other major CVMs

0.4

0.3

0.3

NA

6.4

9.7

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

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

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

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

Heart

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

91

13. 14. 15. 16. 17.

18. 19.

20. 21. 22. 23.

24.

25.

26.

27. 28. 29.

30.

31. 32.

33.

34.

35.

36.

37.

38.

Adolescents, including the Fetus and Young Adult, ed 5. Williams and Wilkins, Baltimore, 1995, p 633. Tam PP, Behringer RR: Mouse gastrulation: the formation of a mammalian body plan. Mech Dev 68:3, 1997. Meyers EN, Martin GR: Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 285:403, 1999. Brand T: Heart development: molecular insights into cardiac specification and early morphogenesis. Dev Biol 258:1, 2003. Zaffran S, Frasch M: Early signals in cardiac development. Circ Res 91:457, 2002. Saga Y, Miyagawa-Tomita S, Takagi A, et al: MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Development 126:3437, 1999. Schneider VA, Mercola M: Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev 15:304, 2001. van den Hoff MJ, Kruithof BP, Moorman AF, et al: Formation of myocardium after the initial development of the linear heart tube. Dev Biol 240:61, 2001. Kawano Y, Kypta R: Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116:2627, 2003. Patterson KD, Cleaver O, Gerber WV, et al: Homeobox genes in cardiovascular development. Curr Top Dev Biol 40:1, 1998. Prall OW, Elliott DA, Harvey RP: Developmental paradigms in heart disease: insights from tinman. Ann Med 34:148, 2002. Tanaka M, Kasahara H, Bartunkova S, et al: Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development. Dev Genet 22:239, 1998. Tanaka M, Chen Z, Bartunkova S, et al: The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development 126:1269, 1999. Schwartz RJ, Olson EN: Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription. Development 126: 4187, 1999. Zou Y, Evans S, Chen J, et al: CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway. Development 124:793, 1997. Yutzey KE, Kirby ML: Wherefore heart thou? Embryonic origins of cardiogenic mesoderm. Dev Dyn 223:307, 2002. Kelly RG, Buckingham ME: The anterior heart-forming field: voyage to the arterial pole of the heart. Trends Genet 18:210, 2002. Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R, et al: The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol 238:97, 2001. DeRuiter MC, Poelmann RE, VanderPlas-de Vries I, et al: The development of the myocardium and endocardium in mouse embryos. Fusion of two heart tubes? Anat Embryol (Berl) 185:461, 1992. Patient RK, McGhee JD: The GATA family (vertebrates and invertebrates). Curr Opin Genet Dev 12:416, 2002. Reiter JF, Verkade H, Stainier DY: Bmp2b and Oep promote early myocardial differentiation through their regulation of gata5. Dev Biol 234:330, 2001. Dickmeis T, Mourrain P, Saint-Etienne L, et al: A crucial component of the endoderm formation pathway, CASANOVA, is encoded by a novel sox-related gene. Genes Dev 15:1487, 2001. Christoffels VM, Habets PE, Franco D, et al: Chamber formation and morphogenesis in the developing mammalian heart. Dev Biol 223:266, 2000. Mavrides E, Moscoso G, Carvalho JS, et al: The anatomy of the umbilical, portal and hepatic venous systems in the human fetus at 14– 19 weeks of gestation. Ultrasound Obstet Gynecol 18:598, 2001. Hove JR, Koster RW, Forouhar AS, et al: Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421: 172, 2003. Bruneau BG, Bao ZZ, Tanaka M, et al: Cardiac expression of the ventricle-specific homeobox gene Irx4 is modulated by Nkx2-5 and dHand. Dev Biol 217:266, 2000. Bruneau BG: Transcriptional regulation of vertebrate cardiac morphogenesis. Circ Res 90:509, 2002.

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

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

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

115.

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117.

118.

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

2.1 Heterotaxy Definition

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

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

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

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

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

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

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

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

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

Heart

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

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

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

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

2.2 Single Ventricle Definition

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

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

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

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

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

Heart

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

2.3 Conotruncal Defects Definition

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

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

97

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

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

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

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

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

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

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

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

Heart

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

Type of Conotruncal Defect

MIM #

Gene

Locus

Unknown

Unknown

Chromosome Abnormality Recombinant 8

179613

TOF, DORV

(partial trisomy 8q)

Truncus

Deletion 17p11.2 (Smith-Magenis)

TOF

NA

Unknown

Unknown

Trisomy 13

VSD conoventricular

NA

Unknown

Unknown

NA

Unknown

Unknown

DORV, TOF Trisomy 18

VSD conoventricular TOF, DORV

Trisomy 21

TOF

NA

Unknown

Unknown

Deletion 22q11.2 spectrum

Truncus

DGS 188400

TBX1

22q11

DiGeorge sequence

IAA, type B

VCF 192430

Velocardiofacial syndrome

TOF, TOF/PA, DORV, VSD conoventricular

Autosomal Dominant Alagille

TOF

118450

JAG1

20p12

CHARGE

Truncus, IAA, type B

214800

CHD7

8q12.1

Adams-Oliver

TOF

100300

Unknown

Unknown

Jones-Waldman

TOF

Unknown

Unknown

Unknown

Townes-Brocks

Truncus, TOF

107480

SALL1

16q12.1

Ritscher-Schinzel (3C)

TOF, DORV

220210

Unknown

Unknown

Thrombocytopenia-absent radius (TAR)

TOF

274000

Unknown

Unknown

Diabetes23

Truncus

NA

NA

NA

Retinoic acid

IAA, type B, TA

NA

NA

NA

Autosomal recessive

Teratogen

dTGA, TOF, DORV Alcohol

TOF

NA

NA

NA

Thalidomide

TOF

NA

NA

NA

Truncus Maternal phenylketonuria

TOF

NA

NA

NA

Trimethadione

TOF, d-TGA

NA

NA

NA

TOF

164210

Unknown

Unknown

Other Hemifacial microsomia FAVS, OAVD, Goldenhar

Heterogeneous

Ectopia cordis

TOF 2

4

NA 20

Compiled from Clark, Ferencz et al., Burn and Goodship,

Lofreddo.

NA

NA

23

Italics indicate if the CVM is the most commonly associated defect(s). FAVS, facio-auriculo-vertebral spectrum; d-TGA, dextro-transposition of the great arteries; DORV, double outlet right ventricle; IAA, interrupted aortic arch; NA, not applicable; OAVD, oculo-auriculo-vertebral dysplasia; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

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

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

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Cardiorespiratory Organs

Conoventricular Ventricular Septal Defects

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

Type B Interrupted Aortic Arch

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

Etiology and Distribution

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

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

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

2.4 Atrioventricular Septal Defects Definition

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

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

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

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

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

Type of Atrioventricular Canal Defect

MIM #

Gene

Locus

Chromosome Abnormality Deletion 3p25

Complete AVC

606217

CRELD1

3q25

Deletion 8p23

Complete AVC

NA

Unknown

Unknown

Trisomy 13

Complete AVC

NA

Unknown

Unknown

Trisomy 18

Complete AVC

NA

Unknown

Unknown

Down syndrome (Trisomy 21)

Complete AVC, ASD primum, VSD canal-type

NA

Unknown

Unknown

Trisomy 22

Complete AVC

NA

Unknown

Unknown

Autosomal Dominant Holt-Oram

Complete AVC, ASD primum

142900

TBX5

12q2

Noonan

Partial AVC

163950

PTPN11

12q24

McKusick-Kaufman

Complete AVC, ASD primum, common atrium

236700

MKKS

20p12

Hydrolethalus

Complete AVC, AVC, NOS

236680

Unknown

11q24

Ellis-van Creveld

Common atrium, ASD primum

225500

EVC

4p16

OFD, type II

ASD primum, AVC, NOS

252100

Unknown

Unknown

OFD, type IV

AVC, NOS

258860

Unknown

Unknown

OFD, type VI

AVC, NOS

277170

Unknown

Unknown

Smith-Lemli-Opitz

Complete AVC, ASD primum, common atrium

270400

DHCR7

11q12

Ritscher-Schinzel (3C)

Complete AVC

220210

Unknown

Unknown

Autosomal Recessive

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

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

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

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

Heart

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

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

2.5 Right Ventricular Outflow Tract Obstructive Defects Definition

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

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

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

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

104

Cardiorespiratory Organs

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

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

Pulmonary Stenosis

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

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

Pulmonary Atresia with Intact Ventricular Septum

Etiology and Distribution

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

Heart

105

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

Type of Pulmonic Stenosis

MIM #

Gene

Locus

Chromosome Abnormality Deletion 4p (Wolf-Hirschhorn)

Valvar

194190

WHSC1

4p16.3

Deletion 4q31, 3212

Valvar

NA

?dHAND

4q33

Deletion 8p2317

Valvar

NA

Unknown

Unknown

Alagille22

Peripheral, valvar

118450

JAG1

20p12

Noonan15

Valvar

163950

PTPN11

12q24

LEOPARD/Multiple lentigines16

Valvar

151100

PTPN11

12q24

Cardio-facio-cutaneous20

Valvar

115150

Unknown

Unknown

Costello14,21

Valvar

218040

Unknown

Unknown

Williams

Peripheral, valvar

194050

ELN

7q11.2

Peripheral

245150

MGP

12p13

Valvar

312870

GPC3

Xq26

Peripheral, valvar

NA

NA

NA

Autosomal Dominant

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

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

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

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

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

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Cardiorespiratory Organs

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

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

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

2.6 Left Ventricular Outflow Tract Obstructive Defects Definition

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

Heart

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

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

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

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

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

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

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

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

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

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

Heart

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

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

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

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

Type of LVOTO

MIM #

Gene

Locus

HLHS

NA

Unknown

Unknown

Chromosome Abnormality Deletion 11q23 (Jacobsen syndrome)29

COA

Trisomy 13

BAV, HLHS

NA

Unknown

Unknown

Trisomy 18

BAV, COA, HLHS

NA

Unknown

Unknown

Trisomy 21

COA

NA

Unknown

Unknown

Turner28

BAV, COA, ASV

NA

Unknown

Unknown

194050

ELN

7q11.2

130160

ELN

7q11.2

146510

GLI3

7p13

100300

Unknown

Unknown

147920

Unknown

Unknown

ASV, COA, HLHS

270400

DHCR7

11q12

COA

606519

Unknown

Unknown

COA, HLHS, ASV

NA

NA

NA

MS, HLHS Autosomal Dominant Williams26

SVAS Aortic stenosis, valvar

Familial SVAS27

SVAS

Pallister-Hall

BAV

Aortic stenosis, valvar MV anomalies Adams-Oliver24

COA, BAV Parachute MV

Kabuki22

COA, Parachute MV

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

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

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Cardiorespiratory Organs

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

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

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

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

Heart

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

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

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

2.7 Atrial Septal Defects Definition

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

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

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

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

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

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

MIM #

Gene

Locus

Chromosome Abnormality Deletion 4p (Wolf-Hirschhorn)

194190

WHSC1

4p16.3

Deletion 4q

NA

Unknown

Unknown

Trisomy 13

NA

Unknown

Unknown

Trisomy 21

NA

Unknown

Unknown

Derivative (22),t(11;22)4

NA

Unknown

Unknown

Trisomy 22

NA

Unknown

Unknown

Holt-Oram5

142900

TBX5

12q2

ASD and conduction defect8

108900

NKX2.5

5q34

Noonan7

163950

PTPN11

12q24

Kabuki

147920

Unknown

Unknown

Autosomal Dominant

Rubinstein-Taybi

180849

CREBBP

16p13

Familial septal defects9

607941

GATA4

8p22-23

Ellis-van Creveld

225500

EVC

4p16

Thrombocytopenia-absent radius (TAR)

274000

Unknown

Unknown

Toriello-Carey

217980

Unknown

Unknown

NA

NA

NA

Autosomal Recessive

Teratogens Alcohol

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

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

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

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

2.8 Ventricular Septal Defects Definition

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

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

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

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

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

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

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

MIM #

Gene

Locus

Trisomy 13

NA

Unknown

Unknown

Trisomy 18

NA

Unknown

Unknown

Trisomy 21

NA

Unknown

Unknown

Holt-Oram4,5

142900

TBX5

12q2

Kabuki

147920

Unknown

Unknown

Townes-Brock

107480

SALL1

16q12.1

180849

CREBBP

16p13

607941

GATA4

8p22-23

Fryns

229850

Unknown

Unknown

Ritscher-Schinzel (3C)

220210

Unknown

Unknown

Thrombocytopenia-absent radius (TAR)

274000

Unknown

Unknown

Toriello-Carey

217980

Unknown

Unknown

312870

GPC3

Xq26

Chromosome Abnormality

Autosomal Dominant

Rubinstein-Taybi 6

Familial septal defects Autosomal Recessive

X-Linked Simpson-Golabi-Behmel Teratogen Maternal hyperphenylalanine

NA

NA

NA

Diabetes

NA

NA

NA

Alcohol

NA

NA

NA

Valproate

NA

NA

NA

Thalidomide

NA

NA

NA

Trimethadione

NA

NA

NA

164210

Unknown

Unknown

Heterogeneous

Unknown

Heterogeneous

Unknown

Other Hemifacial microsomia FAVS, OAVD, Goldenhar VACTERL

NA

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

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

2.9 Anomalies of the Pulmonary Veins Definition

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

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Cardiorespiratory Organs

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

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

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

Total Anomalous Pulmonary Venous Connection

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

Table 2-9. Syndromes and conditions frequently associated with anomalous pulmonary venous connection Type of Anomalous Venous Connection

MIM #

Gene

Locus

Cat eye

Total

NA

unknown

22q

Turner

Partial

NA

unknown

X

Partial

142900

TBX5

12q2

270400

DHCR7

11q12

Causation

Chromosome Abnormality

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

Total 3

Compiled from Burn and Goodship and Lacro et al.

5

Italics indicate if it is the most commonly associated defect(s). NA, not applicable.

Heart

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

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

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

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

2.10 Abnormal Systemic Venous Connections Definition

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

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

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

2.11 Anomalies of the Ductus Arteriosus Definition

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

Anomalies of the Coronary Sinus

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

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

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

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

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

2.12 Aortopulmonary Window (Aortopulmonary Septal Defect) Definition

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

2.13 Anomalies of the Coronary Arteries Definition

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

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

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

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

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Prognosis, Treatment, and Prevention

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

2.14 Anomalies of the Pericardium Definition

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

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

3 Systemic Vasculature Lynne M. Bird and Kenneth Lyons Jones

3.1 Interrupted Aortic Arch Definition

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

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

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

Etiology and Distribution

Prognosis, Treatment, and Prevention

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

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

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

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

Prominent Features

Causation

Cytogenetic Aberrations

Down syndrome12

Hypotonia, flat midface, upslanting palpebral fissures

Chromosomal

Trisomy 187

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

Chromosomal

Trisomy 1313

Cleft lip, cerebral malformations, polydactyly

Chromosomal

Trisomy 5q31.1q35.114

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

Chromosomal

DiGeorge syndrome8

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

Del 22q11.2

Ring chromosome 2115

Chromosomal

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

Townes-Brocks7

Imperforate anus, thumb abnormalities, ear anomalies, hearing loss

AD (107480) SALL1, 16q12.1

Perlman syndrome16

Macrosomia, nephroblastomatosis, facial dysmorphism

AR (267000)

Hydantoin7

Broad nasal bridge, short nose, nail hypoplasia

Prenatal exposure to hydantoin

Retinoic acid17,18

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

Prenatal exposure to isotretinoin

Teratogenic Abnormalities

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

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

Systemic Vasculature

7. 8.

9.

10.

11. 12.

13. 14.

15. 16. 17. 18. 19.

20. 21.

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

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

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

3.2 Right Aortic Arch Definition

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

3.2.1 Right Aortic Arch with Mirror-Image Branching Definition

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

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

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

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

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

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

Diagnosis

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

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

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

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

3.3 Cervical Aortic Arch Definition

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

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

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

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

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

3.4 Double Aortic Arch Definition

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

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

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

Diagnosis

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

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

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

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

3.5 Double-Lumen Aortic Arch Definition

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

Systemic Vasculature

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

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

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

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

Prognosis, Treatment, and Prevention

3.6 Incidental Anomalies of the Aortic Arch

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

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

References (Double-Lumen Aortic Arch)

Reference (Incidental Anomalies of the Aortic Arch)

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

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

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

3.7 Innominate Artery Variants

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

3.7.1 Compression by the Innominate Artery Definition

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

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

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

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

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

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

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

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

3.8 Subclavian Artery Variants 3.8.1 Aberrant Right Subclavian Artery Definition

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

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

129

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

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

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

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

130

Cardiorespiratory Organs

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

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

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

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

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

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

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

3.9 Patent Ductus Arteriosus Definition

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

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

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

Prominent Features

Causation

Down6

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

Chromosomal

Trisomy 187

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

Chromosomal

Trisomy 137

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

Chromosomal

XXXXX8

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

Chromosomal

XXXY and XXXXY9

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

Chromosomal

Deletion 1p3610

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

Del 1p36

Deletion 4p11

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

Del 4p

Deletion 9p12

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

Del 9p

DiGeorge13

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

Del 22q11.2

Alagille (arteriohepatic dysplasia)14

Cholestasis, peculiar facies, peripheral pulmonic stenosis

AD (118450) JAG1, 20p12

Carpenter15

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

AR (201000)

Char16

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

AD (169100) TFAP2B, 6p12

CHARGE27

Coloboma, choanal atresia, genital defects, ear anomalies

AD (214800) CHD7, 8q12.1

Hay-Wells15

Ankyloblepheron, ectodermal dysplasia, cleft lip/palate

AD (106260) TP73L, 3q27

Holt-Oram17

Upper limb defect, narrow shoulders, atrial septal defect

AD (142900) TBX5, 12q24.1

Lymphedema-distichiasis18

Lymphedema, double row of eyelashes, cleft palate

AD (153400) FOXC2, 16q24.3

Meckel-Gruber15

Encephalocele, polydactyly, cystic dysplasia of kidneys

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

Mowat-Wilson19

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

AR (235730) SIP1, 2q22

Neu-Laxova15

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

AR (256520)

Noonan20

Neck webbing, pectus excavatum, cryptorchidism, pulmonic stenosis

AD (163950) PTPN11, 12q24.1

Rubinstein-Taybi21

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

AD (180849) CREBBP, 16p13.3

Various major malformations

Maternal diabetes

Hydantoin

Broad nasal bridge, short nose, nail hypoplasia

Prenatal exposure to hydantoins

Rubella23

Microcephaly, deafness, cataracts

Prenatal rubella infection

Valproate24

Broad nasal bridge, short nose, meningomyelocele

Prenatal exposure to valproic acid

Cytogenetic Abberrations

Genetic Syndromes

Teratogenic Abnormalities

Diabetes22 15

(continued)

131

132

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

Prominent Features

Causation

Coffin-Siris25

Hypoplastic finger and toenails, coarse facies, sparse scalp hair

Unknown AR (135900)

Facio-auriculo-vertebral spectrum26

Ear anomalies, mandibular hypoplasia, vertebral defects

Unknown

VACTERL association28

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

Unknown

Syndromes of Unknown Cause

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

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

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

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

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

3.10 Coarctation of the Aorta Definition

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

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

133

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

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

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

134

Cardiorespiratory Organs

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

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

Table 3-3. Syndromes associated with aortic coarctation Syndrome

Prominent Features

Causation

45,X Turner syndrome8

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

Chromosomal

Down syndrome3,9

Hypotonia, flat midface, upslanting palpebral fissures

Chromosomal

Trisomy 1810

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

Chromosomal

Trisomy 133,10

Cleft lip, cerebral malformations, polydactyly

Chromosomal

Williams syndrome11

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

Del 7q11.23

Arteriohepatic dysplasia12

Cholestasis, peculiar facies, peripheral pulmonic stenosis

AD (118450) JAG1, 20p12

Neurofibromatosis13

Cafe´ au lait spots, multiple neurofibromas, axillary freckling

AD (162200) NF1, 17q11.2

Meckel-Gruber syndrome14

Encephalocele, polydactyly, cystic dysplasia of kidneys

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

Roberts syndrome3

Hypomelia, growth deficiency, midfacial defect

AR (268300)

Peters-Plus syndrome3

Peters anomaly, disproportionate short stature, cleft lip

AR (261540)

Noonan syndrome15

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

AD (163950) PTPN11, 12q24.1

Rubinstein-Taybi16

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

AD (180849) CREBBP, 16p13.3

Alcohol14

Microcephaly, short palpebral fissures, long and smooth philtrum

Prenatal exposure to alcohol

Hydantoin14

Broad nasal bridge, short nose, nail hypoplasia

Prenatal exposure to hydantoin

Valproate17

Broad nasal bridge, short nose, meningomyelocele

Prenatal exposure to valproic acid

Microcephaly, mental deficiency, prenatal-onset growth deficiency

Elevated maternal phenylalanine levels

Facio-auriculo-vertebral spectrum3,19

Ear anomalies, mandibular hypoplasia, vertebral defects

Unknown

VACTERL association3

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

Unknown

PHACES association20

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

Unknown

Kabuki syndrome21

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

Unknown

Cytogenetic Aberrations

Single-gene Conditions

Teratogenic Abnormalities

Maternal PKU

18

Syndromes of Unknown Cause and Associations

PKU, phenylketonuria.

Systemic Vasculature

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

Prognosis, Treatment, and Prevention

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

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

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

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Cardiorespiratory Organs

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

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

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

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

Diagnosis

Definition

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

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

Etiology and Distribution

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

Diagnosis

The majority of PLSVC connecting to the left atrium occurs in association with other cardiac defects.1 When it occurs as an isolated defect, patients can be asymptomatic or minimally symptomatic. Symptoms are usually those of a right-to-left shunt (mild peripheral cyanosis and polycythemia). Cardiovascular examination, chest radiography, and ECG results are usually normal. PLSVC is often an incidental finding during other diagnostic examinations. CT, MRI, or echocardiography with color Doppler can noninvasively diagnose. Etiology and Distribution

Only 8% of PLSVC connects to the left atrium.1 Bilateral superior vena cavae with the PLSVC draining into the left-sided atrium occurs with laterality defects. As in PLSVC connecting to the right atrium, this defect is due to failure of obliteration of the left anterior cardinal vein. The connection to the left atrium occurs when the normal invagination between the left sinus horn and the

Fig. 3-9. Schematic showing persistence of the left superior vena cava, with connection into the left atrium.

Systemic Vasculature

left atrium fails to occur; as a result, the coronary sinus fails to form, and the PLSVC drains into the left atrium. Prognosis, Treatment, and Prevention

Treatment is surgical, either simple ligation of the PLSVC or transposition to the right atrium. Prognosis depends on the associated cardiac defects. Because systemic venous return drains directly into the left atrium, there is a risk of paradoxical emboli to the central nervous system. PLSVC has been reported in Turner syndrome,6 Holt-Oram syndrome,7 Fryns syndrome,8 short-rib polydactyly (Beemer-Langer type),9 and once with Ellis van Creveld syndrome (in association with right isomerism).10 References (Persistent Left Superior Vena Cava) 1. Geva T, van Praagh S: Abnormal systemic venous connections. In: Moss and Adams Heart Disease in Infants, Children and Adolescents, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 773. 2. Sarodia BD, Stoller JK: Persistent left superior vena cava: case report and literature review. Respir Care 45:411, 2000. 3. Campbell M, Deucher DC: The left sided superior vena cava. Br Heart J 16:423, 1954. 4. Tak T, Crouch E, Drake GB: Persistent left superior vena cava: incidence, significance and clinical correlates. Int J Cardiol 82:91, 2002. 5. Jureidini SB, Hormann JW, Williams J, et al.: Morphometric assessment of the innominate vein in the prediction of persistent left superior vena cava. J Am Soc Echocardiogr 11:372, 1998. 6. Fuseini A, MacLoughlin P, Dewhurst NG: Dual-chamber pacing via a persistent left superior vena cava in a patient with Turner’s syndrome. Br J Clin Pract 47:333, 1993. 7. Cheng TO: Persistent left superior vena cava in Holt-Oram syndrome. Int J Cardiol 76:83, 2000. 8. Pinar H, Carpenter MW, Abuelo D, Singer DB: Fryns syndrome: a new definition. Pediatr Pathol 14:467, 1994. 9. Myong NH, Park JW, Chi JG: Short-rib polydactyly syndrome, Beemer-Langer type, with bilateral huge polycystic renal dysplasia: an autopsy case. J Korean Med Sci 13:201, 1998. 10. Digilio MC, Marino B, Ammirati A, et al.: Cardiac malformations in patients with oral-facial-skeletal syndromes: clinical similarities with heterotaxia. Am J Med Genet 84:350, 1999.

3.12 Inferior Vena Cava Variants The inferior vena cava (IVC) is formed between 4 and 12 weeks gestation through a process of development, anastomosis and regression of three sets of paired veins (cardinal, subcardinal, and supracardinal).1 The mature IVC evolves to a unilateral rightsided cava consisting of hepatic, prerenal, renal and postrenal segments. Anomalies are discovered in infants when evaluating cardiac or visceral malformations and in adults incidentally or because of thrombosis of the iliac veins. In a study of 97 consecutive patients with deep venous thrombosis, 31 had involvement of the iliac veins, and 5 of those were found to have an anomalous IVC.1 3.12.1 Left Inferior Vena Cava

An IVC that travels to the left of the aorta and crosses to the right at the level of the renal hila to assume the normal position. The IVC can cross either in front of or behind the aorta.2 This

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anomaly has a prevalence of 0.2–0.5%, and results from persistence of the left supracardinal vein with regression of the right supracardinal vein.2 There is no clinical significance to this anomaly unless abdominal surgery is needed; it can complicate surgical repair of abdominal aortic aneurysms. 3.12.2 Double Inferior Vena Cava

A double inferior vena cava (IVC) is formed from paired venae cavae that travel on either side of the aorta, joining at the level of the renal hila to form a single inferior vena cava on the right side. This anomaly has a prevalence of 1–3% and results from persistence of both supracardinal veins.2 Occasionally, the left-side components originate from persistence of the left subcardinal vein, rather than the left supracardinal vein, and in this case the left ureter is retrocaval and subject to compression.2 Double IVC with both cavae running on the right side is very rare and arises from the persistence of the right supracardinal and right subcardinal veins, which converge into a single vessel at the level of the renal hila. There is no clinical significance. 3.12.3 Interrupted Inferior Vena Cava with Azygous Continuation Definition

Interrupted inferior vena cava with azygous continuation is the absence of the IVC between the renal veins and the hepatic veins.3 The right supracardinal vein persists to connect the caudal IVC to the azygous vein, which courses to the right of the spine. The azygous vein enters the thorax through the aortic hiatus of the diaphragm and joins the superior vena cava just above its junction with the right atrium (Fig. 3-10). Diagnosis

This anomaly, asymptomatic by itself, can be a part of situs abnormalities (left isomerism, situs ambiguus), in which case symptoms are related to the presence of a cardiac defect (usually one producing cyanosis). Diagnosis is by sonography or venous angiography.4 Etiology and Distribution

The IVC is formed between the sixth and eighth weeks from the hepatic vein, right subcardinal vein, subcardinal anastomoses, and right supracardinal vein. Failure of the right subcardinal and hepatic veins to join results in a deficiency of the IVC above the renal veins. Anastomosis between the right subcardinal and right supracardinal veins allows blood from the lower part of the body to reach the azygous vein. Although once thought to be extremely rare in individuals with normal hearts, this defect is being discovered increasingly in asymptomatic individuals who are evaluated noninvasively for unrelated problems. Interrupted IVC has been noted in 0.6– 2.9% of patients with congenital heart disease studied by cardiac catheterization. Commonly associated cardiac defects include cor biloculare, atrioventricular canal, anomalous connections of pulmonary veins, double-outlet right ventricle, large ASD, pulmonary stenosis or atresia, abnormal cardiac position, and anomalies of the superior vena cava.5 Interrupted IVC has been reported in Hennekam syndrome.6

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Cardiorespiratory Organs 8. Basile A, Certo A, Ascenti G, et al.: Embryologic and acquired anomalies of the inferior vena cava with recurrent deep vein thrombosis. Abdom Imaging 28:400, 2003. 9. Castro FJ, Perez C, Narvaez FJ, et al.: Congenital absence of the inferior vena cava as a risk factor for pulmonary thromboembolism. An Med Interna 20:304, 2003. 10. D’Aloia A, Faggiano P, Fiorina C, et al.: Absence of inferior vena cava as a rare cause of deep venous thrombosis complicated by liver and lung embolism. Int J Cardiol 88:327, 2003.

3.13 Miscellaneous Venous Variants 3.13.1 Periureteral Venous Ring

Periureteral venous ring is persistent anastomosis between the right supracardinal and right posterior cardinal veins, forming a venous ring around the right ureter. Compression can lead to hydronephrosis.1 3.13.2 Left Renal Vein Compression

Fig. 3-10. Schematic showing interruption of the inferior vena cava between the renal veins and the hepatic veins. Blood returns to the heart via the azygous vein and the superior vena cava. Prognosis, Treatment, and Prevention

Prognosis is excellent in the absence of associated cardiac defects7; however, there may be an increased risk for recurrent deep vein thrombosis due to venous stasis.8 In those cases associated with laterality defects, prognosis is related to the severity of the associated cardiac anomaly. 3.12.4 Absence of Inferior Vena Cava

Complete absence of IVC has been reported in several patients presenting with deep vein thrombosis.1,9,10 References (Inferior Vena Cava Variants) 1. Obernosterer A, Aschauer M, Schnedl W, et al.: Anomalies of the inferior vena cava in patients with iliac venous thrombosis. Ann Intern Med 136:37, 2002. 2. Minniti S, Visentini S, Procacci C: Congenital anomalies of the venae cavae: embryological origin, imaging features and report of three new variants. Eur Radiol 12:2040, 2002. 3. Geva T, van Praagh S: Abnormal systemic venous connections. In: Moss and Adams Heart Disease in Infants, Children and Adolescents, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 773. 4. Stackelberg B, Lind J, Wegelius C: Absence of inferior vena cava diagnosed by angiocardiography. Cardiologia 21:583, 1952. 5. Anderson RC, Adams P, Burke B: Anomalous inferior vena cava with azygous continuation (infrahepatic interruption of the inferior vena cava). J Pediatr 59:370, 1961. 6. Al-Gazali LI, Hertecant J, Ahmed R, et al.: Further delineation of Hennekam syndrome. Clin Dysmorphol 12:227, 2003. 7. Effler DB, Greer AE, Sifers EC: Anomaly of the vena cava inferior: report of fatality after ligation. J Am Med Assoc 146:1321, 1951.

Left renal vein compression results in hypertension, producing the so-called nutcracker syndrome. Two forms have been described: anterior nutcracker syndrome due to compression of the left renal vein between the superior mesenteric artery and the aorta, and posterior nutcracker syndrome due to retro-aortic position of the left renal vein and compression between the aorta and the spine.2 The resulting left renal venous hypertension can cause left flank or abdominal pain, hematuria, and/or orthostatic proteinuria.3 Left renal vein entrapment (nutcracker phenomenon) should be considered in children with nonglomerular hematuria or proteinuria.4 Other presentations include varicocele, left leg varicose veins, pelvic congestion syndrome, and vulval varices.5 Diagnosis can be made with Doppler sonography, magnetic resonance angiography, or selective left renal venography. Treatment has included transposition of the left renal vein, renal autotransplantation, nephropexy, and stenting.5 3.13.3 Congenital Absence of the Portal Vein Definition

Congenital absence of the portal vein results in the enteric blood bypassing the liver and draining directly into the systemic circulation. Normally the splenic vein and superior mesenteric vein join to form the portal vein; in this anomaly, either each anastomoses directly with the systemic circulation (usually the infrahepatic inferior vena cava or left renal vein) or each forms a confluence that connects directly to the inferior vena cava.6 Diagnosis

This abnormality is typically discovered fortuitously in children while evaluating for another problem. Discovery in adolescents and adults being evaluated for liver pathology has also been reported.7 Diagnosis is suggested by color Doppler sonography demonstrating a portocaval shunt, and confirmed with CT or MRI. Angiography is rarely necessary since the improvement in noninvasive imaging.8 Prenatal diagnosis has been made once.9

Systemic Vasculature

Etiology and Distribution

The portal vein develops between the 4th and 10th gestational weeks from portions of the right and left vitelline veins, and receives flow from the splenic and superior mesenteric vein primordia. Approximately 50 cases of congenital portal vein absence have been reported, and females predominate.7–20 Nodular hyperplasia,7,10–12 hepatocellular adenoma,7 hepatocellular carcinoma,7,13,14 and hepatoblastoma7 have been seen in association. Absence of the portal vein occurs with biliary atresia (usually accompanied by polysplenia)7,15,16 and cardiac defects (ASD, VSD, PDA).7 It has been reported once with oculo-auriculo-vertebral spectrum,17 once with a congenital choledochal cyst,11 and in two patients with Down syndrome.18 Despite the porto-systemic shunt, hepatic encephalopathy is rare.7

Prognosis, Treatment, and Prevention

Long asymptomatic intervals are possible, but serious sequelae have been reported, including hepatic encephalopathy,7,8 liver tumors,7,13,14 and brain abscess.12 Liver transplantation is the only definitive therapy.

References (Miscellaneous Venous Variants) 1. Minniti S, Visentini S, Procacci C: Congenital anomalies of the venae cavae: embryological origin, imaging features and report of three new variants. Eur Radiol 12:2040, 2002. 2. Ali-El-Dein B, Osman Y, Shehab El-Din AB, et al.: Anterior and posterior nutcracker syndrome: a report on 11 cases. Transplant Proc 25:851, 2003. 3. Lee SJ, You ES, Lee JE, et al.: Left renal vein entrapment syndrome in two girls with orthostatic proteinuria. Pediatr Nephrol 11:218, 1997. 4. Ekim M, Bakkaloglu SA, Tu¨mer N, et al.: Orthostatic proteinuria as a result of venous compression (nutcracker phenomenon)—a hypothesis testable with modern imaging techniques. Nephrol Dial Transplant 14:826, 1999. 5. Little AF, Lavoipierre AM: Unusual clinical manifestations of the Nutcracker syndrome. Australas Radiol 46:197, 2002. 6. Morgan G, Superina R: Congenital absence of the portal vein: two cases and a proposed classification system for portasystemic vascular anomalies. J Pediatr Surg 29:1239, 1994. 7. Tanaka Y, Takayanagi M, Shiratori Y, et al.: Congenital absence of portal vein with multiple hyperplastic nodular lesions in the liver. J Gastroenterol 38:288, 2003. 8. Niwa T, Aida N, Tachibana K, et al.: Congenital absence of the portal vein: clinical and radiologic findings. J Comput Assist Tomogr 26:681, 2002. 9. Venkat-Raman N, Murphy KW, Ghaus K, et al.: Congenital absence of portal vein in the fetus: a case report. Ultrasound Obstet Gynecol 17:71, 2001. 10. Arana E, Marti-Bonmati L, Martinez V, et al.: Portal vein absence and nodular regenerative hyperplasia of the liver with giant inferior mesenteric vein. Abdom Imaging 22:506, 1997. 11. Kinjo T, Aoki H, Sunagawa H, et al.: Congenital absence of the portal vein associated with focal nodular hyperplasia of the liver and congenital choledochal cyst: a case report. J Pediatr Surg 36:622, 2001. 12. Alvarez AE, Ribeiro AF, Hessel G, et al.: Abernethy malformation: one of the etiologies of hepatopulmonary syndrome. Pediatr Pulmonol 34:391, 2002. 13. Lundstedt C, Lindell G, Tranberg KG, et al.: Congenital absence of the intrahepatic portion of the portal vein in an adult male resected for hepatocellular carcinoma. Eur Radiol 11:2228, 2001. 14. Pichon N, Maisonnette F, Pichon-Lefievre F, et al.: Hepatocarcinoma with congenital agenesis of the portal vein. Jpn J Clin Oncol 33:314, 2003.

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15. Andreani P, Srinivasan P, Ball CS, et al.: Congenital absence of the portal vein in liver transplantation for biliary atresia. Int J Surg Investig 2:81, 2000. 16. Taoube KA, Alonso Calderon JL, Yandza T, et al.: Congenital absence of portal vein in a girl with biliary atresia treated with liver transplant. Cir Pediatr 12:38, 1999. 17. Morse SS, Taylor KJW, Strauss EB, et al.: Congenital absence of the portal vein in oculoauriculovertebral dysplasia (Goldenhar syndrome). Pediatr Radiol 16:437, 1986. 18. Pipitone S, Garofalo C, Corsello G, et al.: Abnormalities of the umbilico-portal venous system in Down syndrome: a report of two new patients. Am J Med Genet 120A:528, 2003.

3.14 Deep Vein Abnormalities 3.14.1 Aplasia/Hypoplasia of the Deep Venous System

Aplasia/hypoplasia of the deep venous system is deficiency of the deep veins, including iliac, femoral, popliteal, and axillary veins. Superficial veins are the routes for venous drainage from the limbs, and their ligation or excision is contraindicated.1 Symptoms of swelling and aching of the limbs, venous claudication, cyanosis, and varicosities are generally mild unless thrombosis occurs. Acute thrombosis is treated with rest, elevation, and anticoagulation. Both antegrade and retrograde phlebography are most useful in confirming the diagnosis, although great difficulty is often encountered in documenting the extent of the defect.1 Deep vein anomalies occur in 20–50% of patients with Klippel-Trenaunay-Weber syndrome.2,3 Hypoplasia of the deep venous system of the lower limbs has been reported once in association with phakomatosis pigmentovascularis.4 3.14.2 Congenital Vein Valve Aplasia

Congenital vein valve aplasia is a virtually complete lack of valves in all deep and superficial veins. Affected individuals generally present in adolescence with orthostatic leg edema and dilation of superficial veins. The arms are less commonly symptomatic. Although varicose veins and leg swelling leading to significant disability are common, leg ulcers and claudication occur only rarely. Prevention of edema can be achieved by avoiding long periods of standing and use of compressive stockings. Surgery on the incompetent superficial venous system can ameliorate some symptoms, but since there are no competent valves to use for reconstruction, surgical procedures are generally not helpful.5 Autosomal dominant inheritance is well documented.6,7 3.14.3 Iliac Vein Compression

Iliac vein compression occurs when the left common iliac vein is compressed by the overlying right common iliac artery. It was first described in 1851 by Virchow8 and further detailed by May and Thurner9 in the pathology literature and Cockett and Thomas10 in the surgical literature. May-Thurner syndrome and Cockett syndrome are synonyms for iliac vein compression syndrome, which indicates symptomatic left leg venous outflow obstruction. At least one case occurring on the right side has been described.11 At one time, ‘‘spurs’’ or synechiae in the vein were thought to be congenital, but now are believed to represent progressive fibrosis secondary to irritation from chronic pulsatile trauma.12 Two-thirds of patients with Iliac vein compression are female. Most patients present with an acute iliofemoral deep vein

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Cardiorespiratory Organs

thrombosis, or with chronic left leg edema. Diagnosis has been problematic in the past because of difficulty in visualizing the iliac veins by sonography. Lower limb venography is frequently unrevealing if injection of contrast is made in the dorsum of the foot rather than in the popliteal or femoral vein. Magnetic resonance venography is the noninvasive imaging modality of choice.12 Thrombolytic therapy is indicated for an acute iliofemoral deep vein thrombosis of less than 10 days’ duration. Anticoagulant therapy or surgery were formerly the only treatments for chronic obstruction, but endovascular stent placement has gained popularity.12 Early treatment to avoid vein valve incompetence is advisable.

spongy masses that are easily compressed and lack pulsations. Complex lesions may infiltrate soft tissues or bones and present with swelling or asymmetry. One subtype, glomuvenous malformations (venous malformations with glomus cells, glomangioma) are raised, blue-purple lesions with a cobblestone surface, and are painful on palpation. Glomangiomas are more likely to be inherited and are rare in mucosae. Distinction is usually simple based on clinical presentation; the pathognomonic histopathologic finding in glomuvenous malformations is endothelial channels lined by glomus cells, which probably derive from smooth muscle.1

References (Deep Vein Abnormalities)

The incidence of vascular malformations is probably between 1/5000 and 1/10,000 births.1 Most cases are sporadic, but familial occurrence is well described, in which case multiple lesions are common. Activating mutations of the gene TIE2, encoding an endothelial-specific receptor tyrosine kinase, the angiopoietin receptor, have been reported in at least four families with cutaneomucosal venous malformations.1,2 Glomuvenous malformations are usually familial, and a single gene locus, VMGLOM, on the short arm of chromosome 1, encodes a novel protein designated glomulin, which could be involved in the TGF-beta pathway.3 Venous vascular anomalies constitute an important component of the following three syndromes.

1. Gorenstein A, Shifrin E, Gordon RL, et al.: Congenital aplasia of the deep veins of lower extremities in children: the role of ascending functional phlebography. Surgery 99:414, 1986. 2. Servelle M: Klippel and Trenaunay’s syndrome. Ann Surg 201:365, 1985. 3. Dogan R, Faruk Dogan O, Oc M, et al.: A rare vascular malformation, Klippel-Trenaunay syndrome. Report of a case with deep vein agenesis and review of the literature. J Cardiovasc Surg (Torino) 44:95, 2003. 4. Park JG, Roh KY, Lee HJ, et al.: Phakomatosis pigmentovascularis IIb with hypoplasia of the inferior vena cava and the right iliac and femoral veins causing recalcitrant stasis leg ulcers. J Am Acad Dermatol 49:S167, 2003. 5. Plate G, Brudin L, Eklof B, et al.: Physiologic and therapeutic aspects in congenital vein aplasia of the lower limb. Ann Surg 198:229, 1983. 6. Leu HJ: Familiar congenital absence of valves in the deep leg veins. Humangenetik 22:347, 1974. 7. Lodin A, Lindvall N, Gentele H: Congenital absence of venous valves as a cause of leg ulcers. Acta Chir Scand 116:256, 1958-1959. 8. Virchow R: Uber die Erweiterung kleiner Gefasse. Arch Path Anat 13:427, 1851. 9. May R, Thurner J: The cause of the predominately sinistral occurrence of thrombosis of the pelvic veins. Angiology 8:419, 1957. 10. Cockett FB, Thomas ML: The iliac compression syndrome. Br J Surg 52:816, 1965. 11. Molloy S, Jacob S, Buckenham T, et al.: Arterial compression of the right common iliac vein; an unusual anatomical variant. Cardiovasc Surg 10:291, 2002. 12. O’Sullivan GJ, Semba CP, Bittner CA, et al: Endovascular management of iliac vein compression (May-Thurner) syndrome. J Vasc Interv Radiol 11:823, 2000.

3.15 Vascular Malformations Definition

Vascular malformations are developmental defects consisting of abnormal vascular channels, probably caused by dysregulation in signaling that regulates proper formation of the vascular tree. Depending on clinical appearance, natural history, and histopathology, they can be divided into arteriovenous, capillary, lymphatic, venous, and combined lesions. 3.15.1 Venous Malformation Diagnosis

Most venous malformations are cutaneous and/or intramuscular, but they can occur in any organ. They can be flat or raised and are typically violaceous or bluish in color. Simple lesions are non-painful

Etiology and Distribution

Klippel-Trenaunay-Weber Syndrome

The principal features of this disorder are capillary and cavernous vascular malformations, varicosities and deep vein anomalies, and asymmetric limb hypertrophy (Fig. 3-11).4,5 Although the type of vascular defects is variable, venous malformations predominate. Deep vein abnormalities occur frequently. Occasional vascular abnormalities include lymphatic vascular malformations and lymphectasia; vascular malformations of the gastrointestinal tract, urinary system, mesentery, and pleura; and arteriovenous fistulae. Almost all cases are sporadic. There is an equal incidence of males and females, and intelligence is normal. Proteus Syndrome

The principal features of this condition are disproportionate overgrowth (limbs and organs); capillary, venous, and lymphatic vascular malformations; lipomas; and connective tissue nevi. Lesions are distributed in a random, mosaic fashion, and the course is progressive.6 All cases are sporadic, and the sex ratio is equal. The connective tissue nevus presents as a cerebriform growth on the plantar surface, abdomen, hands, or nose; it is almost pathognomonic for Proteus syndrome. Some patients have a characteristic facial phenotype and mental deficiency. Death from pulmonary embolus appears to be a significant risk.7 Maffucci Syndrome

The principal features of this disorder are venous vascular malformations and enchondromas that typically occur in proximity. Lymphatic vascular malformations occasionally occur. The risk for sarcomatous change of the enchondromas is approximately 30%.8,9 Intelligence is normal. All cases are sporadic, and the sex ratio is equal. Prognosis, Treatment, and Prevention

Growth is slow and commensurate with the growth of the individual. If the lesion can be excised in its entirety, surgery is curative. Recurrence after incomplete resection is common. For those lesions not amenable to surgery, sclerotherapy can reduce

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Fig. 3-11. Capillary, venous, and cavernous malformations of the central nervous system may occur in (A) Sturge-Weber syndrome and (B) Klippel-Trenaunay-Weber syndrome.

their bulk; however, redirection of blood to other channels and recurrence are common.1 3.15.2 Arteriovenous Malformation

An arteriovenous malformation is a direct connection between arterioles and venules without an intervening capillary network. Superficial lesions appear pink or red and are warm and pulsatile. These lesions can cause congestive heart failure and are common in the central nervous system, where they can have a catastrophic presentation. Intracranial Arteriovenous Malformation Diagnosis. The majority of AVMs of the brain are supratentorial, most occurring along the middle cerebral artery.10 Some have been observed in the posterior fossa, spinal cord, and choroid plexus. Intracranial bleeding is the most common presentation, with subarachnoid hemorrhage as the initial symptom in 30–60% of patients, followed by seizures. Recurrent headaches prior to hemorrhage occur frequently in adults but rarely in children. Focal neurologic deficits such as hemiplegia/hemiparesis usually occur with large malformations. Although cranial or carotid bruits can be heard in normal children, it has been suggested that over 50% of children with an AVM have a bruit over the cranial vault or eyeball. Definitive diagnosis requires cerebral angiography, CT, or MRI. It is particularly important to rule out multiple intracerebral AVMs, though this is rare. Etiology and Distribution. Brain AVMs occur in approximately 0.14% of the population. Males have a higher incidence than females. The onset of symptoms varies from 1 month to adulthood, and is commonly in the third decade. Most brain AVMs are sporadic, but familial predisposition is well described.11 Both autosomal dominant and autosomal recessive inheritance are implied. Prognosis, Treatment, and Prevention. The natural history demonstrates a 1–2% bleeding rate, and 2–4% annual risk of re-

bleeding.12 The annual risk of death (1%), disability (1%), and developing epilepsy (1%) leads most authors to recommend treatment.12 Small lesions are more likely to rupture than large AVMs.12 To control seizures and reduce the chance of hemorrhage, the treatment of choice for intracranial AVMs is gamma knife irradiation or surgery,11 with adjuvant embolization and radiotherapy in some cases.12 A long-term follow-up study (spanning 31 years) of 68 affected individuals who had not undergone surgery showed that 68% led normal lives, 15 patients died at ages ranging from 14–64 years, 3 were mentally retarded, and 6 were invalids.13 Spontaneous regression of cerebral AVMs, presumed due to thrombosis, has been well documented, but there are no clinical or angiographic features that aid in predicting those lesions that will regress.14 AVMs have been documented in families with dominantly inherited capillary malformations (see 3.15.3) and constitute an important component of the following three conditions. Hereditary Neurocutaneous Vascular Malformation

These central nervous system AVMs are often located in the spinal cord and are also seen in association with cutaneous vascular lesions occurring in the same or adjacent dematome.15 The inheritance is autosomal dominant (MIM 106070). Lymphedema and Cerebral Arteriovenous Anomaly

This autosomal dominant disorder is characterized by idiopathic lymphedema of the lower limbs, pulmonary hypertension, and AVMs (MIM 152900).16 Hereditary Hemorrhage Telangiectasia (HHT, Osler-Weber-Rendu)

This is an autosomal dominant disorder (MIM 187300) characterized by AVM and telangiectases (focal dilations of postcapillary venules) in skin and mucosa.17 Arteriovenous fistulae affect

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the lung, brain,18 and gastrointestinal tract in HHT. The most consistent clinical symptom is epistaxis. Two gene loci for HHT have been identified (ENG encoding endoglin and ALK-1 encoding activin receptor-like kinase 1), and mutations cause loss of function of the encoded proteins.19 Intra- and interfamilial variability is common, but in general mutations in ALK-1 are associated with milder disease.19 Both proteins interact with the TGF-beta receptor complex in vascular endothelial cells. The likely mechanism involves defective TGF-beta signaling and progressive disappearance of the capillary bed. 3.15.3 Capillary Malformations

Capillary malformations are flat, red cutaneous lesions typically located in the head and neck region. Commonly occurring on the eyelids, forehead, and nape of the neck, capillary malformations make up the vascular stains that are present in up to 40% of newborns and fade during infancy. A more prominent ‘‘port-wine stain’’ is present in 0.3% of newborns and can thicken with age and darken from pink to red-purple. Histologically, capillary malformations are composed of numerous dilated capillary-like vessels with decreased neuronal markings, leading some investigators to propose that lack of innervation may cause dilation of cutaneous capillaries.2 The gene locus for dominantly inherited multiple capillary malformations was mapped to chromosome 5q14-21 in several families,2 some of which subsequently were shown to have mutations in RASA1.20 At least one family member in all of the mutation-positive families had an AVM or arteriovenous fistula or soft- and skeletal-tissue hypertrophy. Sturge-Weber Syndrome

An important disorder presenting with a facial port-wine stain is Sturge-Weber syndrome. Vascular eye abnormalities and ipsilateral occipital leptomeningeal angioma accompany the port-wine stain, which does not conform to a dermatomal or vascular distribution. There is one report of a contralateral occipital leptomeningeal angioma in Sturge-Weber syndrome.21 Glaucoma occurs frequently. Seizures occur in 80% of patients and are often intractable; cortical resection or hemispherectomy can provide good long-term seizure control in the majority of these patients.22 The incidence of mental retardation is high (75%), and a small study indicated that the incidence is lower in patients receiving prophylactic antiepileptic treatment.23 There is no correlation between the extent of the facial port-wine stain and the severity of neurologic involvement.24 Neurologic deterioration occurs in some patients.25 Pulsed dye laser can safely fade cutaneous lesions by up to 70%.26 3.15.4 Capillary-Venous Malformation

Capillary-venous malformations are dilated capillary-like vessels and large cavernous channels arranged in a lace-like structure. They have a predilection for the brain (cerebral cavernous malformations, formerly known as cavernomas or cavernous angiomas),1 where they account for 5–13% of all vascular malformations of the brain.27 Diagnosis

Cerebral cavernous malformations (CCMs) can cause various neurologic problems including seizures and headaches. Based on a study by Fortuna et al.28 of 56 children with CCM, the most frequent presentations are seizures, hemorrhage, intracranial

hypertension, and focal neurologic deficits. Diagnosis is most accurately made by MRI. Etiology and Distribution

CCMs occur in 0.5% of the population.2 They have been described in all age groups with no sex predilection.29 CCMs can occur sporadically as single lesions; multiple lesions are more likely to be familial. Autosomal dominant inheritance with reduced penetrance has been well documented.30 Loss-of-function mutations in KRIT1 (encoding a protein that interacts with a member of the RAS family of GTPases involved in signal transduction) are responsible for some familial and sporadic cases.29,31 Other families have mutations in MGC4607, encoding a novel protein, malcavernin,32 or in PDCD10 involved in apoptotic pathways.33 Prognosis, Treatment, and Prevention

Although the natural history of CCMs is not entirely clear, they grow over an extended period of time by progressive ectasia of vascular channels and budding of capillaries from the cavernous spaces, leading to seizures, hemorrhage, or mass effect. The treatment of choice is excision for symptomatic lesions.34 The benefit of intervention for asymptomatic lesions is less clear. References (Vascular Malformations) 1. Vikkula M, Boon LM, Mulliken JB: Molecular genetics of vascular malformations. Matrix Biology 20:327, 2001. 2. Brouillard P, Vikkula M: Vascular malformations: localized defects in vascular morphogenesis. Clin Genet 63:340, 2003. 3. Brouillard P, Boon LM, Mulliken JB, et al.: Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (‘‘glomangiomas’’). Am J Hum Genet 70:866, 2002. 4. Baskerville PA, Ackroyd JS, Thomas ML, et al.: The KlippelTrenaunay-Weber syndrome: clinical, radiological and haemodynamic features and management. Br J Surg 72:232, 1985. 5. Servelle M: Klippel and Trenaunay’s syndrome. Ann Surg 201:365, 1985. 6. Biesecker LG, Happle R, Mulliken JB, et al.: Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84:389, 1999. 7. Slovotinek AM, Vacha SJ, Peters KF, et al.: Sudden death caused by pulmonary thromboembolism in Proteus syndrome. Clin Genet 58:386, 2000. 8. Kaplan RP, Wang JT, Amron DM, et al.: Maffucci’s syndrome: two case reports with a literature review. J Am Acad Dermatol 29:894, 1993. 9. Albregts AE, Rapini RP: Malignancy in Maffucci syndrome. Dermatol Clin 13:73, 1995. 10. Warkany J, Lemire RJ: Arteriovenous malformations of the brain: a teratologic challenge. Teratology 29:333. 1984. 11. Herzig R, Burval S, Vladyka V, et al.: Familial occurrence of cerebral arterio-venous malformation in sisters: case report and review of literature. Eur J Neurol 7:95, 2000. 12. Mattle HP, Schroth G, Seiler RW: Dilemmas in the management of patients with arteriovenous malformations. J Neurol 247:917, 2000. 13. Svein HJ, McRae JA: Arteriovenous anomalies of the brain. Fate of patients not having definitive surgery. J Neurosurg 23:23, 1965. 14. Lee SK, Vilela P, Willinsky R, et al.: Spontaneous regression of cerebral arteriovenous malformations: clinical and angiographic analysis with review of the literature. Neuroradiology 44:11, 2002. 15. Zaremba J, Stepien M, Jelowick M, et al.: Hereditary neurocutaneous angioma: a new genetic entity? J Med Genet 16:443, 1979. 16. Avasthey P, Ray SB: Primary pulmonary hypertension, cerebrovascular malformation, and lymphoedema feet in a family. Br Heart J 30:769, 1968.

Systemic Vasculature 17. Begbie ME, Wallace GMF, Shovlin CL: Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J 79:18, 2003. 18. Putman CM, Chaloupka JC, Fulbright RK, et al.: Exceptional multiplicity of cerebral arteriovenous malformations association with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Am J Neuroradiol 17:1733, 1996. 19. Van den Driesche S, Mummery CL, Westermann CJ: Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis. Cardiovasc Res 58:20, 2003. 20. Eerola I, Boon LM, Mulliken JB, et al.: Capillary malformationarteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 73:1240, 2003. 21. Widdess-Walsh P, Friedman NR: Left-sided facial nevus with contralateral leptomeningeal angiomatosis in a child with Sturge-Weber syndrome: case report. J Child Neurol 18:304, 2003. 22. Arzimanoglou AA, Andermann F, Aicardi J, et al.: Sturge-Weber syndrome: indications and results of surgery in 20 patients. Neurology 55:1472, 2000. 23. Ville D, Enjolras O, Chiron C, et al.: Prophylactic antiepileptic treatment in Sturge-Weber disease. Seizure 11:145, 2002. 24. Inan C, Marcus J: Sturge-Weber syndrome: report of an unusual cutaneous distribution. Brain Dev 21:68, 1999. 25. Comi AM: Pathophysiology of Sturge-Weber syndrome. J Child Neurol 18:509, 2003.

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26. Leaute-Labreze C, Boralevi F, et al.: Pulsed dye laser for Sturge-Weber syndrome. Arch Dis Child 87:434, 2002. 27. Frima-Verhoeven PAW, Op de Coul AAW, Tijssen CC, et al.: Intracranial cavernous angiomas: diagnosis and therapy. Eur Neurol 29:56, 1989. 28. Fortuna A, Ferrante L, Mastronardi L, et al.: Cerebral angioma in children. Child Nerv Syst 5:201, 1989. 29. Verlaan DJ, Davenport WJ, Stefan H, et al.: Cerebral cavernous malformations: mutations in Krit1. Neurology 58:853, 2002. 30. Dobyns WB, Michaels VV, Groover RV, et al.: Familial cavernous malformations of the central nervous system and retina. Ann Neurol 21:578, 1987. 31. Laurans MS, Deluna ML, Shin D, et al.: Mutational analysis of 206 families with cavernous malformations. J Neurosurg 99:38, 2003. 32. Liquori CL, Berg MJ, Siegel AM, et al.: Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73:1459, 2003. 33. Bergametti F, Denier C, Labauge P, et al.: Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76:42, 2005. 34. Folkersma H, Mooij JJ: Follow-up of 13 patients with surgical treatment of cerebral cavernous malformations: effect on epilepsy and patient disability. Clin Neurol Neurosurg 103:67, 2001.

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4 Lymphatic System Judith E. Allanson

T

he lymphatic system plays a fundamental part in regulating the physiologic environment by returning protein, cells, macromolecules, and fluid to the bloodstream, as well as by removing metabolic byproducts, dying or mutant cells, microbes, and inorganic matter.1 It also acts as a conduit for trafficking immune cell populations. Lymphatics were first observed by Herophilos about 300 BC and by Erasistratus about 310–250 BC, but it was not until 1622 that Asellius described lacteals and their content in the mesentery of dogs and human beings. Pecquet described the cisterna chyli and thoracic duct shortly thereafter. Independently, in 1653, Rudbeck and Bartholen introduced the term lymphatics. Although Harvey gave an account of the closed circulation of the blood in this era, interest in the function of the lymphatic system lagged until the twentieth century.2 Over the past decade, the era of molecular lymphology has dawned, with the discovery and characterization of lymphaticdirected vascular growth-modulating factors (VEGF-C and -D and angiopoietin-2) and their corresponding tyrosine kinase endothelial receptors (VEGFR-3 and Tie-2). Subsequently, specific gene mutations and candidate loci have been identified in several forms of hereditary lymphedema, and new mouse models of lymphatic disease have been developed.3–5 VEGF-C and VEGF-D interact with VEGFR-3 in lymphatic endothelial cells. VEGF-C and VEGFR-3 are usually co-expressed at sites where lymphatic vessels sprout. VEGF-C induces growth, migration, and survival of primary lymphatic cells, and, when overexpressed in a mouse model, induces lymphatic vessel hyperplasia. Regulation of lymphangiogenesis is likely to be as complex as angiogenesis. Some insights into the role of additional lymphangiogenic signals have been recently derived from gene targeting studies. Loss of angiopoietin-2, another vascular-specific growth factor that binds the Tie-2 receptor tyrosine kinase, results in abnormal lymphatic patterning and function. Mice with deficient DNA binding of Net, a member of the Ets-domain transcription factor that is co-expressed with VEGFR-3 in lymphatic vessels, succumb neonatally of insufficient lymph drainage. Ang2 knockout mice exhibit arrest of lymphatic development with absent or atretic peripheral lymphatics and chylous effusions, suggesting Ang2 is required for either initial lymphatic network development or subsequent sprouting or remodeling crucial for the linkage of peripheral

lymphatics to the primitive lymph sacs and the central venous system. In humans, VEGFR-3 mutations cause Milroy disease (congenital lymphedema), by reducing tyrosine kinase activity with subsequent failure in transducing VEGF-C/VEGF-D signals, and lymphatic vessel hypoplasia. FOXC2 mutations cause lymphedema–distichiasis syndrome, and mutations in this gene have been described in families with several other lymphedema phenotypes, including lymphedema-ptosis, Meige, and yellow nail syndromes (see Table 4-1 for details). Derailed growth of VEGFR-3/podoplanin-postive lymphatic vessels results in lymphangioma formation, with secondary lymphedema due to impaired lymph drainage. The theories regarding embryologic origin of the lymphatic system development remain controversial. According to the centrifugal theory, the lymphatics develop as saclike outgrowths of the endothelium of the anterior cardinal vein and mesonephric vein into paired sacs, the jugular and iliac lymph sacs.6,7 In addition to these paired sacs, two single sacs form; one is the anlage of the cisterna chyli and lower thoracic duct, and the other develops into the lymphatics of the abdominal viscera. The primary lymph nodes develop from the lymphatic primordia-superficial sacs, the deep cervical nodes from the jugular sacs, and the deep inguinal, internal iliac, and lumbar nodes from the iliac sacs. By continuous elongation, centrifugal outgrowth, and branching, these saclike growths invade most of the tissues of the body. The main trunks show gradual differentiation in their walls and become interrupted by valves and secondary and tertiary lymph nodes. According to the alternative centripetal theory, mesenchymal slits appear in the reticulum of venous plexuses at an early stage of embryonic development (9–12 mm).8–11 By coalition of these spaces, larger lymphatic cavities are formed, which open secondarily into the venous system. Now, a century later, genetic studies support the centrifugal model whereby certain venous endothelial cells become responsive to (as yet unknown) lymphatic-inducing signals, differentiate to the lymphatic lineage, and send out lymphatic sprouts. Prox1, a homeobox transcription factor, plays a critical role in the initial transdifferentiation and budding, while VEGFR-3 is initially expressed in embryonic blood vessels but subsequently restricted to lymphatic vessels once they are committed to this lineage and 145

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express additional lymphatic markers podoplanin, LYVE-1, and Nrp-2. Podoplanin, an integral membrane protein, is expressed in the endothelium of lymphatic capillaries. LYVE-1 is a receptor for the extracellular matrix glycosaminoglycan hyaluronan. Nrp-2 null mice display hypo- or aplastic lymphatic vessels. The role of these additional markers remains to be elucidated.3–5 Other elegant work has demonstrated a substantial centripetal contribution from mesenchymal lymphangioblasts, at least in avian species. Thus, both processes may contribute in various degrees to the ultimate links between the lymphatic and blood vasculatures.3 Anatomic studies show that the cisterna chyli begins as the union of the two major lumbar lymph trunks that drain the lower extremities. It receives efferent vessels from the lateral aortic lymph nodes and from the intestines. Usually one thoracic duct arises from the cisterna chyli, but considerable anatomic variation exists. It ascends on the anterior surface of the vertebral bodies to the level of L2, where it dilates and then passes through the aortic hiatus of the diaphragm, between the aorta and the azygos vein into the posterior mediastinum. Between the seventh and fifth thoracic vertebrae, the duct crosses to the left of the vertebral column and ascends behind the aortic arch and the left subclavian artery along the left border of the esophagus toward the base of the neck. It is joined by the left jugular bud. It arches above the clavicle, passing anterior to the subclavian artery, the vertebral artery, the thyrocervical trunk, and the phrenic nerve to terminate in the region of the left jugular and subclavian veins. The thoracic duct serves as the common trunk of all lymph vessels, with the exception of the right lymphatic duct, and empties into the left subclavian vein as it is joined by the left internal jugular vein. The right lymphatic duct drains the right side of the head and neck, the right upper extremity, the thorax, both lungs, the heart, and the diaphragm. Other connections between the lymphatic system and the central venous system occur at the level of the inferior vena cava, renal, portal, azygos, and hemizygous veins.12–15 Communication between the lymphatics and the veins of the thyroid, kidneys, adrenal glands, and liver functions only when the main lymphatics are obstructed.15,16 Superficial and deep peripheral lymphatics are present in all tissues except the central nervous system, the bone marrow, the intralobular portion of the liver, the coats of the eye, the internal ear, and the placenta.17 The superficial lymphatics consist of a valveless, threelayered, dermal network draining into a valved, subdermal arcade.12 Both the dermal and the subdermal networks follow the course of the superficial veins. The deep lymphatics lie intramuscularly, beneath the deep fascia, and follow the course of the main arteries.18 Connections between the superficial and deep lymphatic systems occur in the supratrochlear, popliteal, and inguinal areas.15,18 Histologically, lymph vessels are composed of three layers: a tunica intima, media, and adventia. Unlike other comparable vascular structures, lymph capillaries, although composed of a single layer of endothelium, lack a well-defined basement membrane and exhibit intercellular gaps when examined by the electron microscope.19 These structural differences allow intercellular diffusion of interstitial protein and lipids into the lymphatic circulation. Centrally directed flow of lymph begins in the intercellular spaces, which are continuous with lymph sinusoids, and subsequently drain into lymphatic capillaries and from there into the afferent lymphatics. The lymph is then filtered through the phagocyte and endotheliumlined channels within the regional lymph nodes and then channeled through the efferent vessels into the lymphatic ducts.20 Abnormalities of the lymphatics are characterized by edema, ectasia, tumor formation, and nodal dysfunction. Commonly, two

or more features are observed simultaneously or sequentially, and occasionally all occur together. The terms lymphangioma, lymphangiectasis, and lymphangiectasia imply dilation of lymphatic spaces. The distinction is arbitrary and loose, since histologic features are similar. In this section, the term lymphangiectasia is used when lymphatic vessel dilation is generalized, analogous to a varicose vein, and lymphangioma is used to describe localized spaces that vary in size from capillary dimensions to cysts several centimeters in diameter. References 1. Mayerson HS: On lymph and lymphatics. Circulation 28:839, 1963. 2. Stone EJ, Hugo NE: Lymphedema. Surg Gynecol Obstet 135:625, 1972. 3. Witte MH, Bernas MJ, Martin CP, et al.: Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microsc Res Tech 55:122, 2001. 4. Alitalo K, Carmeliet P: Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1:219, 2002. 5. Kim H, Dumont DJ: Molecular mechanisms in lymphangiogenesis: model systems and implications in human disease. Clin Genet 64:282, 2003. 6. Sabin FR: The development of the lymphatic system. In: Manual of Human Embryology, Vol 2. F Keibel, FP Mall, eds. JB Lippincott, Philadelphia, 1912, p 709. 7. Ranvier L: Morphologie et developement du systeme lymphatique. Arch Anat Microsc Morphol Exp 1:137, 1897. 8. Kampmeier OF: On lymph flow of the human heart, with reference to the development of channels and first appearance, distribution and physiology of their valves. Am Heart J 4:210, 1928. 9. Lewis FT: The development of the lymphatic system in rabbits. Am J Anat 5:95, 1905. 10. Von Recklinghausen FD: Die Lymphgefasse und ihre Beziehung zum Bindegerwebe. A Hirschwald, Berlin, 1862. 11. Huntington GS: The development of the lymphatic system in the reptiles. Anat Rec 5:261, 1911. 12. Crockett DJ: Lymphatic anatomy and lymphedema. Br J Plast Surg 18:12, 1965. 13. Pick JW, Anson BJ, Burnett HW: Communications between lymphatic and venous system at renal level in man. Q Bull Northwestern Univ Med School 18:307, 1944. 14. Threefoot SA, Kossover MF: Lymphaticovenous communications in man. Arch Intern Med 117:213, 1966. 15. Thompson N: The surgical treatment of chronic lymphedema of the extremities. Surg Clin North Am 47:445, 1967. 16. Wallace S, Jackson L, Dodd GO, et al.: Lymphatic dynamics in certain abnormal states. Am J Roentgenol Radium Ther Nucl Med 91:1187, 1964. 17. Bailey F: The circulatory system: the lymph vascular system. In: Textbook of Histology. WM Copenhaver, ed. Williams & Wilkins, Baltimore, 1964, p 277. 18. Malek P, Belan A, Kocandrle VL: The superficial and deep lymphatic system of the lower extremities and their mutual relationship under physiological and pathological conditions. J Cardiovasc Surg 5:686, 1964. 19. Casley-Smith, JR: Endothelial fenestrae: their occurrence and permeabilities, and their probable physiologic roles. VII Int Congr Electron Microsc Grenoble 3:49, 1970. 20. Kobayashi MR, Miller TA: Lymphedema. Clin Plast Surg 14:303, 1987.

4.1 Primary Lymphatic Anomalies Definition

Primary lymphatic anomalies are a primary abnormality of the lymph-conducting elements, involving both the lymph vessels and

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Fig. 4-1. Pathologic-lymphangiographic classification of generalized lymphatic dysplasia. A. Schematic of normal lymphatic drainage from lower limb. B. Distal obliterative disease. C. Distal and pelvic obliterative disease. D. Pelvic obliterative disease. E. Lymphatic hyperplasia. F. Megalymphatics. (Adapted from Wolfe.3)

lymph nodes. Three pathologic/lymphangiographic categories are recognized: aplasia/hypoplasia, bilateral hyperplasia with malformation or absence of the thoracic duct, and megalymphatics (Fig. 4-1). Hypoplasia refers to a reduction in the number and caliber of the subcutaneous lymphatic channels.1,2 Aplasia, or near complete lack of development, is probably very rare and may be an extreme form of hypoplasia.3,4 Hyperplastic lymphatic vessels are moderately dilated, tortuous channels found in association with abnormalities of the major lymph trunks—the thoracic duct or cisterna chyli. Megalymphatics are large, tortuous, dilated lymph vessels, with valvular incompetence, extending from the cisterna chyli through the retroperitoneum into the root of one limb. Synonyms include unilateral hyperplasia, lymphangiectasia, and varicose lymphatic vessels. Anomalous lymph node structure, particularly fibrosis, is increasingly found in association with lymphatic dysplasia as technology improves and may occasionally be the primary pathology.3,5 This classification is problematic. Failure of lymph vessel filling may be related to the site or nature of injection during lymphangiography, radiographic appearances may change with time, and acquired obliteration of lymphatic vessels cannot be ruled out.5 As methods of investigation improve, one may be able to refine the categories in a more physiologic way. Until then, this simple descriptive classification, which does not imply pathogenetic mechanisms, is chosen. Hypoplasia of lymphatic channels is the most common form of primary lymphatic anomaly and has been subdivided into proximal and distal forms.1 Proximal hypoplasia chiefly affects the pelvic and iliac channels (Fig. 4-1). There is a strong association with small fibrotic regional lymph nodes. Some believe the lymph

node pathology to be the primary event, hence the alternative name for this category—obstructive.5,6 Beyond the obstruction, initial lymph vessel distension is followed by atrophy or ‘‘die back’’ of the peripheral lymphatic trunks, secondary to epithelial proliferation or fibrin thrombus.5,7,8 Distal hypoplasia, also known as nonobstructive hypoplasia, is generally confined to the lymph channels of the calf and thigh.1,6 The vessels are reduced in both number and caliber. A solitary lymphatic vessel, without associated lymph node pathology, is frequently found (Fig. 4-1B). Twenty-three percent of hypoplastic lymphatic vessels display a combination of proximal and distal hypoplasia. Small, deformed fibrosclerotic lymph nodes are seen in one-third of these cases.1 Proximal hypoplasia usually presents with rapid onset of severe, unilateral lymphedema within the first months of life. Edema may first be seen in the thigh but quickly involves the entire limb. By contrast, distal hypoplasia is a milder bilateral disease, with spontaneous, painless onset of soft, pitting edema of the foot and ankle, usually in an adolescent girl. It is only slowly progressive. Thoracic duct malformation has been noted in one-third of cases of bilateral hyperplasia, with inadequate or absent filling in the remaining two-thirds.1 Obstruction to lymphatic flow through the mediastinum leads to an increase in the number and caliber of lymphatic vessels in the limbs, groin, abdomen, and, occasionally, in the mediastinum. Bilateral hyperplasia of the lymphatic vessels frequently causes symmetric, below-knee lymphedema, in association with chylous diseases, intestinal lymphangiectasia, and, occasionally, concomitant pleural effusions.1,9 Symptoms may begin at any time of life.1,2

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Megalymphatics may be associated with abnormalities of the thoracic collecting ducts and the central abdominal ducts above the point where the mesenteric lymphatic vessels join the preaortic lymphatic vessels. Occasionally, the megalymphatics are localized in the retroperitoneal region. Megalymphatics usually present as congenital (or early-onset), unilateral or bilateral swelling of the lower limbs.1 The groin and genitalia are frequently involved, with vesicles, leaking chyle or lymphatic fluid, on the overlying skin. Chylous diseases may be associated.4 Lymph nodes are situated at the confluence point of lymphatic streams. Therefore, all lymph from the periphery passes through nodes. Within the node, lymph is recapillarized in sinusoids, with resulting transformation of its protein and cellular composition.10 Normal lymph nodes vary considerably in appearance, and some fibrosis is usually noted in the hilar and pericortical regions. Lymphoid tissue involutes with age, and fibrolipomatosis is a feature in older patients. Taking these changes into account, primary lymphatic dysplasia is often associated with striking, extensive fibrosis emanating from the hilum of the node and initially affecting the medullary sinuses.3,5 This produces obliteration and then recanalization in adjacent lymph vessels. There is no evidence of acute inflammation or association with cellulitis. Fibrosis is seen most commonly in proximal hypoplasia (41%), combined hypoplasia (34%), and bilateral hyperplasia (28%). The amount of fibrosis seen in association with megalymphatics and distal hypoplasia is little different from the normal situation.3 In one study of hypoplastic lymphatic dysplasia, lymph nodes and lymph vessels were found to be diseased in almost 90% of cases.8 Inguinal, iliac, and lumbar nodes were chiefly involved. Beyond the diseased lymph nodes there was a distended network of vessels with ‘‘dermal backflow’’ from dilated deep lymph vessels into the smaller collectors and plexuses of the skin.8 Proliferation of lymph vessel intima, muscle hypertrophy, and subintimal fibrohyalinosis occurs as a consequence of impeded lymphatic drainage.11 Lymph node disease does not appear to be caused by experimental ligation of either the afferent or efferent lymphatics, suggesting that the lymph node pathology is primary.3 Primary lymphatic dysplasia may present in one of five major ways: (1) lymphedema, (2) chylous disease, (3) intestinal lymphangiectasia, (4) cystic renal lymphangiectasia, or (5) generalized (all of the above).

onset and the second on pathologic findings. Congenital lymphedema occurs in 11–25% of cases; lymphedema praecox, with onset before age 35 years, is the most common, found in 60–80% of cases; and lymphedema tarda, with onset after age 35 years, is found in 12–14% of cases.1,6,12 Lymphatic aplasia/hypoplasia accounts for 90% of cases, with hyperplasia in 7% and megalymphatics in 3% of pathologic/lymphangiographic series.1 Nine times out of 10 primary lymphedema affects the lower limbs (Fig. 4-2). Onset is generally spontaneous, although it may be related to a minor event, such as an insect bite, an episode of skin infection, trauma, or surgery, that interrupts underlying collaterals, thus unmasking a primary dysplasia. Lymphedema is generally confined to tissue superficial to the deep fascia. Absence of lymphatic fluid accumulation below this point is attributed to the pumping action of the muscles and blood vessel pulsations. Rare connections exist between the superficial and deep systems of lymphatic vessels in the popliteal and inguinal areas. Lymphaticovenous communications may also be present, although both their presence and function are controversial.1,6,12 In the upper limb, primary lymphedema is less common, congenital in onset, and severe. The arm is more often affected by secondary lymphedema, following mastectomy. The underlying primary lymphedema pathology is hypoplasia/aplasia or hyperplasia of the lymphatics. In contrast to lower limb lymphedema, upper limb involvement is far more likely to be associated with lymphatic abnormalities elsewhere—genital edema, intestinal lymphangiectasia, and thoracic duct abnormalities.1 Lymphedema of the head and neck usually occurs with underlying hypoplasia/aplasia of the lymphatic channels. It is conspicuous and disfiguring. Onset at menarche is common. It may be spontaneous or precipitated by insect bites. Primary genital lymphedema is most frequently associated with proximal or obstructive hypoplasia of lymphatic vessels (Fig. 4-3). Fifty percent of cases present with concomitant lymphedema of the lower limb. Onset is generally in adolescence or early adulthood. Genital lymphedema is most frequently found in males, where anatomic differences allow smaller degrees of obstruction to produce lymphedema.1 Hypoplastic lymphatic vessels of the genital skin and subcutaneous tissue, which drain to the

Lymphedema

Fig. 4-2. Bilateral lymphedema affecting the legs and feet in a 3-week-old infant. His maternal aunt was similarly affected, and the lymphedema was still present at age 30 years. The mother had no evidence of lymphedema but was presumed to have the gene for this condition (OMIM 153100, Nonne-Milroy disease).

Lymphedema is an accumulation of lymph in the interstitial spaces, principally of the subcutaneous fat, caused by a disturbance in equilibrium between the load to be cleared and the transport capacity of the clearing system. Lymphatic stasis results in an interstitial excess of lymph, consisting of 4% protein and increased alpha-globulins, which stretches the reticular fibers attached to the lymphatic vessels, causing dilation. This subsequently leads to valvular incompetence, disoriented flow, backflow, and pooling.12 This situation is initially reversible; however, progressive subcutaneous fibrosis leads to irreversible brawny edema.12 The disturbance probably occurs because of a combination of factors—tissue pressure, inflammation, and hormonal changes at puberty, in pregnancy, and during menopause—in addition to an underlying dysplasia of the lymphatic system.1,5 Diagnosis

Many classifications of lymphedema have been used historically, and the reader is referred to Browse and Stewart5 for details. Two classifications continue in common usage, one based on age of

Lymphatic System

149

Fig. 4-3. Top: lymphangioscintigraphy (LAS) in 13-year-old boy with left leg and penile lymphedema and scrotal lymph fistula demonstrates normal tracer transport on the right. On the left, however, tracer disperses just above the injection site and appears in the scrotum at 48 minutes, with increased scrotal density at 4 hours. Some radioactivity superior to the scrotum at 237 minutes represents tracer accumulation in the urinary bladder. Bottom: direct

lymphography (with ethiodol) in same patient demonstrates hypoplastic lymphatics (insert shows gross genital edema) (left) and reflux of contrast material into scrotum (middle). Fine, dysplastic retroperitoneal lymphatics and near total absence of paravertebral nodes are seen at 24 hours (right). (Courtesy of Dr. Charles L. Witte, University of Arizona College of Medicine, Tucson, AZ.)

medial superficial inguinal nodes, cause lymphedema. Lymphatic vessel pathology in the testes and adnexa, which drain to the lumbar and iliac nodes, leads to hydrocele. Lymphedema and hydrocele may be seen concurrently if both lumbar and iliac lymph vessels and lymph nodes are diseased. Additional findings include cellulitis or abscess formation, condylomas, vesicles, buboes, and sexual dysfunction. Occasionally, genital lymphatic dysplasia is of the megalymphatic type, with chylous hydrocele and chylous vesicles on the scrotal skin.1

The objectives of diagnosis are first to discover the cause and second to define the type. Conventional oil-contrast lymphangiography has long been the mainstay for lymphatic imaging. However, the emergence of computed tomography and magnetic resonance imaging has curtailed its use. Because of recent improvements and refinements, lymphangioscintigraphy now permits high-resolution imaging of peripheral lymphatic vessels.100 It has value for diagnosis, delineation of pathogenesis, and evaluation of treatment efficacy. It is essentially noninvasive, can easily be

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repeated, and does not adversely affect lymphatic endothelium.100 An intradermal injection into the first interdigital web space is followed by scintigrams in the ilioinguinal region 30 and 60 minutes later (Fig. 4-4). This is a relatively simple technique and may differentiate between primary, secondary, and venous causes of edema. 99Tc radionuclide scanning can locate obstruction, the so-called enhanced pattern of unilateral increased flow, and inguinal lymph node enlargement seen with hyperplasia of the lymphatic vessels.13 Obstruction may be manifested by delayed transit time; extensive extravasation of contrast material through the lymph vessel walls; dilated, tortuous, beaded lymphatic vessels; delayed clearing of contrast or collateral circulation; and dermal backflow (Fig. 4-5).14 Direct lymphangiography can then be used to better define the type of anomaly present. Lymphangiography is performed by localization of a lymphatic vessel in the interdigital web area of the foot using various dyes, such as patent blue violet, with subsequent cannulation of that lymphatic vessel and infusion of lipiodal and ethiodinated oil (Fig. 4-6). Difficulty in cannulating the distal lymphatic channel has often erroneously led to the diagnosis of aplasia.4 The oil may produce allergic reactions and pulmonary oil emboli.1 Watersoluble lymphangiographic agents have been used with minimal side effects; however, the resulting images seem poorer than with the oil-based alternatives. Inguinal lymphangiography is important to differentiate between distal disease, which carries a good prognosis, and proximal obstructive hypoplasia with reduced lymph node opacification and slight coarsening of the internal architecture, which has a poor prognosis.3,14 It is important to remember that interpretation of this radiographic data can be deceiving. There is no absolute correlation between the lymphangiographic findings and clinical severity or between the presence of anatomic abnormality and the likelihood of edema. Physiologic derangement must accompany dysplasia to cause lymphedema.2 The key to the differential diagnosis is to rule out venous disease, whether secondary to chronic venous insufficiency, postphlebitis syndrome, or iliac vein compression. Clinical signs of venous pathology are usually significant enough to make the diagnosis and typically include hyperpigmentation, brawny edema, loss of nails and skin adnexae, and venous stasis ulcers. These changes do not occur with lymphedema, in which capillary perfusion is not impaired. Lymphedema is a genetically determined diffuse enlargement of the subcutaneous tissues of the lower limbs, with loss of their contour. It has a distinct predilection for women and is most frequently symmetric and bilateral. Body habitus is often slim above the waist, with obesity about the pelvis and lower extremities.2 Repeated episodes of infection are uncommon. Primary lymphedema must be distinguished from secondary lymphedema, occurring because of surgical extirpation of lymph nodes or lymph vessels; carcinoma, especially lymphocytic proliferative disorders such as Hodgkin’s disease; filariasis, the leading cause of lymphedema in underdeveloped countries; repeated inflammation; and high dose irradiation. It should also be distinguished from simple edema occurring in the presence of cirrhosis, nephrotic syndrome, congestive cardiac failure, renal failure, or myxedema.1 Congenital absence or malformation of the thoracic duct should be distinguished from traumatic and surgical anomalies of the duct, mediastinitis, tumor, and venous thrombosis.5 Congenital malformations, unrelated to the lymphatics, are seen with primary lymphatic anomalies to a varying extent. Wolfe3 reports a 6% incidence overall, with a 22% incidence in the bilateral hyperplasia group. Kinmonth1 reports a 17.4% frequency. In patients with unilateral megalymphatics, one almost invariably

Fig. 4-4. Normal (early and later phase) lower limb lymphangioscintigraphy (LAS) using 99mTc-HSA (technetium-human serum albumin). Scintigraphic ‘‘bands’’ represent peripheral lymphatic trunks (left) with groin lymph nodes and retroperitoneal lymphatic trunks (right). Once the radiotracer reaches the bloodstream, the heart and liver are rapidly visualized. A small amount of tracer is seen accumulated in the urinary bladder. Circular markers in the midline are xiphoid, symphysis, and knee. (Courtesy of Dr. Charles L. Witte, University of Arizona College of Medicine, Tucson, AZ.)

finds a circumscribed pink patch or capillary angioma—the socalled vin rose angioma—on the skin of the limb or the trunk near the root of the limb. A number of patients with bilateral hyperplasia of the lymphatic vessels have blotchy red angiomas or erythrocyanosis around the edges of their feet. These are usually symmetric and different from the vin rose angioma. Individuals with bilateral hyperplasia also have an increased incidence of cleft palate and congenital heart defects, especially valvular pulmonary stenosis. In one review, congenital heart defects were seen in five of 31 cases of bilateral hyperplasia with abnormalities of the thoracic duct, in contrast to six cases of congenital heart disease seen in 425 individuals with hypoplastic lymphatics.15 The latter incidence (1.4%) is not statistically different from the incidence of congenital heart defects in the general population. Inherited forms of primary lymphatic dysplasia, with or without other malformations,

Lymphatic System

151

Fig. 4-5. Left two panels: lymphangioscintigraphy (LAS) in a 16-year-old girl with severe hypoplastic lymphedema of the left leg. The right leg is normal, showing peripheral trunks, groin nodes, retroperitoneal nodes and lymphatics in early (30 minute) and delayed (4 hour) films. The left leg shows no migration of tracer from the left foot (cf. Fig. 4-4). Middle two panels: LAS in a 13-year-old girl with right-sided lymphedema demonstrating marked lymphatic

hypoplasia. Left side is normal. Right side shows little or no cephalad migration of the tracer. Right panels: 37-year-old woman with right leg edema since age 3 years. LAS shows dermal diffusion of the tracer with nonvisualization of both the right groin nodes and retroperitoneal trunks (cf. normal left leg). (Courtesy of Dr. Charles L. Witte, University of Arizona College of Medicine, Tucson, AZ.)

are fairly numerous and are listed in Table 4-1. Perhaps the most well-known of these is Milroy disease (congenital and familial lymphedema), which occurs in 3.4% of patients with lymphedema and affects one in 6000 individuals with a male to female ratio of 1:2.3.1 Meige disease (familial lymphedema praecox) is less common than Milroy disease.

possible mechanisms. In the Butch Landrace pig, autosomal dominant congenital lymphedema (Milroy disease) occurs secondary to nonobstructive distal hypoplasia. The degree of edema is varied. Clinical features are correlated pathologically with the gradation of lymphatic involvement, from total aplasia to minor hypoplasia.51 Cystic and angiomatous configurations are noted, and the prevertebral trunks, lung, and mesenteric vessels are decreased in number, thin-walled, and wide. Lymph nodes are present sporadically in the axillary, gluteal, and inguinal regions. These animals clearly have features in common with cystic hygroma, lymphangioma, and pulmonary and intestinal lymphangiectasia, pointing to a common mechanism in the pathogenesis of these diseases.

Etiology and Distribution

The embryology of the lymphatic system is reviewed in detail in the chapter introduction. The cause of primary lymph vessel and node pathology is unknown. However, three animal models suggest

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Fig. 4-6. Top three illustrations: conventional oil-contrast lymphography in a 13-year-old girl with chylometrorrhea or chylocolporrhea (leakage of visceral lymph through the uterus or vagina) demonstrating massive lymph ‘‘lakes’’ (stasis) in the true pelvis with contrast extravasation into the vaginal vault (arrow). Treatment is usually directed at ligating communicating lymphatics between the retroperitoneum and uterus or vagina. Bottom three illustrations: 15-year-old boy with right leg lymphedema. Conventional oil-contrast lymphography (right two photographs) shows hyperplastic collateral calf lymphatics consistent with primary lymphedema. Lymphangioscintigraphy (left) shows prompt tracer transport in the right leg but with intense and extensive dermal diffusion of tracer into the right calf. (Courtesy of Dr. Charles L. Witte, University of Arizona College of Medicine, Tucson, AZ.)

Embryologically, the lymph vessel primordia are present, but they are underdeveloped and fail to fuse; secondary outgrowth is delayed and progressively inhibited.52 Edema formation, with increasing pressure and structural changes in the tissue surrounding the lymphatics, may cause inhibition of lymphatic outgrowth, which in turn aggravates the lymphedema and fibrosis. Structural abnormalities of the vessels themselves, such as dilation, irregularity, and valvular deficiency, may be due to increased lymph flow through too few vessels.53 The poodle provides a second animal model, this time for autosomal dominant proximal (obstructive) hypoplasia.53 Pathologic studies reveal absence of regional lymph nodes with dilation, increased tortuosity, increased numbers of distal channels, and blind-ending afferent lymph vessels.54 Since central lymphatic vessels and nodes are present, and essentially normal, it appears

that the peripheral and central lymphatic systems fail to make adequate connections, with resultant obstruction to lymphatic drainage from the tissues of the limbs. In Ayrshire cattle, congenital autosomal recessive lymphedema occurs secondary to bilateral hyperplasia of the lymphatics.55 The gene may be present in other breeds.56 Affected cattle can be picked out by the presence of a small accessory earlobe on the dorsal surface of the ear. Internally, the thoracic duct is dilated and tortuous throughout its course, with occasional pulmonary lymphangiectasia; afferent and efferent lymph vessels are tortuous, dilated, and enlarged. There is extensive endothelial proliferation, forming strands of tissue that stretch across the lumen, often dividing it completely, which provides considerable resistance to flow. These pathologic changes, affecting peripheral lymph vessels and secondary and tertiary lymph nodes, suggest a disturbance in organization and growth of the lymphatic endothelium during peripheral lymphatic development, after the primary node and vessel primordia have formed. Estimates of the overall incidence of primary lymphatic dysplasia vary considerably, from one per 67,000 to one per 6000 in the under 20 population.1,57,58 The overall sex ratio is three females to one male. This may reflect the hormonal influence in females at menarche, during pregnancy, or during menopause, plus the fact that subcutaneous tissue pressure is approximately 7 mm Hg greater in males, which may be enough to prevent lymphedema in some cases. Proximal hypoplasia is equally frequent in males and females, with a positive family history in 10% of cases. Distal hypoplasia appears almost exclusively in females, with a positive family history in 22–46% of cases.1,3 Combination proximal-distal hypoplasia is more common in women. Bilateral hyperplasia, with abnormalities of the thoracic duct, occurs twice as often in men as in women. There is a positive family history in one-third of cases. Unilateral megalymphatics are more common in males and are never familial. Prognosis, Prevention, and Treatment

In approximately 50% of patients, an equilibrium point is reached after several years of increased swelling, and, irrespective of treatment measures, swelling remains stable.1,3,57 In other patients, there is a slow, constant, inexorable progression. Once the lymphatic system is unable to drain the interstitium adequately, metabolic byproducts accumulate. Inflammatory changes stimulate migration of macrocytes, whose phagocytic activity is impaired by protein-rich interstitial fluid. The macrocytes are unable to degrade and remove the offending stimuli. Deposition of collagen exceeds macrophage proteolysis, resulting in fibrosis. Chronic injury leads to transformation of smooth muscle cells within the walls of the lymph vessels, which become thickened, fibrosed channels. The combination of subcutaneous and lymphatic vessel fibrosis leads to obstruction and dilation of the lymphatic vessels and valvular incompetence.2 The initial stages are reversible. Long-term, inexorable progression produces fibrokeratotic skin, verrucous growths, and, rarely, malignant angioendothelioma.59 Occasionally, chylous xanthomas, raised yellow nodules approximately 5 mm in diameter, are noted on the skin of children or adolescents. They probably only occur in those individuals with megalymphatics, in whom chylous connections exist between intestinal and lower limb lymphatics.60 An incompetent lymphatic system may lead to deposition of lymph-derived lipoprotein in the skin, which, in association with failure to remove tissue lipid, may lead to accumulation of large amounts of lipid within the skin.61 The xanthomas tend to resolve if lymphatic

Table 4-1. Genetic syndromes with lymphedema/generalized lymphatic dysplasia Causation Gene/Locus

Syndrome

Period of Onset

Prominent Features

Lymph Pathology

Distichiasislymphedema25–27,38,101,102,129

Puberty or later

Distichiasis, recurrent lymphangitis, congenital heart disease, ptosis, varicose veins, cleft palate, spinal extradural cysts

Hypoplasia, bilateral hyperplasia with thoracic duct obstruction

AD (153400) FOXC2, 16q24.3

Familial protein-losing enteropathy48

Childhood

Growth retardation, hepatic vein stenosis, abdominal pain, ascites, diarrhea

Unknown

AR (226300)

Hennekam43,103

Congenital/childhood

Intestinal lymphangiectasia, lymphedema, mental retardation, hypertelorism, ear and tooth anomalies, seizures, cardiac and blood vessel anomalies, glaucoma, hearing loss, renal anomalies

Unknown

AR (235510)

Hypotrichosislymphedematelangiectasia104

Variable

Sparse scalp hair, absent brows and lashes, thin transparent skin, lymphedema, hydrocele, telangiectasia of palms and soles

Unknown

AR and AD SOX18, 20q13

Intestinal lymphangiectasia45,46

Congenital

Intestinal lymphangiectasia, pulmonary lymphangiectasia, double hair whorl, floating ribs

Bilateral hyperplasia with thoracic duct abnormality

AD (152800)

Intestinal lymphangiectasia47

Congenital

Intestinal lymphangiectasia

Unknown

AR

Intestinal lymphangiectasiaaplasia cutis congenita44

Congenital

Intestinal lymphangiectasia, aplasia cutis, optic disc coloboma

Unknown

AR (207731)

Isolated lymphedema18,19

Congenital

Lymphangiectasia-skeletal anomalies34

None

AR

Metaepiphyseal anomalies, unusual face, turricephaly

Unknown

AR/XLR

Lymphedema-atrial septal defect105

Congenital

Lymphedema of the lower limbs, atrial septal defect, hydrocele

Unknown

AR

Lymphedema-hematologic abnormality39

Childhood/puberty

Sensorineural deafmutism, acute myeloblastic anemia, pancytopenia

Dilated lymph vessels

AR/AD

Lymphedemacerebrovascular malformation20

Puberty or later

Cerebral arteriovenous anomaly, primary pulmonary hypertension

Unknown

AD

Lymphedemacholestasis35,106

Congenital/early childhood

Recurrent cholestatic jaundice

Distal hypoplasia

AR (214900) 15q

Lymphedema-chylous ascites49,50

Congenital

Chylous ascites, glaucoma

None

AR

Lymphedema-cleft palate24

Puberty

Cleft palate

Unknown

AD

Lymphedema-Fabry disease42

Praecox

Fabry disease; skin, renal, and neurologic abnormalities

Aplasia

XLR

Lymphedemahypoparathyroidism36

Congenital

Hypoparathyroidism, nephropathy, mitral valve prolapse, brachydactyly, telecanthus, ptosis

Unknown

AR/XLR (247410)

Lymphedemamicrocephaly-chorioretinal dysplasia22,23,107

Congenital

Microcephaly with occipital flattening, variable intelligence with occasional mild mental retardation

Unknown

AD (152950)

(continued)

153

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Table 4-1. Genetic syndromes with lymphedema/generalized lymphatic dysplasia (continued) Prominent Features

Lymph Pathology

Causation Gene/Locus

Congenital/praecox

Unilateral/bilateral pes cavus

Distal hypoplasia

AD

Puberty

Congenital ptosis

Proximal hypoplasia

AD (153000) FOXC2, 16q24.3

Lymphedemarecurrent lymphangitis41

Childhood

Recurrent lymphangitis

Distal hypoplasia

AD

Lymphedema-unusual face28

Congenital

Unusual face, partial ectropion lower lid, heart defect

Distal hypoplasia

AR/XLR

Meige disease17,129

Puberty or later

Lymphedema

Hypoplasia

AD (153200) FOXC2, 16q24.3

Nonne-Milroy disease16,108

Congenital

Lymphedema

Hypoplasia

AD (153100) VEGFR-3, 5q35.3

Noonan29,30,109

Congenital

Short stature, congenital heart defect, webbed neck, pectus, unusual facies

Commonly bilateral hyperplasia with abnormal thoracic duct, but hypoplasia and megalymphatics seen

AD (163950) PTPN11, 12q24

Turner31–33

Congenital

Short stature, congenital heart defect, webbed neck, facial dysmorphism

Mostly hypoplasia, occasional megalymphatics

Chromosomal (45,X)

Urioste syndrome110

Congenital

Persistent mullerian derivatives; lymphangiectasis; hepatic failure; postaxial polydactyly; renal, genital, and craniofacial anomalies

Intestinal lymphangiectasia

AR (235255)

XY female1

Congenital/praecox

Gonadal dysgenesis, androgen insensitivity

Distal hypoplasia

Unknown

Yellow nail37,29

Adulthood

Yellow nails, pleural effusions, thyroid disease, immune deficiency

Hypoplasia

AD (153300) FOXC2, 16q24.3

Syndrome

Period of Onset

Lymphedema-pes cavus40 Lymphedema-ptosis21,129

drainage is improved by either compression or elevation.59 Xanthomas have been noted in unusual sites—the ear concha, preauricular area, vocal cords—in an older woman with type 2A hyperlipidemia.59 One of the primary complications of lymphedema is infection, which occurs in one-third of cases.57 The protein-rich edema fluid promotes bacterial growth, producing cellulitis and lymphangitis with fever, chills, nausea and vomiting, malaise, and headache. Local signs include erythema, induration, tenderness, and lymphadenopathy.17 Staphylococci and streptococci are the most frequent pathogens. Aggressive treatment is necessary to avoid additional injury. Twenty-five percent of cases have recurrent lymphangitis,17 which is particularly common in proximal hypoplastic lymphatic dysplasia.3 Some physicians recommend prophylactic antibiotics for patients with repeated attacks of cellulitis. Penicillin, given orally 1 week per month, has been shown to decrease the infection rate markedly.57 Lymphangiosarcoma was first described in lymphedematous tissue after radical mastectomy and is also known as StewartTreves tumor. It is rare in primary lymphedema and presents as single or multiple, bruiselike, bluish-red, hemorrhagic nodules on the skin, which progress to ulceration and satellite tumor formation. Hematogenous spread is common, with a survival time averaging 19 months.17 Duration of lymphedema prior to tumor

formation is 11 to 40 years, with a mean of 27 years.17 Chronic lymph stasis impairs local immune surveillance and stimulates vicarious angiogenesis, predisposing to chiefly vascular tumors such as Stewart-Treves and Kaposi’s sarcoma.111 Other rare complications include epidermodysplasia verruciformis, an extensive, flat, wartlike lesion with high likelihood of malignant conversion to squamous cell carcinoma, caused by human papillomavirus; and necrotizing fasciitis, a rapidly progressive gangrenous process affecting subcutaneous fascia with an infectious etiology and a mortality of 8–68%.62,63 This rare infection is in contrast to the usual banal infections seen in lymphedema. Recurrent septic arthritis and sterile knee effusions have also been noted rarely.64,65 Full details of the treatment of primary lymphedema are beyond the scope of this chapter. However, interested readers are referred to several other excellent books and articles.1,2,4,17,57,112 The principles of treatment, however, are pertinent to this discussion. The overwhelming majority of patients with lymphedema can be satisfactorily managed nonoperatively. Surgical intervention cannot provide a cure. Medical management is commonly divided into two separate categories, mechanical and pharmacologic, both of which are aimed at controlling the accumulation of protein-rich edema, reducing the incidence of infection, and stopping the development of verrucous growths and hyperkeratotic

Lymphatic System

skin. Mechanical support includes elevation of the involved extremity, graded pressure garments, lymphatic massage, intermittent compression machines, limb hyperthermia, and meticulous skin care.2 During the early stages of lymphedema, limb elevation combined with a custom-fitted graded pressure garment, such as an Ace elastic bandage or Jobst form-fitted pressure stocking, is often successful in minimizing swelling. The edema usually improves slowly over a period of days. New garments must be obtained every few months to ensure adequate compression of the limb. External pneumatic compression promotes flow through existing lymphatics by increasing interstitial pressure and thus increasing transcapillary exchange of extravascular protein and water. Low-pressure, intermittent pumping devices, such as the Jobst pump, Flowtron-aire pump, Wright linear pump, and Lympha-press, work on the principle of sequential, intermittent pneumatic compression of the limb, beginning at the hand and foot and ending with the proximal portion of the limb.57 Each must be used together with a support stocking. Early edema responds quite readily to external pneumatic compression; however, 30–40% of limbs are resistant, primarily in those cases of advanced lymphedema with fibrotic subcutaneous tissue. The compression devices are contraindicated in patients with deep vein thrombosis, severe arterial insufficiency, and acute infection. Limb hyperthermia has been used by the Chinese for centuries.2 Heat controls the recurrence of infection by increasing blood flow, providing nutrition to local cells, hastening the repair of damaged tissue, and reopening lymphatico-venous communications. At this point, the therapeutic indications for this method are uncertain.2 Pharmacologic considerations include antibiotics for treatment of lymphangitis; diuretics, which reduce limb volume by hemoconcentration but are of little value over a long period of time; and benzopyrones, which have been shown experimentally to reduce high-protein edema.2 These agents bind to proteins in the interstitium and stimulate proteolysis by enhancing macrophage phagocytic activity. In addition, they facilitate resorption of protein through the vascular system, decreasing subepithelial fibrosis. Long-term follow-up reveals increasing objective and subjective improvement. Benzopyrone treatment shows promise.113 Indications for surgery include functional impairment related to the progressive enlargement of the extremity, recurrent episodes of infection, and cosmesis. Numerous procedures, both physiologic and excisional, for treating lymphedema have been described since the nineteenth century.2 Physiologic procedures attempt to improve the lymphatic drainage by microvascular techniques, local flaps, or distant pedicles. The excisional procedures remove varying amounts of lymphedematous, subcutaneous tissue.2 Adequate preoperative and postoperative care is of the utmost importance. Prior to operation, the patient should be hospitalized and the extremity elevated for several days to eliminate all residual edema.57 If necessary, a pneumatic pump should be used. Postoperatively, the patient should always wear adequate support and take proper care of the feet to avoid infection. Surgical treatment is not advised for infants less than age 2 years, since, occasionally, edema will diminish once the child begins to walk. It is clear that the results of surgical treatment have been less than satisfying, and, if surgery is considered, the patient should be forewarned that there is only a limited success rate and that complications, especially cosmetic ones, are frequent.57 In one 8-year follow-up study, 70% of patients had at least a 50% reduction in size of the extremity.2 The incidence of cellulitis was significantly

155

decreased. Progressive and continued swelling occurred postoperatively in 6% of patients. Postoperative complications included ischemic necrosis (6%) and loss of sensation on either side of the incision.2 Individuals with proximal (obstructive) hypoplastic lymphatic dysplasia who have demonstrable adequate lymph flow from the foot to the inguinal region, no lymphatic obstruction above the level of the superior mesenteric artery (including the cisterna chyli or thoracic duct), and normal mesenteric lymphatics (no evidence of a protein-losing enteropathy) are good candidates for an enteromesenteric bridge, which bridges the pelvic block by way of the mesenteric lymphatics, successfully establishing lymphatic drainage. Both short- and long-term follow-up indicate good clinical results, with improved lymphangiographic results in three-fourths of the patients. Surgical treatment of genital lymphedema is also successful.57 Recognition that primary congenital lymphedema (Milroy disease) is caused by mutations in VEGFR-3 has led to the development of a mouse model.114 Using virus-mediated VEGF-C gene therapy, researchers have generated functional lymphatic vessels in the lymphedema mice.114 Such growth factor therapy may be applicable to human lymphedema. Intestinal Lymphangiectasia

Intestinal lymphangiectasia is characterized by dilation of the lymphatic channels in the mucosa, serosa, and mesentery of the small bowel. Involvement of lymphatic vessels is variable; the entire small bowel may be affected, or the changes may be confined to a small segment.66 Diagnosis

At the onset, two-thirds of patients have a few gastrointestinal symptoms; however, the majority develop diarrhea, with or without steatorrhea, at some time during the course of the disease.67 Gastrointestinal protein loss may occur as a result of rupture of the dilated lymphatic vessels, with consequent discharge of their contents into the bowel lumen. Alternatively, protein, transuding from the intestinal capillaries, may enter the lumen through an intact epithelium when the mesenteric lymphatics are obstructed and cannot fulfill their normal function in protein transport.67 In the majority of patients, protein loss leads to severe symmetric or asymmetric edema, which may be limited to the lower limbs, may involve the scrotum or anterior abdominal wall, may be generalized without effusions, or may be generalized with pleural or ascitic effusions.68 These effusions are chylous in 30– 50% of cases.67–69 Twenty percent have lymphedema. There is also considerable enteric loss of lymphocytes and immunoglobulins G, A, and M.69,70 This leads to an immune deficiency state, with abnormalities of both the humoral and cellular immune systems. There is increased susceptibility to infection. A more marked deficiency of the cellular immune system, as assessed by intradermal delayed hypersensitivity skin tests or skin allograft survival, is characteristically seen.69 In vitro studies of lymphocyte function, undertaken to assess whether the cellular immune defect is simply the result of a reduced number of peripheral blood lymphocytes, suggest that the residual lymphocyte population may be qualitatively as well as quantitatively defective.69 The diagnosis of intestinal lymphangiectasia often begins with studies to detect and quantitate protein loss. The metabolism of serum albumin can be studied with 51Cr-labeled albumin, 131I-labeled polyvinyl pyrrolidone, and 131I-labeled serum

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proteins.66–68 Fecal fat estimation and xylose tolerance may be used as adjuncts. Barium meal appearance is characteristic, with mucosal edema and ‘‘puddling’’ of the radiocontrast material around the enlarged lymphatics of the small bowel.71 Peroral jejunal biopsy and lymphography provide definitive diagnosis.66,67 Affected portions of the small intestine are edematous with a dusky, congested serosal surface that shows areas of fibrinous exudate. Serosal lymphatic vessels are often dilated and may contain yellow nodules, less than 5 mm in diameter, along their course.67 The intestinal villi have enlarged, bleblike tips, imparting a white, pebbly, almost papillary appearance to the mucosal surface. Microscopic examination of the small bowel reveals a variable degree of dilation of the lymph vessels of the mucosa and submucosa. In some areas the dilated lymphatic vessels do not disturb villous architecture, whereas in other areas plexiform enlargement of many channels results in widening and distortion of the villi. There may be an increase in elastic fibers of the mucosal lymphatics. Mesenteric lymphatics may have a thickened and fragmented elastica interna with hypertrophy of the muscular layers of the media. Mesenteric lymph nodes are similarly affected, with hypertrophy of the capsular elastic fibers and fibrous thickening of the trabeculae. The sinuses of the majority of nodes are dilated and relatively acellular, but there may be reticulum cell hyperplasia.67 Lymphography demonstrates that the intestinal lymphatics are both numerous and abnormally dilated.66 There are frequent reports of associated lymphatic dilation in the lower limbs, pelvis, and retroperitoneal space, abnormalities of the cisterna chyli or thoracic duct, and occasional limb lymphatic hypoplasia and hypoplasia of the inguinal, pelvic, and retroperitoneal lymph nodes.66–68 Most patients with intestinal lymphangiectasia are young. In one study, one-third of patients had onset of symptoms before age 10 years, while the oldest patient was 28 years old.67 Males and females appear to be equally affected. Differential diagnosis of hypoproteinemia due to proteinlosing enteropathy includes adenocarcinoma of the stomach, giant hypertrophic gastritis (Menetrier disease), acute gastroenteritis, ulcerative colitis, regional ileitis (Crohn disease), Whipple disease, nontropical sprue, and renal or hepatic disease.67,72 Differential diagnosis of radiologic findings also includes secondary lymphedema due to retroperitoneal fibrosis, retroperitoneal tumors, intestinal scleroderma, pancreatitis, constrictive pericarditis, congestive cardiac failure, radiation enteritis, mesenteric and diffuse lymphomas, and abdominal tuberculosis.73 Intestinal lymphangiectasia has been reported in association with nephrotic syndrome, Graves disease, Behcet disease, ataxia telangiectasia, aplasia cutis congenita, and Noonan syndrome.44,74–77,115 Familial cases are rare, but are described with both autosomal recessive and autosomal dominant patterns of inheritance.45–47 Familial protein-losing enteropathy has also been reported.48 Prenatal ultrasound has demonstrated multiple small cysts in the abdomen that later proved to be lymphangiectasia in the mesentery of the small bowel. The fetal abdomen was filled with small cystic spaces containing fine, low-level echoes.78 Etiology and Distribution

The high incidence of concomitant chylous effusions and lymphedema, together with evidence of abnormal peripheral and retroperitoneal lymphatics, cisterna chyli, and thoracic duct, indicates that intestinal lymphangiectasia is often part of a generalized dysplasia of the lymphatic system.68 The enteric component

occurs because of an anatomic block to flow through the central lymph vessels.66,67 The severity of the systemic lymphatic disorder correlates with the significance of clinical symptoms.68 Intestinal lymphangiectasia has been described in the small intestine of several types of dogs.116 The disease resembles proteinlosing enteropathy of man, characterized by dilation of the intestinal lymphatics, panhypoproteinemia, edema, hydrothorax, hydropericardium, and hypocalcemia. In addition to the typical intestinal findings, pathologic examination may reveal atrophy of the mesenteric lymph nodes or lymphadenopathy, and dilated lacteals. Prognosis, Prevention, and Treatment

Treatment of intestinal lymphangiectasia is difficult and often unsatisfactory. The goal is to maintain plasma protein level, and thus circulating blood volume, and to inhibit excessive extravascular retention by reducing enteric loss of protein. Symptomatic relief may be obtained by intravenous albumin, diuretics, and a low-fat diet.67 Medium-chain triglycerides, which are absorbed into the portal vein rather than through the lymphatics of the bowel, may be of value, since reduced fat absorption causes a reduction in intestinal lymph flow.70,79 In refractory cases, treatment with a long-acting somatostatin analog has shown promise, although the mechanism of action is unclear.117 Somatostatin may decrease protein loss, reduce intestinal blood flow, inhibit triglyceride resorption, and reduce lymph flow. It may directly affect lymphatic vessels or have an effect outside the gut.117 There may be a subset of patients who have increased tissue or plasma fibrinolytic activity, which may cause gastrointestinal bleeding from diffuse areas of hyperfibrinolysis, and who may respond to antiplasmin therapy.118 Surgical resection of a localized segment of intestine may be successful, and lymphaticovenous anastomosis is occasionally used.70,79 Cystic Renal Lymphangiectasia

Cystic renal lymphangiectasia is characterized by dilated endothelial-lined spaces, primarily in the cortex with sparing of the medulla. Glomeruli and tubules are generally normal in appearance.119,120 Diagnosis

Only 11 reports of cystic renal lymphangiectasia are found in the literature, eight males and three females.120 The majority of affected individuals were diagnosed early in life during evaluation of a renal mass. Age at diagnosis has ranged from 1 day to 10 years. Symptoms prompting evaluation have included abdominal mass or distension, hypertension, ascites, hematuria, proteinuria, nephromegaly, pyelonephritis, and renal insufficiency.120 The disease may be unilateral or bilateral, but extrarenal involvement is rare. Sonography may demonstrate a discrete mass with or without septations, multiple renal cortical cysts, or diffusely echogenic kidneys with decreased corticomedullary differentiation.120 Renal biopsy reveals dilated endothelial-lined spaces, primarily in the cortex with sparing of the medulla. Mild dilation of accompanying interlobar arteries and veins may be present. Glomeruli and tubules are generally normal in appearance.119,120 Unfortunately, biopsy may be complicated by persistent lymphatic leak. The differential diagnosis includes cystic renal dysplasia with or without urinary tract anomalies, cystic neoplasia, localized cystic disease, hereditary (autosomal dominant or recessive) polycystic disease, and familial renal lymphangiomatosis.120 Renal cystic

Lymphatic System

lymphangiectasia is distinct from lymphangiomatosis, which is characterized by osseous or multiorgan involvement, often with poor prognosis. Etiology and Distribution

This disorder is localized to the renal cortex and rarely demonstrates extrarenal involvement. Etiology is not known. Prognosis, Prevention, and Treatment

The prognosis for children is promising without specific therapy. In some individuals, conservative treatment with antihypertensives has resulted in stabilization or even amelioration of symptoms. In others, a surgical approach with unilateral nephrectomy has been chosen, with good outcomes. There are no reports of progressive renal insufficiency. Adult cases are often discovered coincidentally at autopsy. Chylous Diseases

Dietary fats, in the form of long-chain triglycerides, are transformed into chylomicra and very low density lipoproteins. These are secreted into the intestinal lacteals and lymphatics and transported to the cisterna chyli and then to the thoracic duct as chyle. Chyle is alkaline and bacteriostatic, a characteristic probably due to its high fatty acid content, with a specific gravity invariably greater than 1.012. It has a total fat content greater than 1000 mg/dL, with elevated concentrations of chylomicra and triglycerides, plus fat-soluble vitamins. Protein content varies from 2.2 to 6 g/dL, and electrolyte composition is similar to that of serum. Of the cellular elements, lymphocytes (the T-cell type) predominate.80,81 Between 1.5 and 2.5 liters of chyle empty into the venous system daily. Both volume and flow rate vary considerably, depending on the type of meal and its fat content in particular. Ingestion of fat increases lymph flow in the thoracic duct to two to 10 times the resting level, for several hours. Ingestion of water also increases chyle flow, whereas ingestion of proteins or carbohydrates has little effect.81 Starvation reduces flow to the merest trickle of clear lymph. The flow of chyle also depends on contraction of the thoracic duct wall, adjacent arterial pulsations, and intrathoracic and intra-abdominal pressure changes.81 Diagnosis

Chylous complications of general lymphatic dysplasia affect many areas of the body, particularly the lower limbs where chylous vesicles complicate early onset of lymphedema. The underlying lymphatic anomaly is usually bilateral hyperplasia with abnormalities of the thoracic duct or megalymphatics.1 There may be associated involvement of the perineum and genitalia, including chylocele. Chyle may enter the urinary tract at various levels, generally by fistulous communication with the urethra, bladder, or renal pelvis. Megalymphatics are frequently the underlying pathology. Chylopericardium is rare and generally leads to cardiac tamponade.1 The remainder of this discussion concentrates on chylothorax and chylous ascites. The symptoms and signs of chylothorax are those encountered with a comparable pleural effusion of any etiology. The presence of chyle is suspected only after thoracocentesis. Respiratory insufficiency is the chief complaint.80 Fifty percent of infants with neonatal chylothorax have symptoms within the first 24 hours; 75% have symptoms by the end of the first week.80,81 The effusion is initially serous and assumes its typical chylous

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appearance only after milk feedings have commenced. Pleuritic chest pain and high fever are rare, because chyle is not irritating to the pleural surface.81 Cyanosis, absence of fever, increased respiratory rate, and dullness to percussion of the lungs are characteristic findings. The metabolic effects of chylothorax are a serious threat to life and are proportional to the duration and volume of lymph drainage. Substantial loss of proteins, fats, electrolytes, bicarbonate, fat-soluble vitamins, and lymphocytes leads to malnutrition, metabolic acidosis, and compromised immunologic status.80,81 The diagnosis of chylothorax depends on accurate assessment of clinical features, presence of a pleural effusion on chest radiographs, and demonstration of chyle in pleural fluid obtained by thoracocentesis.80 Milky or creamy pleural fluid is considered to be diagnostic; however, confirmation can be obtained by analysis of the fluid’s composition. Computed tomography scans may demonstrate pleural thickening.81 An alternative diagnostic method involves ingestion of radiolabeled triglyceride (131I-triolein). Samples of pleural fluid collected within 46 hours of administration that demonstrate a high level of radioactivity confirm the presence of chylothorax.81 Lymphoscintigraphy, using 99Tc human serum albumin or dextran by intradermal injection into the web space between the toes, or lymphangiography may demonstrate obstruction to the cisterna chyli and chylous reflux in both chylothorax and chylous ascites.80 Tumors, particularly lymphomas, are responsible for over 50% of chylothoraces and are the most common cause in adults.81 Hence, a nontraumatic chylothorax in an adult demands a careful search for malignancy. Chylothorax may develop when a tumor compresses or directly invades the thoracic duct or when the lymphatics are obliterated following radiotherapy.81 The second leading cause of chylothorax is trauma, which accounts for approximately 25% of cases. Surgical trauma is more common than nonsurgical trauma. The thoracic duct can be injured during cardiovascular surgery, corrective surgery for congenital heart disease or tracheoesophageal fistula, coronary bypass grafting, Bochdalek herniorrhaphy, esophageal resection, esophagoscopy, stellate ganglion blockade, thoracic sympathectomy, radical neck dissection, and high translumbar aortography, and following use of the superior vena cava and subclavian vein for central hyperalimentation or hemodynamic monitoring.81 Nonsurgical trauma includes penetrating injuries to the thoracic duct due to gunshot or stab wounds and nonpenetrating injuries following sudden hyperextension of the spine, fracture of vertebrae or ribs, and blast and crush injuries. Less impressive trauma includes weight-lifting, straining, severe bouts of coughing or vomiting, and vigorous stretching while yawning.81 Rare causes, accounting for less than 10% of cases, include filariasis, lymph node enlargement, tuberculosis, amyloidosis, sarcoidosis, cirrhosis, congestive cardiac failure, aneurysm of the thoracic aorta, tuberous sclerosis, and pulmonary lymphangioleiomyomatosis. Occasionally, the thoracic duct is involved in a lymphangiomatous malformation, either alone or as part of generalized lymphangiomatosis.83,84 The reader is referred to the section on lymphangiomatosis for further details. So-called idiopathic chylothorax accounts for about 15% of cases, usually of neonatal onset. Causal hypotheses include increased fetal venous pressure during delivery, leading to rupture of a weak thoracic duct. Chylothorax has been seen in association with tracheoesophageal fistula, hemangiomas, and cutis marmorata telangiectatica congenita.80,85,86 This latter condition is comprised of dilated capillaries, veins, and lymphatics in both the dermis and the

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subcutaneous tissues. Concomitant malformations of venous and lymphatic systems are also seen in Klippel-Trenauney-Weber syndrome. Chylothorax has been described in infants with Down syndrome, although malformations of the major lymphatic vessels have not been substantiated.87–89 Abnormalities of the thoracic duct, accompanied by chylothorax, have been noted in Noonan syndrome.30,87 Chylothorax has also been described in cardio-faciocutaneous syndrome121 and Adams-Oliver syndrome.122 Lee and Young49 described two siblings with chylous ascites and lymphedema secondary to abnormalities of the thoracic duct, while Williams and Josephson123 reported an Amish brother and sister with congenital chylothorax. Further details of associated syndromes are given in Table 4-1. Successful ultrasonographic prenatal diagnosis of chylothorax has been reported on several occasions.90 Antenatal thoracocentesis allows expansion of the lungs, but this is not sustained, and fluid reaccumulates within hours. Placement of a pleuroamniotic shunt may improve morbidity and mortality.91 Successful intrapleural sclerotherapy has been reported in utero.124 Chylous ascites results from effusion or leakage of lymphatic fluid from the mesentery, cisterna chyli, or lower thoracic duct into the peritoneum and generally presents with abdominal distension.82 Intestinal lymphangiectasia is considered a variant in which proteins, lymphocytes, and immunoglobulins are lost into the gastrointestinal tract, and fat is malabsorbed. Clinical features are discussed in an earlier section. Chylous ascites may form because of compression of the retroperitoneal lymphatics by glandular enlargement, tumor formation, or abdominal adhesions. In the developed world, the most common causes are malignancy and cirrhosis, which account for two-thirds of all cases. In contrast, infectious etiologies such as tuberculosis and filariasis account for the majority of cases in developing countries.125 In children, 50% of cases are caused by congenital abnormalities of the lymphatic system.80 Etiology and Distribution

The embryology of the lymphatic system is reviewed in the chapter introduction. Various malformations of the lymphatic system lead to chylothorax, including absence or atresia of the thoracic duct, multiple dilated lymphatic channels with failure of the peripheral channels to communicate with the central lymphatics, and multiple fistulas between the thoracic duct and the pleural space due to failure of communication of multiple segmental components of the embryonic duct.92,93 Following obstruction of the thoracic duct, chyle refluxes by two routes, either through the left posterior intercostal lymphatics to the parietal pleura or through the bronchomediastinal vessels to the pulmonary parenchyma and visceral pleura. Subsequently, it leaks from the parietal or visceral pleural lymphatics into the pleural cavities.94 Interestingly, ligation of the thoracic duct in both humans or experimental animals fails to produce chylothorax because of extensive collateral vessels and lymphaticovenous anastomoses.81 Chylous ascites occurs with fistulous communication between the peritoneum and hypoplastic lymphatics or megalymphatics, or obstruction of the cisterna chyli, with retrograde chylous reflux into the peritoneal space and the lumen of the small intestine.1,80 When atresia of the cisterna chyli is associated with aplasia/ hypoplasia of lymph nodes and lymphatic vessels of the small bowel and mesentery, intestinal lymphangiectasia and proteinlosing enteropathy are not seen.82 Thoracic duct obstruction, with resultant dilation of mediastinal and pleural lymphatics, has been incriminated as a cause of

chylothorax in the dog, notably the Afghan hound.95 Congenital obstruction of the thoracic duct has been postulated, yet the affected dogs are middle-aged or older.95 Both chylothorax and chylous ascites are rare conditions. Between 1955 and 1982, only 16 primary cases were reported by the Mayo Clinic. The male to female ratio is 2:1.80,96 Sixty percent of cases of chylothorax are right-sided, probably because the thoracic duct travels on the right side of the vertebral bodies during most of its thoracic course. Nix et al.,97 reviewing 123 cases of chylothorax, noted that only 10% of cases were due to intrinsic lymphatic abnormalities. They also reviewed 146 cases of chylous ascites and found lymphatic malformations in 22% of the total.97 Prognosis, Prevention, and Treatment

In up to 75% of cases of chylothorax or chylous ascites, the symptoms resolve or stabilize with conservative treatment.80 In the group with neonatal onset, irrespective of the etiology, mortality is up to 50%, with death related to malnutrition and secondary infection. Poor prognosis is associated with delivery prior to 35 weeks gestation, abnormal karyotype, presence of other congenital anomalies, or hydrops.81,126 The first principle of management of chylothorax is to maintain adequate nutrition and minimize chyle formation. Modern hyperalimentation techniques, combined with meticulous replacement of water and electrolytes, can, to a large extent, prevent the serious metabolic consequences of prolonged loss of chyle due to repeated thoracocentesis or chest tube drainage. The substitution of dietary fat with medium-chain triglycerides, which are absorbed directly into the portal venous system, causes a dramatic reduction in chyle flow. Fat-soluble vitamin supplementation is necessary. Adequate drainage of the pleural space prevents cardiorespiratory embarrassment, and a fully expanded lung may promote pleural symphysis. If the chylothorax persists after one or two thoracocenteses, a chest tube with slight negative pressure is inserted, and total parenteral nutrition should replace oral diet. In an attempt to maintain nutrition, chyle removed by thoracocentesis can be returned orally, per rectum, or by intravenous infusion.80,98 Use of a somatostatin analog to reduce thoracic duct flow has been successful in one patient.127 If none of these procedures controls the effusion, surgical exploration of the major lymphatic vessels, pleurodesis, or both should be performed.128 It is not clear whether pleurodesis, by decortication, counters the chylous effusion by obliterating the pleural space or by removing the primary cause— an abnormal pleura.71 Conservative management in the treatment of chylous ascites should be given a fair trial before surgery is considered. Treatment should begin with several therapeutic paracenteses, a high-protein, low-fat diet with medium-chain triglycerides, and added fatsoluble and water-soluble vitamins.49,80 After 2 weeks, a drain should be inserted and maintained with slight negative pressure. The next step should include total parenteral nutrition. Surgery may benefit patients with postoperative, neoplastic, and congenital causes.125 Peritoneovenous anastomosis has been performed with mixed results.49,80 The only treatment for chylopericardium is partial pericardiectomy, with or without ligation of the thoracic duct. Generalized Lymphatic Dysplasia

Although generalized lymphatic dysplasia is, by definition, a combination of lymphedema, intestinal lymphangiectasia, and chylous disorders, which have been reviewed individually, there

Lymphatic System

are some points concerning this entity that should be discussed in their own right. There are few reports of documented generalized lymphatic dysplasia in the literature.80 Lymphedema is usually present at birth but may develop later. The presenting symptom is often shortness of breath secondary to chylothorax, with onset in childhood. In one 19-year-old, the onset was heralded by episodes of scrotal swelling and groin pain, associated with shaking, chills, and fever. The overlap with generalized lymphangiomatosis is significant. Chang et al.99 described one case with lymphangiomatous tissue in the posterior mediastinum and peritoneum, in addition to generalized lymphatic dilation in the internal organs. Smeltzer et al.80 reported a patient suspected of having lymphangiomas of the femur and clavicle, leading to pathologic fracture, who, at autopsy, was found to have probable lymphangiomas in the spleen. Chang et al.99 have tried to distinguish between the terms lymphangioma and lymphangiectasis. They define lymphangioma as a primary truly dysplastic process, whereas lymphangiectasis is a secondary dilation of preexisting, normally developed lymphatic vessels, that is, a deformation or disruption. The distinction is difficult to make clinically. After reviewing the literature, Smeltzer et al.80 believe the pathogenic mechanism begins with a congenital malformation of the thoracic duct, the cisterna chyli, or the connection between normally developing peripheral lymphatic vessels and central vessels. This initial malformation reduces the normal flow of lymph from the limbs. The peripheral lymphatics, having an increasing load, dilate, form collaterals, and often rupture, leaking chyle into the pleural and peritoneal cavities or into the limbs. Once the effusion begins, the pressure gradient rarely allows it to stop spontaneously, and it often persists until the patient dies from respiratory insufficiency. Autopsies of six children with generalized lymphatic abnormality revealed dilation of lymphatics throughout the body. The thoracic duct was normal in two patients, obstructed in two, atrophied in one, and not seen in one. Only two of the eight patients were female. However, in view of the small number of cases, little significance can be attached to this ratio. Most individuals have died, and the condition of the survivors has worsened after the initial diagnosis. The consistency of findings, both during the patient’s life and at autopsy, has led Smeltzer et al.80 to suggest the following treatment plan. First, the diagnosis should be made on the basis of history and physical examination, with thoracocentesis or paracentesis to document the chylous nature of the effusion. Conservative treatment, consisting of a high-protein, medium-chain triglyceride diet with vitamin supplements, should be started, with several repeat taps during the first 2 weeks. If no improvement is seen, total parenteral nutrition should be instituted with no oral feedings, accompanied by repeated aspirations of the effusions. Surgery, with blind ligation of the thoracic duct and pleural decortication, must be considered a last resort. References (Primary Lymphatic Anomalies) 1. Kinmonth JB: The Lymphatics. Surgery, Lymphography and Diseases of the Chyle and Lymph Systems. Edward Arnold, London, 1982. 2. Kobayashi MR, Miller TA: Lymphedema. Clin Plast Surg 14:303, 1987. 3. Wolfe JHN: The prognosis and possible cause of primary lymphedema. Ann R Coll Surg Engl 66:251, 1984. 4. Browse NL: The diagnosis and management of primary lymphedema. J Vasc Surg 3:181, 1986. 5. Browse NL, Stewart G: Lymphedema: pathophysiology and classification. J Cardiovasc Surg 26:91, 1985.

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6. Gough MH: Primary lymphedema: clinical and lymphographic studies. Br J Surg 53:917, 1966. 7. Fyfe NCM, Wolfe JHN, Kinmonth JB: ‘‘Die-back’’ in primary lymphedema—lymphographic and clinical correlations. Lymphology 15:66, 1982. 8. Kinmonth JB, Eustace PW: Lymph nodes and vessels in primary lymphedema. Their relative importance in aetiology. Ann R Coll Surg Engl 58:278, 1976. 9. Lewis M, Kallenbach J, Zaltzman M, et al.: Pleurectomy in the management of massive pleural effusion associated with primary lymphedema: demonstration of abnormal pleural lymphatics. Thorax 38:637, 1983. 10. Rada IO, Tudose N, Bibescu Roxin R: Lympho-nodal fibrosclerosis in primary lymphedema. Part two: consequences of lympho-nodal fibrosclerosis on lymph stasis in primary lymphedema. Lymphology 16:223, 1983. 11. Tudose N, Rada IO: Structural and ultrastructural changes of lymph nodes in primary lymphoedema. Morphol Embryol (Bucur) 30:29, 1984. 12. Stone EJ, Hugo NE: Lymphedema. Surg Gynecol Obstet 135:625, 1972. 13. Intenzo CM, Desai AG, Kim SS, et al.: Lymphedema of the lower extremities: evaluation by microcolloidal imaging. Clin Nucl Med 14: 107, 1989. 14. Dan SJ, Efremidis SC, Tey PH, et al.: Primary lymphedema: four cases with vessel and node findings. Mt Sinai J Med 50:69, 1983. 15. Corbett CRR, Dale RF, Coltart DJ, et al.: Congenital heart disease in patients with primary lymphedemas. Lymphology 15:85, 1982. 16. Lewis JM, Wald ER: Lymphedema praecox. J Pediatr 104:641, 1984. 17. Kostler E: Das trophodem (Nonne-Milroy-Meige). Dermatol Monatsschr 162:465, 1976. 18. Kajii T, Tsukahara M: Congenital lymphedema in two siblings. Jpn J Hum Genet 30:31, 1985. 19. Esterly JR: Congenital hereditary lymphedema. J Med Genet 2:93, 1965. 20. Avasthey P, Roy SB: Primary pulmonary hypertension, cerebrovascular malformation, and lymphedema feet in a family. Br Heart J 30:769, 1968. 21. Bloom D: Hereditary lymphedema (Nonne-Milroy-Meige). Report of a family with hereditary lymphedema associated with ptosis of the eyelids in several generations. N Y J Med 41:856, 1941. 22. Leung AKC: Dominantly inherited syndrome of microcephaly and congenital lymphedema. Clin Genet 27:611, 1985. 23. Crowe CA, Dickerman LH: Brief clinical report: a genetic association between microcephaly and lymphedema. Am J Med Genet 24:131, 1986. 24. Figueroa AA, Pruzanski S, Rollnick BR: Meige disease (familial lymphedema praecox) and cleft palate: report of a family and review of the literature. Cleft Palate J 20:151, 1983. 25. Falls HF, Kertesz ED: A new syndrome combining pterygium colli with developmental anomalies of the eyelids and lymphatics of the lower extremities. Trans Am Ophthalmol Soc 62:248, 1964. 26. Robinow M, Johnson GF, Verhagen AD: Distichiasis-Lymphedema. A hereditary syndrome of multiple congenital defects. Am J Dis Child 119:343, 1970. 27. Schwartz JF, O’Brien MS, Hoffman JC: Hereditary spinal arachnoid cysts, distichiasis and lymphedema. Ann Neurol 7:340, 1980. 28. Mucke J, Hoepffner W, Scheerschmidt G, et al.: Early onset lymphoedema, recessive form: a new form of genetic lymphoedema syndrome. Eur J Pediatr 145:195, 1986. 29. Herzog DB, Logan R, Kooistra JB: The Noonan syndrome with intestinal lymphangiectasia. J Pediatr 88:270, 1976. 30. Witt DR, Hoyme HE, Zonana J, et al.: Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet 27:841, 1987. 31. Benson PF, Gough MH, Polani PE: Lymphangiography and chromosome studies in females with lymphoedema and possible ovarian dysgenesis. Arch Dis Child 40:27, 1965.

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32. Van der Putte SCJ: Lymphatic malformation in human fetuses. A study of fetuses with Turner’s syndrome or Status Bonnevie-Ullrich. Virchows Arch 376:233, 1977. 33. Vittay P, Bosze P, Gaal M, et al.: Lymph vessel defects in patients with ovarian dysgenesis. Clin Genet 18:387, 1980. 34. Wasser ST, Beyreiss K, Himmel D, et al.: Exsudative Enteropathie bei kongenitaler intestinaler Lymphangiektasie mit multiplen Skelettveranderungen. Acta Paediatr Acad Sci Hung 15:17, 1974. 35. Aagenaes O: Hereditary recurrent cholestasis with lymphoedema: two new families. Acta Paediatr Scand 63:465, 1974. 36. Dahlberg PJ, Borer WZ, Newcomer KL, et al.: Autosomal or X-linked recessive syndrome of congenital lymphedema, hypoparathyroidism, nephropathy, prolapsing mitral valve and brachytelephalangy. Am J Med Genet 16:99, 1983. 37. Nordkild P, Kromann-Andersen H, Struve-Christensen E: Yellow nail syndrome—the triad of yellow nails, lymphedema and pleural effusions. A review of the literature and a case report. Acta Med Scand 219:221, 1986. 38. Kaariainen H: Hereditary lymphedema: a new combination of lymphatic symptoms not fitting into present classifications. Clin Genet 26:254, 1984. 39. Emberger JM, Navarro M, Dejean M, et al.: Surdi-mutite, lymphoedeme des membres inferieurs et anomalies hematologiques (Leucose aigue, cytopenies) a transmission autosomique dominante. J Genet Hum 27:237, 1979. 40. Jackson BT, Kinmonth JB: Pes cavus and lymphedema. An unusual familial syndrome. J Bone Joint Surg Br 52-B:518, 1970. 41. Holmes LB, Fields JP, Zabriskie JB: Hereditary late-onset lymphedema. Pediatrics 61:575, 1978. 42. Gemignani F, Pietrini V, Tagliavini F, et al.: Fabry’s disease with familial lymphedema of the lower limbs. Case report and family study. Eur Neurol 18:84, 1979. 43. Hennekam RCM, Geerdink RA, Hamel BCJ, et al.: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet 34:593, 1989. 44. Bronspiegel N, Zelnick N, Rabinowitz H, et al.: Aplasia cutis congenita and intestinal lymphangiectasia. Am J Dis Child 139:509, 1985. 45. Murphy EA: Familial lymphatic dysplasia with intestinal lymphangiectasia. Birth Defects Orig Artic Ser VIII(2):180, 1972. 46. Vardy PA, Lebenthal E, Shwachman H: Intestinal lymphangiectasia: a reappraisal. Pediatrics 55:842, 1975. 47. Parfitt AM: Familial neonatal hypoproteinemia with exudative enteropathy and intestinal lymphangiectasis. Arch Dis Child 41:54, 1966. 48. Shani M, Theodor E, Frand M, et al.: A family with protein-losing enteropathy. Gastroenterology 66:433, 1974. 49. Lee CH, Young JR: Chylous ascites in siblings. J Pediatr 42:83, 1953. 50. Flores S, Leungas J, Arredondo-Vega F, et al.: Chylous ascites in sibs from a consanguineous marriage. Am J Med Genet 3:145, 1979. 51. Van der Putte SCJ: Congenital hereditary lymphedema in the pig. Lymphology 11:1, 1978. 52. Van der Putte SCJ: Pathogenesis of congenital hereditary lymphedema in the pig. Lymphology 11:10, 1978. 53. Patterson DF, Medway W, Luginbuhl H, et al.: Congenital hereditary lymphedema in the dog. J Med Genet 4:145, 1967. 54. Luginbuhl H, Chacko SK, Patterson DF, et al.: Congenital hereditary lymphedema in the dog. J Med Genet 4:153, 1967. 55. Morris B, Blood DC, Sidman WR, et al.: Congenital lymphatic oedema in Ayrshire cattle. Aust J Exp Biol 32:265, 1954. 56. Mulei CM, Atwell RB: Congenital lymphedema in an Ayrshire-Friesian crossbred female calf. Aust Vet J 66:227, 1989. 57. Smeltzer DM, Stickler GB, Schirger A: Primary lymphedema in children and adolescents: a follow-up study and review. Pediatrics 76:206, 1985. 58. Dale RF: The inheritance of primary lymphedema. J Med Genet 22: 274, 1985. 59. Tatnall FM, Sarkany I: Primary facial lymphedema with xanthomas. J R Soc Med 81:113, 1988. 60. Mishkel MA: Xanthomatosis and chylous lymphedema. Arch Dermatol 106:601, 1972.

61. Wells GC: Primary unilateral megalymphatic lymphedema. J R Soc Med 72:63, 1979. 62. Ostrow RS, Manias D, Mitchell AJ, et al.: Epidermodysplasia verruciformis. A case associated with primary lymphatic dysplasia, depressed cell-mediated immunity and Bowen’s disease containing human papillomavirus 16 DNA. Arch Dermatol 123:1511, 1987. 63. Kiaer T, Larsen J: Necrotizing fasciitis in congenital lymphedema. Acta Chir Scand 154:665, 1988. 64. Albornoz MA, Myers AR: Recurrent septic arthritis and Milroy’s disease. J Rheumatol 15:1726, 1988. 65. Frayha RA, Tabbara KR, Mooradian A: Transudative knee effusions in Milroy’s disease. J Rheumatol 8:670, 1981. 66. Mistilis SP, Skyring AP, Stephen DD: Intestinal lymphangiectasia. Mechanism of enteric loss of plasma-protein and fat. Lancet 1:77, 1965. 67. Waldmann TA, Steinfeld JL, Dutcher TF, et al.: The role of the gastrointestinal system in ‘‘idiopathic hypoproteinemia.’’ Gastroenterology 41:197, 1961. 68. Pomerantz M, Waldmann TA: Systemic lymphatic abnormalities associated with gastrointestinal protein loss secondary to intestinal lymphangiectasia. Gastroenterology 45:703, 1963. 69. Weiden PL, Blaese RM, Strober W, et al.: Impaired lymphocyte transformation in intestinal lymphangiectasia: evidence for at least two functionally distinct lymphocyte populations in man. J Clin Invest 51:1319, 1972. 70. McGuigan JE, Purkerson ML, Trudeau WL, et al.: Studies of the immunological defects associated with intestinal lymphangiectasia. Ann Intern Med 68:398, 1968. 71. Barrett DS, Large SR, Rees GM: Pleurectomy for chylothorax associated with intestinal lymphangiectasia. Thorax 42:557, 1987. 72. McDonagh TJ, Gueft B, Pyun K, et al.: Hypoproteinemia, chylous ascites, steatorrhea, and protein-losing enteropathy due to chronic inflammatory obstruction of major intestinal lymph vessels. Gastroenterology 48:642, 1965. 73. Fairlie NC, Nakielny R, Polacarz SV: Case report: the computed tomographic appearances of lymphangiectasia in the pelvis. Clin Radiol 39:560, 1988. 74. De Sousa JS, Guerreiro O, Cunha A, et al.: Association of nephrotic syndrome with intestinal lymphangiectasia. Arch Dis Child 43:245, 1968. 75. Madhaven T, Rupe CE: Intestinal lymphangiectasia with normal immunological function. Henry Ford Hosp Med J 18:65, 1970. 76. Asakura H, Morita A, Morishita T, et al.: Histopathological and electron microscopic studies of lymphangiectasia of the small intestine in Behcet’s disease. Gut 14:196, 1973. 77. Scott RE: Ataxia-telangiectasia. Arch Pathol 88:78, 1969. 78. Dewbury KC, Rao KS, Poll V: Prenatal ultrasound demonstration of lymphangiectasia in the mesentery of the small bowel. Br J Radiol 54:687, 1981. 79. Campbell RSF, Brobst D, Bisgard G: Intestinal lymphangiectasia in a dog. JAMA 153:1050, 1968. 80. Smeltzer DM, Stickler GB, Fleming RE: Primary lymphatic dysplasia in children: chylothorax, chylous ascites, and generalised lymphatic dysplasia. Eur J Pediatr 145:286, 1986. 81. Sassoon CS, Light RW: Chylothorax and pseudochylothorax. Clin Chest Med 6:163, 1985. 82. Warwick WJ, Holman RT, Quie PG, et al.: Chylous ascites and lymphedema. Am J Dis Child 98:317, 1959. 83. Bell KA, Simon BK: Chylothorax and lymphangiomas of bone: unusual manifestations of lymphatic disease. South Med J 71:459, 1978. 84. Morphis LG, Arcinue EL, Krause JR: Generalized lymphangioma in infancy with chylothorax. Pediatrics 46:566, 1970. 85. Harvey JG, Houlsby W, Sherman K, et al.: Congenital chylothorax: report of unique case associated with ‘‘H’’-type tracheo-oesophageal fistula. Br J Surg 66:485, 1979. 86. Pearl KN, Wilson RG: Management problem in a child with congenital marble skin and chylothorax requiring repeated drainage. Lancet 2:90, 1981.

Lymphatic System 87. Van Aerde J, Campbell AN, Smyth JA, et al.: Spontaneous chylothorax in newborns. Am J Dis Child 138:961, 1984. 88. Yoss BS, Lipsitz PJ: Chylothorax in two mongoloid infants. Clin Genet 12:357, 1977. 89. Ho NK, Leong NKY, Lim SB: Chylothorax in Down’s syndrome associated with hydrops fetalis. J Sing Paediatr Soc 31:90, 1989. 90. Meizner I, Carmi R, Bar-ziv J: Congenital chylothorax—prenatal ultrasonic diagnosis and successful postpartum management. Prenat Diagn 6:217, 1986. 91. Booth P, Nicolaides KH, Greenough A, et al.: Pleuro-amniotic shunting for fetal chylothorax. Early Hum Dev 15:365, 1987. 92. Bessone LN, Ferguson TB, Burford TH: Chylothorax. Ann Thor Surg 12:527, 1971. 93. Said DM, Rosalinas AA, Reichelderfer TE: Chylothorax in the newborn. Report of a case associated with polyhydramnios. Med Ann DC 37:536, 1968. 94. Gullane PJ, Marsh AS: Bilateral spontaneous chylothorax presenting as a neck mass. J Otolaryngol 13:255, 1984. 95. Birchard SJ, Fossum TW: Chylothorax in the dog and cat. Vet Clin North Am 17:271, 1987. 96. Yancy WS, Spock A: Spontaneous neonatal pleural effusion. J Pediatr Surg 2:313, 1967. 97. Nix JT, Albert M, Dugas JE, et al.: Chylothorax and chylous ascites. A study of 302 selected cases. Am J Gastroenterol 28:40, 1957. 98. Hesseling PB, Hoffman H: Chylothorax. A review of the literature and report of 3 cases. S Afr Med J 60:675, 1981. 99. Chang CK, Viseskul C, Opitz JM, et al.: Generalised lymphangiectasis associated with chylothorax: a possible dysplasia of the lymphatic system. Z Kinderheilkd 118:9, 1974. 100. Witte CL, Witte MH, Unger EC, et al.: Advances in imaging of lymph flow disorders. Radiographics 20:1697, 2000. 101. Fang JM, Dagenais SL, Erickson RP, et al.: Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67:1382, 2000. 102. Brice G, Mansour S, Bell R, et al.: Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet 39:478, 2002. 103. Van Balkom IDC, Alders M, Allanson J, et al.: Lymphedemalymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet 112:412, 2002. 104. Irrthum A, Devriendt K, Chitayat D, et al.: Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 72:1470, 2003. 105. Irons M, Bianchi DW, Geggel RL, et al.: Possible new autosomal recessive syndrome of lymphedema, hydroceles, atrial septal defect, and characteristic facial changes. Am J Med Genet 66:69, 1996. 106. Bull LN, Roche E, Song EJ, et al.: Mapping of the locus for cholestasislymphedema syndrome (Aagenaes syndrome) to a 6.6cM interval on chromosome 15q. Am J Hum Genet 67:994, 2000. 107. Limwongse C, Wyszynski RE, Dickerman LH, et al.: Microcephalylymphedema-chorioretinal dysplasia: a unique genetic syndrome with variable expression and possible characteristic facial appearance. Am J Med Genet 86:215, 1999. 108. Evans AL, Bell R, Brice G, et al.: Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphoedema. J Med Genet 40:697, 2003. 109. Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465, 2001. 110. Urioste M, Rodriguez JI, Barcia JM, et al.: Persistence of mullerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J Med Genet 47:494, 1993. 111. Ruocco V, Schwartz RA, Ruocco E: Lymphedema: An immunologically vulnerable site for development of neoplasms. J Am Acad Dermatol 47:124, 2002.

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112. Cohen SR, Payne DK, Tunkel RS: Lymphedema. Strategies for management. Cancer 92:980, 2001. 113. Casley-Smith JR, Morgan RG, Piller NB: Treatment of lymphedema of the arms and legs with 5,6-benzo-(a)-pyrone. N Engl J Med 329:1158, 1993. 114. Karkkainen MJ, Saaristo A, Jussila L, et al.: A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 98:12677, 2001. 115. Keberle M, Mork H, Jenett M, et al.: Computed tomography after lymphangiography in the diagnosis of intestinal lymphangiectasia with protein-losing enteropathy in Noonan’s syndrome. Eur Radiol 10: 1591, 2000. 116. Kull PA, Hess R, Craig LE, et al.: Clinical, clinicopathologic, radiographic, and ultrasonographic characteristics of intestinal lymphangiectasia in dogs: 17 cases (1996-1998). J Am Vet Med Assoc 219:197, 2001. 117. Takahashi H, Imai K: What are the objectives of treatment for intestinal lymphangiectasia? J Gastroenterol 36:137, 2001. 118. MacLean JE, Cohen E, Weinstein W: Primary intestinal and thoracic lymphangiectasia: a response to antiplasmin therapy. Pediatrics 109: 1177, 2002. 119. Simonton SC, Saltzman DA, Brennom W, et al.: Cystic renal lymphangiectasia: a distinctive clinicopathological entity in the pediatric age group. Ped Pathol Lab Med 17:293, 1997. 120. Cadnapaphornchai MA, Ford DM, Tyson RW, et al.: Cystic renal lymphangiectasia presenting as renal insufficiency in childhood. Pediatr Nephrol 15:129, 2000. 121. Chan PC, Chiu HC, Hwu WH: Spontaneous chylothorax in a case of cardio-facio-cutaneous syndrome. Clin Dysmorphol 11:297, 2002. 122. Farrell SA, Warda LJ, LaFlair P, et al.: Adams-Oliver syndrome: a case with juvenile chronic myelogenous leukemia and chylothorax. Am J Med Genet 47:1175, 1993. 123. Williams MS, Josephson KD: Unusual autosomal recessive lymphatic anomalies in two unrelated Amish families. Am J Med Genet 73:286, 1997. 124. Tanemura M, Nishikawa N, Kojima K, et al.: A case of successful fetal therapy for congenital chylothorax by intrapleural injection of OK432. Ultrasound Obstet Gynecol 18:371, 2001. 125. Cardenas A, Chopra S: Chylous ascites. Am J Gastroenterol 97:1897, 2002. 126. Dubin PJ, King IN, Gallagher PG: Congenital chylothorax. Curr Opin Pediatr 12:505, 2000. 127. Demos NJ, Kozel J, Scerbo JE: Somatostatin in the treatment of chylothorax. Chest 119:964, 2001. 128. Noel AA, Gloviczki P, Bender CE, et al.: Treatment of symptomatic primary chylous disorders. J Vasc Surg 34:785, 2001. 129. Finegold DN, Kimak MA, Lawrence EC, et al.: Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Mol Genet 15:1185, 2001.

4.2 Pulmonary Lymphangiectasia Definition

Pulmonary lymphangiectasia is the congenital dilation of the superficial lymphatics of the pleura and septa and of the intrapulmonary lymphatics in the peribronchial and perivascular adventitia. These lymphatics normally drain to the paratracheal, peribronchial, and pleuropulmonary lymph nodes. Diagnosis

Pulmonary lymphangiectasia is characterized by intercommunicating, thin-walled, endothelium-lined, fluid-filled cysts of greatly varying diameter, situated in abundant subpleural, peribronchial,

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and interlobular connective tissue.1 The pleural surface is smooth and intact but shows multiple localized areas of swelling, which are fluctuant on palpation. Minute cysts may be seen to a lesser extent in the lung substance. The lungs are bulky and firm, with clearly defined lobulation. They have the consistency of sponge rubber, are resistant to compression, and deflate slowly.2 Although the entire lung is generally affected, lobar involvement has been reported.3,25 The majority of affected individuals are stillborn or die within the first 24 hours of life.2 Liveborn individuals typically develop acute respiratory distress with tachypnea, cyanosis, subcostal retraction, and prolonged expiration very soon after birth.7 High concentrations of oxygen do not provide relief. Those who survive the newborn period often suffer attacks of chronic respiratory distress precipitated by respiratory infections, with wheezing and coughing. The signs and symptoms mimic chronic asthma. Recurrent pneumonia may be described.26 Delayed onset may be accompanied by sweating, poor feeding, hepatomegaly, peripheral edema, and other signs of congestive cardiac failure.4 Rare presentations include acute dyspnea and chest pain, resulting from pneumothorax, and pleural effusions associated with disordered lymphatic drainage, which may be ascertained by prenatal ultrasonography.5,6 In the past, pulmonary lymphangiectasia has been the domain of the pathologist, which is not surprising for a disease seen almost exclusively in stillborn infants and neonates dying in the first hours of life. Over the past few years a number of clinical reports have stressed the rather characteristic radiographic findings.2,7 In severe pulmonary lymphangiectasia, the chest radiograph generally shows large, punctate, military-like lesions distributed throughout the lungs, reticular areas of increased density that represent dilated lymphatics, Kerley B lines at the costophrenic angles, and overaeration of the lung fields, with a flattened diaphragm and a normal-sized heart. The diffuse reticular pattern, interspersed with small cystic areas, is one example of so-called honeycomb lung. In less extreme cases the radiograph shows only a diffuse congestive pattern that precludes confident diagnosis. Infants who survive may demonstrate decreased interstitial markings over time and increased hyperinflation associated with persistent patchy areas of ground-glass opacity.27 Lung biopsy is the only definitive diagnostic method. Microscopic examination reveals the presence of multiple cystic spaces and dilated channels, lined by flattened endothelial cells and supported by various amounts of fibrous connective tissue. They occur predominantly subpleurally, between the connective tissue septa of the lung, and peribronchially, in close approximation to the pulmonary vasculature, but without connection to either arteries or veins.1,8 The lung parenchyma is often diffusely atelectatic, with the exception of a few respiratory bronchioles and alveolar ducts.9 The distribution of cysts and dilated channels corresponds to the site of normal lymph vessels. The endotheliumlike lining distinguishes them from bronchiogenic cysts, which are lined by cylindrical bronchial or respiratory epithelium. Pulmonary lymphangiectasia shares some characteristics with lymphangiomatosis. However, in lymphangiectasia, the cysts are thin-walled and separated by normal connective tissue, whereas lymphangioma cysts are separated by thick, fibrous-tissue septa, in which lymph follicles and lymphocytes, islets of fat cells, and smooth muscle fibers may be found.9 Histologically, congenital lymphangiectasia must be differentiated from the dilated but normal lymphatics seen in hyaline membrane disease and hydrops

fetalis, from cystic disease of bronchial origin, and from interstitial emphysema. Peripheral pulmonary cystic disease is rarely fatal in the newborn period, the distribution of the cysts is somewhat different, and they are air-filled rather than fluid-filled, with a cuboidal epithelial rather than an endothelial lining. Radiographically, this disease process can generally be differentiated from the more common causes of respiratory distress in newborns, such as hyaline membrane disease, by lack of ground-glass appearance, and by the presence of overaeration of the lung fields. Transient tachypnea of the newborn may be distinguished by the presence of cardiomegaly and engorged pulmonary vasculature rather than a reticulonodular pulmonary interstitial pattern.10 Pulmonary lymphangiectasia does closely resemble ‘‘aspiration syndrome’’ and infectious pneumonitis in the newborn; however, Kerley B lines are not seen in the latter two conditions.10 Certain features are common to both pulmonary lymphangiectasia and Wilson-Mikity syndrome, although the latter is more likely to be found in premature infants, with onset after the 1st week of life, in association with maternal hemorrhage. Chest radiographs are quite similar, particularly in the early stages of Wilson-Mikity syndrome.11 The differential diagnosis also includes pneumocystis carinii pneumonia, Hamman-Rich syndrome, and adenomatous dysplasia. Between one-third and one-half of all cases are associated with congenital heart defects, particularly total anomalous pulmonary venous drainage, hypoplastic left heart syndrome, and premature closure of the foramen ovale.1,4,12–14 Intrauterine obstruction to pulmonary venous flow caused by these cardiac anomalies, or blind-ending common pulmonary vein, may increase pulmonary venous pressure, leading to lymphatic dilation.15 It is unclear whether hemodynamic factors are solely responsible for dilated lymphatic channels or whether there is a coexistent congenital lymphatic malformation. Factors in favor of a coexistent lymphatic malformation include absence of arterialization of the pulmonary veins, normally found when increased pulmonary venous pressure occurs secondary to acquired cardiac disease, such as mitral stenosis, and lack of pulmonary lymphangiectasia in many cases of obstructed pulmonary venous return.13 Pulmonary lymphangiectasia and complex congenital heart disease have been found in combination with asplenia and Noonan syndrome.4,16,17 Single cases have been reported with omphalocele, malrotation of the intestine, cretinism, arachnodactyly, trisomy 13, ureterovesical obstruction, Ehlers-Danlos syndrome, ichthyosis, cystic fibrosis, cystic hyperplasia of the bile ducts, and diaphragmatic hernia through the foramen of Bochdalek.4,14,18 Four cases have been associated with polycystic kidney disease.14 One infant born to a woman with phenylketonuria had pulmonary lymphangiectasia, hypoplastic left heart, and microcephaly.19 Etiology and Distribution

The lymphatics first grow into the lung bud in week 9 of intrauterine life. They rapidly and extensively invade the whole developing organ so that, by the end of week 14, the subpleural lymphatic plexus is well-developed.8 At the 12–16 week stage, large lymphatics, situated in the connective tissue, divide the pulmonary parenchyma into fairly distinct lobules. The lymphatics are so large in comparison to the size of the whole organ that there is a reversal of the normal tissue proportions. Normally, by weeks 18–20, the lobulations become less prominent, the connective tissue diminishes in amount, and the lymphatics become much narrower.8 Congenital pulmonary lymphangiectasia probably represents continued growth of the lung, with the tissue elements maintaining

Lymphatic System

their 12–16 week proportions. This accounts for normally developed parenchyma and grossly dilated lymphatic vessels with only slightly hypertrophied walls.8 Giammalvo, a proponent of the centripetal theory of lymphatic embryology, thought that cystic dilation of the lymphatics resulted from failure of or delay in linkage of isolated lymphatic spaces.20 Laurence infers that, if this were the explanation, cysts would probably be confined to the peripheral portions of the lungs where fusion occurs last, whereas, in fact, the distribution is diffuse and more in keeping with Laurence’s developmental arrest theory.8 Noonan and colleagues have classified pulmonary lymphangiectasia into three groups.1 In group 1, the dilated pulmonary lymphatics are part of a generalized form of lymphangiectasia, with coexisting intestinal lymphangiectasia, peripheral lymphedema, and dilated lymphatics of the lung, heart, pancreas, mesentery, and mediastinum.9,21–23 Pulmonary involvement in this group is less severe and is often associated with a much better prognosis. Group 2 includes those cases with congenital heart disease and obstruction to pulmonary venous flow mentioned previously. Group 3 comprises patients with a primary developmental defect of the lung lymphatics. This group clearly forms the majority and is associated with the worst prognosis. Since the first case of pulmonary lymphangiectasia was reported in 1856 by Virchow, over 100 cases have been described.13 No particular racial or ethnic predilection is apparent, but there is a fairly striking sex discrepancy, with a male to female ratio of 2:1.4,11,14 Two sibs with isolated pulmonary lymphangiectasia have been reported, and two other sib pairs, in whom pulmonary lymphangiectasia is associated with total anomalous pulmonary venous drainage, are described.4,24 Several families have been reported in which multiple siblings have nonimmune hydrops fetalis, chylothorax, pulmonary lymphangiectasia, distal lymphedema, and swelling of the face, a phenotype similar to Hennekam syndrome (see Table 4-1).28,29 Autosomal recessive inheritance seems likely. Prognosis, Prevention, and Treatment

The majority of affected individuals are stillborn or die within the first 24 hours of life. In series analyzed by France and Brown and by Fronstin et al., less than one-quarter of patients survived the 1st week.4,11 However, long-term survival is reported in a few individuals.1 Lobar pulmonary lymphangiectasia is cured by resection of the affected lobe(s).3,25 In the majority, treatment is merely palliative, with digoxin and diuretics given for congestive cardiac failure. Improvement occasionally follows atrial balloon septostomy in total anomalous pulmonary venous drainage. References (Pulmonary Lymphangiectasia) 1. Noonan JA, Walters LR, Reeves JT: Congenital pulmonary lymphangiectasis. Am J Dis Child 120:314, 1970. 2. Javett SN, Webster I, Braudo JL: Congenital dilatation of the pulmonary lymphatics. Pediatrics 31:416, 1963. 3. Wagenaar SS, Swierenga J, Wagenvoort CA: Late presentation of primary pulmonary lymphangiectasis. Thorax 33:791, 1978. 4. France NE, Brown RJK: Congenital pulmonary lymphangiectasis: report of 11 examples with special reference to cardiovascular findings. Arch Dis Child 46:528, 1971. 5. Siegal A, Katsenstein M, Wolach B: Neonatal pneumothorax, a rare complication of pulmonary cystic lymphangiectasis. Eur J Respir Dis 66:153, 1985. 6. Wilson RH, Duncan A, Hume R, et al.: Prenatal pleural effusion associated with congenital pulmonary lymphangiectasia. Prenat Diagn 5:73, 1985.

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7. Arkoff RS: Congenital pulmonary lymphangiectasis. Calif Med 109:464, 1968. 8. Laurence KM: Congenital pulmonary cystic lymphangiectasis. J Pathol Bacteriol 70:325, 1955. 9. Frank JF, Piper PG: Congenital pulmonary cystic lymphangiectasis. JAMA 171:1094, 1959. 10. Smith PL: Radiologic seminar CXCV: pulmonary lymphangiectasia. An uncommon cause of respiratory distress in the newborn. J Miss State Med Assoc 20:225, 1979. 11. Fronstin MH, Hooper GS, Besse BE, et al.: Congenital pulmonary cystic lymphangiectasis. Am J Dis Child 114:330, 1967. 12. Shortland-Webb WR, Tozer RA, Cameron AH: Intra-uterine closure of the atrial septum. J Clin Pathol 19:549, 1966. 13. Moerman PL, Van Dijck H, Lauweryns JM, et al.: Premature closure of the foramen ovale and congenital pulmonary cystic lymphangiectasis in aortic valve atresia or in severe aortic valve stenosis. Am J Cardiol 57:703, 1986. 14. Felman AH, Rhatigan RM, Pierson KK: Pulmonary lymphangiectasia: observation in 17 patients and proposed classification. Am J Radiol 116: 548, 1972. 15. Rywlin AM, Fojaco RM: Congenital pulmonary lymphangiectasis associated with a blind common pulmonary vein. Pediatrics 41:931, 1968. 16. Esterly JR, Oppenheimer EH: Lymphangiectasis and other pulmonary lesions in the asplenia syndrome. Arch Pathol 90:553, 1970. 17. Witt DR, Hoyme HE, Zonana J, et al.: Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet 27:841, 1987. 18. Liew SH: A case of congenital pulmonary lymphangiectasis. Med J Malaysia 28:293, 1974. 19. Huntley CC, Stevenson RE: Maternal phenylketonuria. Course of two pregnancies. Obstet Gynecol 34:694, 1969. 20. Giammalvo JT: Congenital lymphangiomatosis of the lung: a form of cystic disease. Lab Invest 4:450, 1955. 21. Mann TP: Hemihypertrophy left side of body. Congenital lymphatic oedema of left arm. Radiological enlargement of heart shadow. Proc R Soc Med 48:12, 1955. 22. McKendry JBJ, Lindsay WK, Gerstein MC: Congenital defects of the lymphatics in infancy. Pediatrics 19:21, 1957. 23. Ekelund H, Palmstierna S, Ostberg G: Congenital pulmonary lymphangiectasis. Acta Paediatr Scand 55:121, 1966. 24. Scott-Emuakpor AB, Warren ST, Kapur S, et al.: Familial occurrence of congenital pulmonary lymphangiectasis. Am J Dis Child 135:532, 1981. 25. Rettwitz-Volk W, Schlosser R, Ahrens P, et al.: Congenital unilobar lymphangiectasis. Pediatr Pulmonol 27:290, 1999. 26. Bouchard S, Di Lorenzo M, Youssef S, et al.: Pulmonary lymphangiectasia revisited. J Pediatr Surg 35:796, 2000. 27. Chung CJ, Fordham LA, Barker P, et al.: Children with congenital pulmonary lymphangiectasia: after infancy. Am J Roentgenol 173:1583, 1999. 28. Njolstad PR, Reigstad H, Westby J, et al.: Familial non-immune hydrops fetalis and congenital pulmonary lymphangiectasia. Eur J Pediatr 157:498, 1998. 29. Jacquemont S, Barbarot S, Boceno M, et al.: Familial congenital pulmonary lymphangiectasia, non-immune hydrops fetalis, facial and lower limb lymphedema: confirmation of Njolstad’s report. Am J Med Genet 93:264, 2000.

4.3 Fetal Cystic Hygroma Definition

Fetal cystic hygroma is a single or multiloculated fluid-filled cavity, most often in the posterior nuchal region, caused by failure

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Fig. 4-7. Large fetal cystic hygroma in a fetus (18 weeks gestation with Turner syndrome [45,X]). (Courtesy of Dr. Will Blackburn, Fairhope, AL.)

of or delay in jugular lymphaticovenous communication (Fig. 4-7). The term fetal cystic hygroma is used here to distinguish jugular lymphatic obstruction from cystic lymphangioma, which is also designated by some as cystic hygroma or giant cystic hygroma (see Section 4.4). Diagnosis

Fetal cystic hygromas (FCH) are generally bilateral, thin-walled, unilocular or multilocular, fluid-filled cavities in the posterior aspect of the neck.1 They may be asymmetric or symmetric.1–3 In most cases, the cavities are subdivided into a variable number of compartments by incomplete septa. They are lined by smooth endothelium and contain turbid light-brown fluid. The cavities may extend posteriorly from the upper part of the occipital bone to the level of the seventh cervical vertebra or scapular area, medially to beneath the sternocleidomastoid muscle, and rarely into the axilla or anterior chest wall.4 They are found superficial to the musculature of the neck, with a deep connection to the proximal part of the internal jugular vein.2 Dilated lymphatic vessels are often found in the walls of the cavity.5,6 There may be associated serpiginous, or multilocular, intradermal fluid collections in the skin and subcutaneous tissues of the thorax and abdomen.7 Some cavities are continuous, with intricate systems of irregular lymph channels, extending into the edematous connective tissue around adjacent anatomic structures, while others are well-demarcated.2 Absence of the lymphaticovenous communication near the jugulosubclavian junction, with blind-ending thoracic duct, paratracheal, and internal mammary lymph trunks, is described.2 Fetal cystic hygromas are frequently reported in association with abnormalities of the major lymph trunks. Aplasia, hypoplasia, or dilation of the lymphatic channels leads to peripheral edema and pleural, pericardial, and peritoneal effusions.1,2,6 Generalized hydrops accompanies 60–90% of FCH cases.1,4,8,9 Fetal cystic hygromas can be diagnosed reliably by ultrasound.8 The posterolateral position and cystic appearance are

characteristic (Fig. 4-8). Larger FCH are frequently divided by random, incomplete septa. They often have a dense midline septum, which represents the nuchal ligament and provides a useful landmark to differentiate FCH from other craniocervical masses. Maternal serum or amniotic fluid alpha-fetoprotein estimation has been used to aid diagnosis. However, the concentration of alphafetoprotein is inconsistent and adds little to the sonographic findings.8,10 Alpha-fetoprotein concentration in hygroma fluid is often markedly elevated.8 Transvaginal ultrasonography enables very early detection of FCH. Certain sonographic features help to differentiate FCH from other craniocervical masses, for example, encephalocele or other neural tube defects, cystic teratoma, twin sac of a blighted ovum, or nuchal edema. These features include an intact skull and spinal column, the lack of a solid component to the mass, a constant position of the mass relative to the fetal head, and cysts and septa.8 Microscopic appearance of FCH is characterized by dilated endothelium-lined spaces filled with serous fluid and focal and interstitial lymphoid aggregates.2 The tissues lining the cysts may be edematous, and distinct lymphatic channels are often observed.6,11 Blood vessels and nerves course within the thin septa separating the cysts. These features contrast with those observed in lymphangiomas removed from infants and children, in which lymphoid follicles and bundles of smooth muscle are regularly found in the cyst walls. Fetal cystic hygroma is a nonspecific malformation found in a number of unrelated conditions, the most common of which is Turner syndrome (45,X). Between 50% and 75% of all cases are cytogenetically abnormal.9,12,13 Of these, 40–80% are 45,X, while the majority of the remainder are autosomal trisomies.3,8,10,11,15 Within the group that is chromosomally normal are a number of single-gene disorders and patterns of malformations resulting from in utero exposure to known teratogens.29,33,35–46 A complete list is given in Table 4-2 on pp. 166–167. Congenital heart defects are found in association with FCH. In Turner syndrome, a spectrum of cardiac defects occurs that is

Lymphatic System

Fig. 4-8. Transverse sonogram showing a fetal cystic hygroma with characteristic midline septum. The cystic hygroma is slightly larger than the fetal head. P, placenta; CH, cystic hygroma; S, septum; FH, fetal head. (Reprinted with permission from Chervenak FA, et al.: N Engl J Med 309:822, 1983.8)

limited, almost exclusively, to those associated with decreased left heart blood flow, including coarctation of the aorta, hypoplastic left heart, aortic atresia, aortic valve stenosis, and bicuspid aortic valve.15,16 Different cardiac defects have been described when FCH is associated with trisomy 13 (double outlet right ventricle and agenesis of the semilunar valves) and trisomy 21 (abnormality of the atrioventricular orifice or valves).19 Septal defects, pulmonary valvular stenosis, and hypoplastic left heart have been reported with FCH in Noonan syndrome.36 Other malformations observed in rare instances include hydronephrosis, double ureter, horseshoe kidney, bilateral renal agenesis, two vessel cord, intrauterine growth retardation, and polysplenia syndrome.1,4,11 Etiology and Distribution

The jugular lymphatic sacs develop lateral to the internal jugular vein, beneath the sternocleidomastoid muscle, and extend to the posterior triangle of the neck. The right jugular lymphatic sac will become the right lymphatic duct, providing lymphatic drainage for the right side of the head and neck, the right upper extremity, both lungs, the heart, and the diaphragm. The left jugular lymphatic sac, after connecting with other lymphatic primordia, will become the thoracic duct, which serves as the common lymph trunk draining all other parts of the body. Normally, the two jugular lymphatic sacs drain into their respective internal jugular veins by way of two or three small foramina.2 In FCH, the lymphatic sacs do not connect normally with the venous system (Fig. 4-9). Failure of development of this communication results in stasis of lymph fluid, which causes a host of consequences secondary to jugular lymphatic obstruction. This is apparently a lethal anomaly unless the communication between the jugular lymph sac and the jugular vein develops by middle to late fetal life.

165

Once the link does occur, the distended jugular lymph sac collapses, leaving redundant skin in the neck region, with alteration in the posterior hairline and hair directional patterning plus elevation and sometimes protrusion or posterior angulation of the auricle. As the neck lengthens, the redundant skin forms folds known as pterygium colli. Peripheral accumulation of lymphedema fluid causes full subcutaneous tissues with relative overgrowth of the overlying skin, prominent fingertip pads, and narrow hyperconvex nails, which are often deeply set at the base. Peripheral lymphedema may not completely disappear by birth, leaving puffy hands and feet. Distension of lymph channels in the thoracic wall may distort the placement of the nipples and symmetry of the chest. Dilated vessels in the lower abdominal wall may impede descent of the testes into the scrotum, leading to cryptorchidism. Further support for the jugular lymphatic obstruction pathogenesis of fetal cystic hygroma comes from the description of a fetus with a unilateral left cystic hygroma and edema of the entire body except the right arm, apparently caused by interrupted communication between the thoracic duct and left jugular vein, with normal connection between the right lymphatic duct and venous system.17 Clark suggests that dilated lymphatic vessels at the base of the heart encroach on the ascending aorta, increasing resistance to left-sided blood flow.15 This can alter the proportion of aortic and pulmonary flow, creating a branch point at the juxtaductal aorta, which forms the aortic flange and manifests as coarctation. Severe reduction in left heart blood flow may lead to hypoplastic left heart or aortic atresia. Less severe flow reduction may result in partial opening of the aortic valve leaflets, which then fuse, causing bicuspid aortic valve. This pathogenetic link between FCH and congenital heart defects is supported by findings in Turner syndrome in which the incidence of congenital heart disease differs significantly between those patients with neck webbing and those without neck webbing.16,18 The difference is most striking when one looks at coarctation of the aorta, of which the incidence is 25% in those with neck webbing and 3% in those without neck webbing.15 Two animal models also confirm the pathogenetic link between FCH, hydrops, and congenital heart defects. The embryology of the heart’s lymphatic system has been studied in the chick embryo.15 Lymphatic vessels coalesce at the base of the heart, and

Fig. 4-9. Lymphatic system in a normal fetus (left) with a patent connection between the jugular lymphatic sac and the internal jugular vein; cystic hygroma and hydrops (right) from failed lymphaticovenous connection. (Reprinted with permission from Chervenak FA, et al.: N Engl J Med 309:822, 1983.8)

Table 4-2. Syndromes with fetal cystic hygroma Syndrome

Prominent Features

Causation Gene/Locus

Achondrogenesis type II37

Short-limbed dwarfism, decreased vertebral ossification, large head with normal ossification of the calvarium, subcutaneous edema

AR (200610) 12q13.11-q13.2

Alcohol, prenatal33

Growth and mental impairment, microcephaly, small palpebral fissures, ptosis, smooth philtrum, heart defects

Teratogen exposure

Aminopterin, prenatal33

Defective cranial ossification, hypertelorism, micrognathia, growth impairment

Teratogen exposure

Campomelic dysplasia48

Anterior bowing of femora and tibiae, dimples over location of maximum curvature, sex reversal, flat face, prenatal growth deficiency

AD (114290) SOX9, 17q24.3-q25.1

Chromosome aberrations: Dup(11p)31

Hydrops, cleft lip and palate, preductal coarctation, left diaphragmatic hernia, intestinal malrotation, cryptorchidism

Chromosomal

11q;22q Translocation34

Low birth weight, delayed psychomotor development, hypotonia, microcephaly, craniofacial asymmetry, malformed ears with pits and tags, cleft palate, congenital heart disease, cryptorchidism

Chromosomal

Trisomy 1328

Microcephaly, microphthalmia, cleft lip/palate, polydactyly, cardiac and renal defects, mental retardation

Chromosomal

Del(13q)33

Microcephaly, prominent nasal bridge, radial hypoplasia, mental retardation

Chromosomal

Trisomy 1827

Growth and mental impairment, micrognathia, cardiac defects, overlapping digits

Chromosomal

Del(18p)32

Retinal coloboma, absent labia minora, external ear abnormalities, midface hypoplasia, epicanthal folds, high-arched palate

Chromosomal

Down27

Growth and mental impairment, microbrachycephaly, upslanted palpebral fissures, Brushfield spots, small mouth, flat facies, hypotonia, cardiac defects

Chromosomal

Trisomy 22/mosaicism32

Facial asymmetry, telecanthus, ptosis, down-slanting palpebrae, preauricular pits, short neck, low posterior hairline, clitoromegaly

Chromosomal

Turner3,11

Hydrops, preductal coarctation, short stature, ovarian dysgenesis, facial dysmorphism, excess nuchal skin, low posterior hairline, low-set and posteriorly angulated ears, widely spaced nipples, deep-set nails

Chromosomal

45,X/46,XY46

Hydrops, hypoplastic left heart, ambiguous genitalia

Chromosomal

Klinefelter29

Tall stature, mild learning disabilities, eunuchoid habitus if untreated in adolescence

Chromosomal

49,XXXXY47

Facial dysmorphism, tall stature, mental retardation, congenital heart defects

Tetraploidy30

Hydrops, preductal coarctation, intestinal malrotation, horseshoe kidney

Chromosomal

Cowchock38

Cleft palate, asplenia

AR

Cumming39

Campomelia; short gut; polysplenia; polycystic kidneys, pancreas, and liver

AR (211890) (continued)

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Lymphatic System

167

Table 4-2. Syndromes with fetal cystic hygroma (continued) Syndrome

Prominent Features

Causation Gene/Locus

Distichiasis-lymphedema

Distichiasis, lymphedema, spinal extradural cysts, congenital heart disease

AD (153400) FOXC2, 16.24.3

Holoprosencephaly13

Cyclopia, cebocephaly, ethmocephaly, single central incisor, absent sense of smell, proboscis, midline brain anomalies

Chromosomal anomalies; AR (236100) AD (142945) SHH, 7q36 (603073) ZIC2, 13q32 AD (157170) SIX3, 2p21 AD (142946) TGIF, 18p11

Lethal multiple pterygium42

Hydrops, cleft palate, joint contractures, multiple pterygia, muscular atrophy, gracile bones, pulmonary and cardiac hypoplasia

AR (253290)

Lethal multiple pterygium, X-linked43

Cleft palate, multiple pterygia, radioulnar hypoplasia, dislocated hips

XL (312150)

Noonan35,36,49

Short stature, congenital heart defect, mental retardation, downward-slanting palpebrae, widely spaced eyes, ptosis, pectus deformity, webbed neck, cryptorchidism, other lymphatic abnormalities including hydrops, peripheral lymphedema, chylous effusions

AD (163950) PTPN11, 12q24

Hydrops, short neck

AR (257350)

Oculodentodigital

Close-spaced eyes, microphthalmos, dental enamel hypoplasia, camptodactyly of fifth fingers, thin hypoplastic alae nasi, fine sparse hair

AD (164200) Connexin 43, 6q21q23.2

Thrombocytopenia-absent radius13

Radial agenesis with normal thumbs, thrombocytopenia in early infancy, variable lower limb anomalies

AD (274000)

Trimethadione, prenatal33

Growth and mental impairment, V-shaped eyebrows, epicanthus, microcephaly, retroverted pinnae

Teratogen exposure

44

Nuchal blebs40,41 13

the lymphatic ducts course to the jugular lymphatic sac, parallel to the aorta. Clark speculates that the increase in hydrostatic pressure within the jugular lymphatic sac would also distend the cardiac lymphatics, leading to reduced cardiac blood flow and anomalous development.15 Mouse trisomy 16 is the animal model of human trisomy 21 because of cardiovascular malformations common to both and homologous gene loci on the concerned chromosomes.19 Cystic accumulation of fluid at the back of the fetus has been observed in mouse trisomy 16, and cardiovascular malformations such as persistent truncus arteriosus, double outlet right ventricle, and aortic arch anomalies have been recognized.19 In a histologic study of normal mouse fetuses, the communication between the jugular lymphatic sac and the jugular vein was recognized from day 14. In trisomy 16 fetuses, the communication was not formed until days 15–16, and nuchal edema always appeared on day 14. The edema was largely caused by cystic dilation of lymph vessels in the nuchal region and was followed by generalized subcutaneous accumulation of fluid. Miyabara et al. speculate that the malformations observed in mouse trisomy 16, including abnormal lymph vessels, cardiovascular malformations, and hypoplastic thymus, may be related to the abnormal migration of neural crest cells and abnormal distribution of extracellular matrix.19 This alternative mechanism may

explain the variation between the pattern of cardiac defects seen in trisomy 21 and that found in Turner syndrome. The role of fetal proteins in the etiology of edema and FCH is unclear. In studies of Turner syndrome fetuses, Shepard et al. have found significantly reduced concentrations of plasma protein and albumin compared with gestational age-appropriate controls.20 Hypoalbuminemia may result from decreased production, altered distribution, or decreased half-life. Lymphatic abnormalities could increase the extravascular component, allowing redistribution with consequent dilution of albumin. The effect of lower oncotic pressure on the development of the lymphatic system in the embryo and early fetus is unknown. FCH is found in one per 700 to 1000 prenatal diagnostic ultrasound scans, but the incidence is higher, around 1%, when transvaginal ultrasonography is used from the end of the first trimester to the early second trimester.5,21 FCH accounts for between 1% and 5% of malformations diagnosed before 26 weeks gestation.5,10 A study of spontaneously aborted fetuses has documented FCH in one of 875. The incidence increased to one of 200 in fetuses with an over 3 cm crown to rump length.11 More than 150 cases are now described in the literature. There does not appear to be any ethnic or racial predisposition. More females than males are

168

Cardiorespiratory Organs

ascertained because of the frequent association with Turner syndrome. Prognosis, Prevention, and Treatment

The natural history of FCH is variable and depends to a large extent on the presence or absence of hydrops. Concomitant hydrops is described in 60–90% of cases, and in these cases the outlook is generally grave, although resolution is reported.1,4,8,9,13 Data from several large series suggest that less than 10% of continuing pregnancies result in liveborn infants.9,l0,13 The majority of cases are terminated at the parents’ request.10 Over 90% of the remainder result in spontaneous abortion, intrauterine fetal demise, or early neonatal death.9,10,13,14 There are many reports of FCH without hydrops in which resolution of the FCH occurred. Excess nuchal skin, minor degrees of pedal edema, and, in one case, bicuspid aortic valve were noted.13,22–26 In these cases, fetal cystic hygromas were diagnosed by ultrasound at 11–16 weeks gestation and had resolved by 16–29 weeks gestation. Within this group are cases with a chromosome abnormality and cases that are cytogenetically normal. Prognosis may also depend on the gestational timing of ascertainment. In the past the diagnosis of FCH has been made at gestational ages greater than 9–15 weeks. Most cases are septated and multiloculated, with a poor prognosis. The septated lesions may be associated with complete obstruction of the cervical lymphatic sacs. The accumulating lymphatic fluid infiltrates between the cervical tissues, creating multilocular cysts and ultimately generalized fetal hydrops. In contrast, nonseptated FCH may represent temporary accumulation of lymph with enlargement of the lymphatic sacs. Increasing pressure within the sacs overcomes an incomplete obstruction with subsequent gradual decompression. This may be a normal variant in the development of lymphaticovenous communication, which has gone unnoticed until the advent of early, transvaginal ultrasound. Early reports speculated that one might be able to distinguish between the septated lesions (with bad outcome) and the early-onset, nonseptated lesions (with good outcome). It now seems clear that this distinction is too simplistic and resolving FCH cases may or may not be septated.13,14,23,25,26 A high incidence of chromosome abnormality is found in FCH, whether diagnosis is made in the first or early second trimester. However the etiology appears to differ depending on gestational age at ascertainment. In the first trimester, there is a high incidence of trisomies 21, 18, and 13, while Turner syndrome is less common. This latter diagnosis is much more frequently found when ascertainment occurs in the second trimester.14 The prenatal diagnosis of cystic hygroma poses a serious dilemma for pregnancy management and family counseling. The diagnosis of FCH should be sonographically confirmed and distinguished from other craniocervical masses. A detailed search for other malformations, intrauterine growth retardation, and generalized hydrops should be combined with an estimate of the extent of the FCH. Amniocentesis and fetal karyotyping are essential. Alpha-fetoprotein estimation provides little additional information. In those cases in which a chromosome abnormality can be detected or in which additional malformations are identified by ultrasonography, an informed decision may be reached more easily. When the diagnosis and/or prognosis is uncertain, however, parental adjustment to an already difficult situation is further complicated by the inability to obtain precise information. Optimal care requires a multidisciplinary approach, including obstetrician, radiologist, geneticist, neonatologist, and surgeon. When termination of pregnancy or fetal demise occurs, autopsy

is essential. The FCH must be confirmed histologically and differentiated from nuchal edema. A cytogenetic study should be performed if it was not completed antemortem, and a detailed search should be made for the features of the various syndromes detailed in Table 4-2. References (Fetal Cystic Hygroma) 1. Garden AS, Benzie RJ, Miskin M, et al.: Fetal cystic hygroma colli: antenatal diagnosis, significance and management. Am J Obstet Gynecol 154:224, 1986. 2. Van der Putte SCJ: Lymphatic malformation in human fetuses. A study of fetuses with Turner’s syndrome or Status Bonnevie-Ullrich. Virchows Arch Pathol Anat 376:233, 1977. 3. Singh RP, Carr DH: The anatomy and histology of XO human embryos and fetuses. Anat Rec 155:369, 1966. 4. Gembruch U, Hansmann M, Bald R, et al.: Prenatal diagnosis and management in fetuses with cystic hygroma colli. Eur J Obstet Gynecol Reprod Biol 29:241, 1988. 5. Bronshtein M, Rottem S, Yotte N, et al.: First-trimester and early second trimester diagnosis of nuchal cystic hygroma by transvaginal sonography: diverse prognosis of the septated from the nonseptated lesion. Am J Obstet Gynecol 161:78, 1989. 6. Chitayat D, Kalousek DK, Bamforth JS: Lymphatic abnormalities in fetuses with posterior cervical cystic hygroma. Am J Med Genet 33:352, 1989. 7. Philips HE, McGahan JP: Intrauterine fetal cystic hygroma: sonographic detection. Am J Radiol 136:799, 1981. 8. Chervenak FA, Isaacson G, Blakemore KJ, et al.: Fetal cystic hygroma: cause and natural history. New Eng J Med 309:822, 1983. 9. Abramowicz JS, Warsof SL, Doyle DL, et al.: Congenital cystic hygroma of the neck diagnosed prenatally: outcome with normal and abnormal karyotype. Prenat Diagn 9:321, 1989. 10. Cohen MM, Schwartz S, Schwartz MF, et al.: Antenatal detection of cystic hygroma. Obstet Gynecol Surg 44:481, 1989. 11. Byrne J, Blanc WA, Warburton D, et al.: The significance of cystic hygroma in fetuses. Hum Pathol 15:61, 1984. 12. Kalousek DK, Seller MJ: Differential diagnosis of posterior cervical hygroma in previable fetuses. Am J Med Genet 28:83, 1987. 13. Bernstein HS, Filly RA, Goldberg JD, et al.: Prognosis of fetuses with a cystic hygroma. Prenat Diagn 11:349, 1991. 14. Johnson MP, Johnson A, Holzgreve W, et al.: First-trimester simple hygroma: cause and outcome. Am J Obstet Gynecol 168:156, 1993. 15. Clark EB: Neck web and congenital heart defects: a pathogenic association in 45 X-O Turner syndrome? Teratology 29:355, 1984. 16. Lacro RV, Jones KL, Benirschke K: Coarctation of the aorta in Turner syndrome: a pathologic study of fetuses with nuchal cystic hygromas, hydrops fetalis, and female genitalia. Pediatrics 81:445, 1988. 17. Shaub M, Wilson R, Collea J: Fetal cystic lymphangioma (cystic hygroma): prepartum ultrasonic findings. Radiology 121:449, 1976. 18. Lin AE, Garver KL: Monozygotic Turner syndrome twins—correlation of phenotype severity and heart defect. Am J Med Genet 29:529, 1988. 19. Miyabara S, Sugihara H, Maehara N, et al.: Significance of cardiovascular malformations in cystic hygroma: a new interpretation of the pathogenesis. Am J Med Genet 34:489, 1989. 20. Shepard TH, Wener MH, Myhre SA, et al.: Lowered plasma albumin concentration in fetal Turner syndrome. J Pediatr 108:114, 1986. 21. Marchese C, Savin E, Dragone E, et al.: Cystic hygroma: prenatal diagnosis and genetic counseling. Prenat Diagn 5:221, 1985. 22. Chodirker BN, Harman CR, Greenberg CR: Spontaneous resolution of a cystic hygroma in a fetus with Turner syndrome. Prenat Diagn 8:291, 1988. 23. Macken MB, Grantmyre EB, Vincer MJ: Regression of nuchal cystic hygroma in utero. J Ultrasound Med 8:101, 1989. 24. Darby BG: Resolution of cystic hygroma. Prenat Diagn 9:447, 1989. 25. Distell BM, Hertzberg BS, Bowie JD: Spontaneous resolution of a cystic neck mass in a fetus with normal karyotype. Am J Radiol 153:380, 1989. 26. Rodis JF, Vintzileos AM, Campbell WA, et al.: Spontaneous resolution of fetal cystic hygroma in Down’s syndrome. Obstet Gynecol 71:976, 1988.

Lymphatic System 27. Pearce JM, Griffin D, Campbell S: Cystic hygroma in trisomy 18 and 21. Prenat Diagn 4:371, 1984. 28. Greenberg F, Carpenter RJ, Ledbetter DH: Cystic hygroma and hydrops fetalis in a fetus with trisomy 13. Clin Genet 24:389, 1983. 29. Hoyme HE, Byrne-Essif KE: Prenatal edema and the ‘‘Noonan phenotype’’ in Klinefelter syndrome. Clin Res 38:187A, 1990. 30. Fryns JP, Vanderberghe K, Moerman F, et al.: Tetraploidy with hydrops fetalis, cystic nuchal hygroma and 90,XX karyotype. Clin Genet 31:158, 1987. 31. Fryns JP, Kleczkowska A, Vandenberghe K, et al.: Cystic hygroma and hydrops fetalis in dup (1lp) syndrome. Am J Med Genet 22:287, 1985. 32. Pagon RA, Hall JG, Davenport SLH, et al.: Abnormal skin fibroblast cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes. Am J Med Genet 31:54, 1979. 33. Graham JM Jr, Stephens TD, Shepard TH: Nuchal cystic hygroma in a fetus with presumed Roberts syndrome. Am J Med Genet 15:163, 1983. 34. Fraccaro M, Lindstell J, Ford CE, et al.: The 1lq; 22q translocation: a European collaborative analysis of 43 cases. Hum Genet 56:21, 1980. 35. Allanson JE: Noonan syndrome. J Med Genet 24:9, 1987. 36. Witt DR, Hoyme HE, Zonana J, et al.: Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet 27:841, 1987. 37. Wenstrom KD, Williamson RA, Hoover WW, et al.: Achondrogenesis type II (Langer-Saldino) in association with jugular lymphatic obstruction sequence. Prenat Diagn 9:527, 1989. 38. Cowchock FS, Wapner RJ, Kurtz A, et al.: Brief clinical report: not all cystic hygromas occur in the Ullrich Turner syndrome. Am J Med Genet 12:327, 1982. 39. Cumming WA, Ohlsson A, Ali A: Brief clinical report: campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:785, 1986. 40. Bieber FR, Petres RE, Bieber JM, et al.: Prenatal detection of a familial nuchal bleb simulating encephalocele. Birth Defects Orig Artic Ser XV(5A):51, 1979. 41. Dallapiccola B, Zelante L, Perla G, et al.: Prenatal diagnosis of recurrence of cystic hygroma with normal chromosomes. Prenat Diagn 4:383, 1984. 42. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809, 1984. 43. Tolmie JL, Patrick A, Yates JRW: A lethal multiple pterygium syndrome with apparent X-linked recessive inheritance. Am J Med Genet 27:913, 1987. 44. Robinow M, Johnson GF, Verhage AD: Distichiasis-lymphedema: a hereditary syndrome of multiple congenital defects. Am J Dis Child 119: 343, 1970. 45. Watson WJ, Thorp JM, Seeds JW: Familial cystic hygroma with normal karyotype. Prenat Diagn 10:37, 1990. 46. Verp MS, Sheikh Z, Anarose AP, et al.: Cystic hygroma and 45,X/46,XY mosaicism. Am J Med Genet 33:402, 1989. 47. Cullen MT, Gabrielli S, Green JJ, et al.: Diagnosis and significance of cystic hygroma in the first trimester. Prenat Diagn 11:643–651, 1991. 48. Tricoire J, Sarramon MF, Rolland M, et al.: Familial cystic hygroma. Report of 8 cases in 3 families. Genet Couns 4:265, 1993. 49. Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465, 2001.

4.4 Lymphangioma Definition

Lymphangioma is lymph-containing, endothelial-lined spaces, which vary in size from channels of capillary dimensions to cysts several centimeters in diameter.

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Diagnosis

Lymphangiomas are abnormal structures consisting of endotheliallined spaces of various sizes, supported by connective tissue stroma of varying thicknesses, often containing lymph nodes, round cells, and, occasionally, vestiges of smooth muscle and other neighboring tissues (Figs. 4-10 to 4-13). They may be small and circumscribed or so large and diffuse that adequate therapy is difficult. The cysts and capillaries are filled with thin, watery, clear to straw-colored fluid.

Fig. 4-10. High-power microscopic view of a cystic lymphangioma, showing numerous small and large spaces lined by flat endothelium. Many spaces are filled with eosinophilic fluid (hematoxylin-eosin, X128). (Reprinted with permission from Karmody CS, et al.: Otolaryng Head Neck Surg 90:283, 1982.89)

Fig. 4-11. Newborn infant with a giant beardlike cyst lymphangioma causing respiratory distress. (Reprinted with permission from Seashore JH, et al.: Am J Surg 149:459, 1985.46)

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Cardiorespiratory Organs

Fig. 4-12. Cystic lymphangioma of the axilla in a 2-week-old male infant. (Courtesy of Dr. Charles I. Scott Jr, A. I. duPont Institute, Wilmington, DE.)

This fluid may contain lymphocytes, monocytes, and occasional polymorphonuclear cells. The contents of the cyst may be bloody following trauma.1 Landing and Farber2 have classified lymphangiomas into three groups: 1. Capillary: thin-walled, endothelial-lined capillary-sized channels, confined to the dermis and epidermis, that clinically present as slightly elevated papules or wartlike excrescences on skin or mucous membranes. They are generally white or purple in hue, the latter being due to a blood coagulum within the lesion.3,4 They may be single or multiple and may involve the oral region, particularly the tongue, and the genital region. They are often referred to as lymphangioma simplex. Lymphangioma cutis circumscriptum is another capillary type, characterized by multiple bleblike nodules with hyperkeratosis, located on the face, chest, and extremities.3,5 Histologically, these often extend deeper into the dermis than lymphangioma simplex, and there are increased numbers of

confluent lesions in the papillary layer of the dermis.6 Capillary lymphangioma has been alternatively classified into ‘‘classic’’ and ‘‘localized’’ groups based on differing presentation and prognosis.4 Classic lesions are usually present at birth or soon thereafter, but may appear in adulthood. The affected area may be quite extensive and most frequently involves the proximal extremities, notably the upper arm, axilla, and adjacent chest wall. Although usually asymptomatic, minor bleeding and infection can occur. In contrast, a localized lesion may become apparent at any age, without a particular anatomic predilection. Mucous membranes may be involved, and symptoms are uncommon.4 2. Cavernous: lesions composed of dilated, endothelial-lined lymphatic sinuses within a delicate reticular network of areolar tissue.3,4 Contained within the malformation are irregular masses of lymphocytes, lymph nodes, lymph follicles, and many interconnecting channels. The cavernous element may extend deep into the underlying muscles and surrounding tissues.5 The skin overlying a cavernous lymphangioma is typically unaffected, and the lesion frequently feels much like a lipoma or cyst but is occasionally fibrotic, depending on the number of previous episodes of lymphangitis.6 Gross pathologic appearance is that of a multilocular cyst, lined with a glistening white membrane, adherent to surrounding structures.3 Cavernous lesions may be single or multiple and can be found in any area of the body, although they typically occur in the tongue, mouth, parotid gland, and larynx. Patients most commonly present with a painless mass that has gradually enlarged. Symptoms result from mass effects as well as from local tissue invasion. The tongue may be the single most common anatomic site affected.4 3. Cystic (cystic hygroma): the most common of the lymphangiomas,4 composed of cysts from a few millimeters to several centimeters in diameter.1 From 75% to 90% are found in the neck, and about 20% are located in the axilla.4 The posterior cervical triangle is most frequently involved. Presentation in the anterior triangle of the neck is associated with extensive infiltration of local structures and can involve the floor of the mouth, tongue, or upper respiratory tract.3 About 2–3% of cervical cystic lymphangiomas extend to the mediastinum and even to the diaphragm.4 Less than 1% are located exclusively in the mediastinum.4 Curiously, while cervicomediastinal cystic lymphangiomas are typically found

Fig. 4-13. Cystic lymphangiomas of the neck. Left: large lymphangioma of the left side of the neck in a 3-day-old infant. Middle: smaller lymphangioma of left supraclavicular area in a 3-year-old girl. Right: lymphangioma of anterior neck in a 6-year-old male. (Courtesy of Dr. Charles I. Scott Jr, A. I. duPont Institute, Wilmington, DE.)

Lymphatic System Table 4-3. Anatomic location of lymphangiomas Site

No.

Percent

Head

219

20

Neck

438

41

Axilla

130

13

Trunk

122

11

Extremities

122

11

Mediastinum

13

1

Abdomen/genitalia

39

3

1075

100

Total

Data are compiled from several sources.1,7,9–12

in infants, pure mediastinal lesions predominate in adults.4 Other less common sites include the groin, pelvis, retroperitoneal space, viscera, and bones.4 Several large reviews document the anatomic variability.1,7–12 Details of location, based on the above series, are provided in Table 4-3. Subsections, based on anatomic location, detailing demographic, clinical, and diagnostic features are provided at the end of this entry. Cystic lymphangiomas usually present as a painless mass, often associated with marked distortion of the tissues.5 Other clinical features depend on the size and location of the lymphangioma. They tend to be soft, compressible, and rounded or lobulated. Cystic lymphangiomas are also known as cystic hygromas. The term lymphangioma is used here to differentiate these malformations from fetal cystic hygroma (jugular lymphatic obstruction sequence) that has totally separate embryologic, pathologic, and clinical features. Although cystic and cavernous lymphangiomas may appear quite different clinically, there is no sharp dividing line between the two. Moreover, all three types of lymphangioma are not infrequently found together. There is some evidence that cystic lymphangiomas might first have been cavernous lesions. The physical structure of the tumor may be determined by the nature of the surrounding tissues.1 In the lips, cheek, tongue, and, to a lesser extent, the floor of the mouth, there are muscle fibers interlocking with the superficial tissues, leading to the development of smaller capillary or cavernous lymphangiomas. In the neck, axilla, and chest wall, where there are clearly defined tissue planes with loose fatty tissue surrounding large compact muscles and neurovascular structures, there is ample space for expansion of single cysts and for tongues of cystic structures to insinuate themselves among the large vessel and nerve trunks forming cystic lesions. Combinations of capillary, cavernous, and cystic lymphangiomas are frequently seen, with the cystic portions and the cavernous/capillary portions occupying separate but neighboring regions, dictated by the nature of the surrounding tissues.1 While a number of these malformations have been described in adults, between 50% and 65% are present at birth and 80–90% are detected before the end of the 2nd year of life.1,7,10,12–14 Both ultrasonography and computed tomography (CT) scanning have been used in diagnosis. Ultrasound delineates cystic masses with indistinct borders.15,16 The masses are often multilocular, with linear septations of variable thicknesses. Most lymphangiomas have solid components related to the cyst walls or to the septa. This sonographic appearance is reminiscent of benign multilocular cysts of the kidney or mucinous cystadenoma of the ovary. Sonographic-pathologic correlation demonstrates that the echo-

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genic component often corresponds to a cluster of abnormal lymphatic channels, too small to be individually resolved by ultrasound. The thickness and echogenicity of the septa vary with the amount of connective tissue, muscle tissue, and adipose tissue present in between the cysts.15 Large lesions have ill-defined boundaries, with some cysts dissecting between normal planes. CT scanning is considered by some to be the best method for examining neck masses.16 The differential diagnosis of a predominantly cystic, extrathyroidal neck mass includes branchial cleft cyst and thyroglossal duct cyst.15 These embryologic remains occur in characteristic locations: the former is found anterolateral to the carotid sheath, and the latter is found in the midline. Both tend to be unilocular, unlike most cystic lymphangiomas. Abscesses and resolving hematomas can also be cystic but are often more localized with an appropriate clinical presentation.15 Teratoma is a rare lesion but has a complex echo pattern that may be difficult to distinguish from cystic lymphangioma. Enlarged lymph nodes are usually solid and hypoechoic but can occasionally mimic cystic masses. Most other neck masses are solid and are therefore more circumscribed and less fluctuant than lymphangioma.3 Such solid masses include neuroblastoma, lipoma, salivary gland tumor, and neurofibroma.15 Hemangioma may be especially difficult to differentiate clinically from lymphangioma because both are soft on palpation. The distinction is difficult even with electron microscopy and is simply made on the basis of presence or absence of red cells and lymph. Sonography can be helpful, since hemangiomas are primarily echogenic, some containing small serpiginous anechoic spaces.15 Diagnostic difficulties can arise, however, if the cystic lymphangioma contains a large solid component. Meningoencephaloceles are alternative causes of masses in the occipital region.10 Fetal cystic hygroma is an etiologically distinct condition that results from jugular lymphatic obstruction in utero. It is histologically distinct from cystic lymphangioma (see Section 4.3) and is rarely present at birth. It is marked by other phenotypic features, including redundant neck skin, seen after jugular-venous communication occurs and the cystic hygroma decompresses. Details of the differential diagnosis of lymphangioma in other locations are given in the anatomic subsections at the end of this entry. Anomalies, including congenital heart defects, cleft lip, and spina bifida, are rarely described in association with lymphangiomas.17 Prenatal ultrasonographic diagnosis of cystic lymphangioma in various sites usually occurs as an incidental finding in the third trimester. The masses contain multiple cysts and solid portions within and between the cysts and thus have an appearance different from a fetal cystic hygroma caused by jugular lymphatic obstruction.18 Etiology and Distribution

Goetsch19 believed that a cystic lymphangioma represented a true infiltrating neoplasm, while Willis20 regarded lymphangioma as a hamartoma, that is, an embryologic tumor formed by excessive growth of tissues in their normal location. He compared them with hemangiomas.20 The most likely explanation is built on the centrifugal embryologic theory of Sabin,21 which has been validated by Van der Putte.22 In the process of centrifugal growth and outpouching of the lymphatic primordia, various areas of the lymphatic anlage grow abnormally, become sequestered, and never achieve efficient anastomoses with the larger lymph channels.1 Functionally they exist as a localized area of lymphatic stasis due to congenital blockage of regional lymphatic drainage. There is no evidence to support active infiltration of surrounding tissues, as described by Goetsch.19

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Lymphangioma is a rare tumor and accounts for only 6% of benign tumors in childhood and for 5% of vascular growths. In a series of 152 benign neck tumors, only four lymphangiomas were detected.12 In another series of 768 benign tumors, seen over a 15-year period, only 48 were lymphangiomas.14 The sexes are affected equally. Prognosis, Prevention, and Treatment

Lymphangiomas may spontaneously involute either completely or partially. Broomhead was the first to report a 16% complete spontaneous involution of cavernous lymphangiomas of the neck.23 With no treatment, most of the masses were gone by the time the patients reached age 2 years. More recently, Grabb et al. presented evidence of complete spontaneous involution in 40% and partial involution in 29% of patients.24 Involution was complete by age 2 to 3 years in many patients and by age 5 years in all the untreated patients. The exact percentage of lymphangiomas that involute is not yet known because many of these benign lesions are operated on early in life. Grabb et al. estimated that the true rate for partial or complete involution of all lymphangiomas of the head and neck is between 15% and 70% during the first 20 years of life.24 Noninvoluting lymphangiomas may grow slowly, at the same rate or at a greater rate than the child’s growth. Lymphangiomas of the head and neck region can enlarge over a period of a few hours in conjunction with an upper respiratory tract infection and then will recede over a period of months to approximately their original size. The goals of treatment are eradication of the lesion with complete healing, absence of morbidity and mortality, and good aesthetic result. Surgical excision seems to be the most reliable form of therapy, and generally clinicians agree with the recommendation of Grabbe et al. to wait until approximately the 3rd year of life before considering excision.24 This remains a controversial topic, with some surgeons promoting early radical excision during infancy, with cure rates ranging from 80–100%.25,26 It was stressed that the infant must be free of infection. Medical treatment during episodes of infection is essential, and corticosteroids are recommended, in addition to antibiotics, to reduce edema in inflamed lymphangioma tissue.4 Localized capillary lymphangiomas are readily treated, if indicated, by surgical excision, with full cure. Occasional recurrence may be related to deeper subcutaneous cisterns as described by Whimster.27 Therefore, excision to or including the fascia is recommended. Capillary lymphangiomas are also amenable to electrodesiccation and cryotherapy, although the results of these alternative treatment modes may not compare well with those of surgery.3,4 Definitive treatment of cavernous lymphangiomas requires complete excision. This may not always be feasible, particularly when lesions involve the tongue and floor of the mouth.4 In the anterior triangle, respiration and swallowing may be compromised, making prompt surgical intervention imperative. Staged resection is indicated when function and cosmesis would otherwise be compromised.4 Although isolated reports of successful excision of cystic lymphangiomas were scattered throughout the nineteenth-century literature, the associated morbidity and mortality encouraged examination of other modalities of treatment.4 Mortality rates approaching 50% were the norm in the preantibiotic era. As a consequence, radiotherapy was frequently used; however, the associated risks of malignancy and growth retardation are not justified by its sporadic success.4 Incision and drainage or aspiration may serve as temporizing measures. In life-threatening situations, such as airway compromise, they do not provide more than a

transient regression of the lymphangioma. If conservative measures fail, tracheostomy may be required. A variety of sclerosants, including sodium morrhuate, hypertonic saline, glucose, tetracycline, and boiling water, have been injected into cystic lymphangiomas with variable success. Nevertheless, scarring of the cyst walls, resulting from the use of these agents, may make subsequent excision extremely difficult.4 More recently, bleomycin has been introduced as a sclerosant and has met with some favorable response.28 The use of picibanil, a potent immunostimulant, as a sclerosant for head and neck lymphangiomas has been studied in a prospective randomized trial.90 Eightysix percent of 22 patients had a successful outcome, defined as complete or more than 60% reduction in size. It is clear that surgical excision remains the treatment of choice. Debulking or partial excision may be dictated by certain instances in which a more extended procedure might cause additional facial deformity, but the recurrence rate will be significantly higher. Rupture of the cyst increases the difficulty of surgically defining its margins.4 Death following surgery is now rare, in marked contrast to half a century ago.4 The most frequent postoperative complication is edema of the neighboring tissues, often with associated lymph accumulation and lymphatic drainage, which may occur in up to 50% of patients.1 When large tumors are resected, or when abnormal lymphatic channels have been left, a drain should be inserted to prevent loculation of the accumulating fluid. A mildpressure dressing will eliminate potential spaces.1 The anatomic location and the extent of surgery are related to the success of treatment, and recurrence may certainly occur. The recurrence rate of excised cavernous lesions of the tongue and floor of the mouth is probably the highest of all lymphangiomas. In one series, a recurrence rate of 50% was reported, with a new lesion appearing within 4 years. This has been attributed to the greater difficulty of complete removal of this more invasive lesion.4 Surgical sites with the lowest recurrence rate are the axilla and trunk.17 Overall, recurrence is said to occur in 6% with ‘‘complete’’ excision and in 35% with ‘‘incomplete’’ excision.17 In general, tumors that extend over several adjacent anatomic regions are more prone to recurrence or persistence than are more localized lesions.1 As a rule, a tumor with a large cavernous or capillary component may be twice as hard to eradicate as one consisting primarily of cystic elements. As this is not a malignant lesion, vital structures should not be sacrificed, and cysts that cannot be removed completely should be unroofed to promote atrophy and scarring.17 Eye

Ocular involvement is infrequent but may include the lids, conjunctiva, or orbit. Lymphangioma accounts for 3% of all ocular masses. Rootman et al. classified these lesions into superficial, deep, and combined types.29 The clinical manifestations, prognosis, and management directly correlate with the pathophysiology and location of the lesions. Superficial lesions are isolated multicystic abnormalities of cosmetic significance only. Typically there is a small eyelid or conjunctival mass that neither affects vision nor displaces the globe. If cosmetically unacceptable, it can be removed with relative ease due to limited location and small size.29 The differential diagnosis in this site includes epidermal inclusion cyst, hydrocystoma of either eccrine or apocrine origin, and, occasionally, cystic basal cell carcinoma, none of which would normally be associated with hemorrhage. A deep lesion usually presents with sudden proptosis due to spontaneous hemorrhage into a previously unrecognized lesion.

Lymphatic System

Hemorrhage is often disproportionate to the apparent minor degree of injury. Bleeding may be mild, producing subconjunctival hemorrhage, or severe, causing rapid increase in proptosis, even to the point of severe corneal exposure, potential optic nerve stretching or compression, or globe compression requiring emergency decompression. The majority of cases occur in childhood, although late onset up to age 59 years has been reported.30 Occasionally, an extensive congenital lesion of the orbit may occur, which may be ulcerative, rapidly growing, and repeatedly bleeding, producing destruction of the surrounding face. Differential diagnosis of this latter variety includes hemangioma, encephalocele, or rapidly growing malignant mesenchymal tumor. The differential diagnosis of orbital masses in children includes cellulitis, pseudotumor, dermoid and epidermoid cyst, capillary hemangioma, rhabdomyosarcoma, optic nerve glioma, neurofibroma, leukemia, and metastatic tumor (frequently neuroblastoma).31 In adults, the differential diagnosis includes Graves disease, pseudotumor, secondary tumor (frequently from the sinuses), lacrimal gland tumor, lymphoma, sinus mucocele, and dermoid and epidermoid cysts. The combined lesions are usually recognized within the 1st year of life and grow slowly over years. There may be spontaneous hemorrhage into the deep portion, producing some of the symptoms noted with the deep lesions. Combined lesions are frequently massive, involving the intraconal, extraconal, preseptal, and postseptal spaces. Very large lesions produce significant cosmetic disfigurement and frequently cause decreased vision from optic atrophy or amblyopia. Astigmatism, proptosis, strabismus, and decreased visual acuity may be presenting features. Diagnosis of these lesions is frequently based on venography, computerized axial tomography, conventional radiographs, and nuclear magnetic resonance imaging. It is generally believed that there are no lymphatics in the orbit. Embryonal rests may occur in this area, but it is more likely that the site of origin of the tumor is in the anterior lid or conjunctiva, where lymphatics are numerous.30 The objectives of treatment include drainage of acute hemorrhage, obliteration of large cystic spaces, and excision of as much tumor mass as possible, without jeopardizing normal orbital structures. Sclerosing agents and radiotherapy have been attempted, but are no longer recommended. Laser treatment has been introduced, but it has frequent complications. Surgical excision remains the treatment of choice. Recurrence may be observed even after long periods of observation and probably occurs in 10–15% of cases.26 In some cases, complete excision is not possible due to the diffuse, nonencapsulated growth pattern that allows these lesions to interdigitate with normal orbital structures. In this situation, multiple subtotal excisions may result in less than satisfactory results. Wilson et al. have had some success with conservative management consisting of activity limitation or bed rest as an outpatient or inpatient, cold compresses, and monitoring visual acuity, pupillary light reaction, and appetite.32 The differential diagnosis includes conjunctival hemorrhagic lymphangiectasis. This unusual condition occurs because of an abnormal communication between a conjunctival blood vessel and conjunctival lymphatic channel, resulting in either permanent or intermittent filling of the lymphatic with blood. The site and etiology of these abnormal communications remain obscure, although, in some cases, they may be congenital.33 Salivary Gland

Lymphangioma of the salivary gland is rare. Two parotid lesions were noted out of a total of 300 tumors of the major salivary

173

glands treated over a 9-year period.34 In a review of the pathology of 2500 salivary gland tumors, three lymphangiomas were found by Noone and Brown.35 Two arose primarily in the parotid and one in the submaxillary gland. These lesions usually present as subcutaneous cystic masses evident at birth or appearing within the first 2 years of life, although they have been noted in the 3rd decade or later. They may be associated with facial nerve paralysis, which probably occurs secondary to infection or hemorrhage. The differential diagnosis includes parotid abscess, tuberculosis, hemangioma, lymphoma, branchial cleft cyst, lipoma, mucocele, sialocele, unilateral mumps, and cyst associated with obstruction. Operative excision remains the treatment of choice, whenever feasible without sacrifice of neurovascular structures. Recurrence has been reported and can be treated with further excisional surgery. Aspiration, excision and drainage, radiotherapy, and injection of sclerosing agents have all been attempted in the past but have proved unsatisfactory. Larynx/Pharynx

Lesions of the larynx/pharynx are rare. Bill and Sumner reported only one laryngeal lymphangioma in a series of 61 patients.1 Only six cases were found in a review of 866 laryngeal anomalies performed over a 30-year period.36 Onset is uncommon in the older child and rare in the adult.37 In general, patients present with symptoms referable to airway compromise—progressive dyspnea, sudden airway obstruction, stridor, sleep apnea, or voice change. Dysphagia, drooling, and oral bleeding may occur when the tongue and floor of the mouth are involved.37 A mass involving the larynx or parapharyngeal tissue can be diagnosed by radiography of the neck, ultrasonography, barium esophagography, or CT scan. Differential diagnosis includes dermoid or foregut cyst and carcinoma. Complete excision should always be the goal of therapy. Transitory Horner syndrome, recurrent laryngeal palsy, and damage to the spinal accessory nerve may accompany surgery.38 Follow-up over an 18-year period is reported in one case.36 Subtotal excision had been originally performed, and several subsequent endoscopic procedures were required for removal of residual tumor along the posterior pharyngeal wall. Oral Cavity

Lymphangioma involves the tongue more frequently than any other intraoral site but may also be seen in the lips (macrocheilia), buccal mucosa, gingiva, and palate.39 These lesions are a common cause of macroglossia in children. They usually present within the first few years of life, and growth is usually slow, with quiescence for many years. Embryologically, lymphangiomas are derived from lymphatic tissue that originates in the lateral swellings of the tongue and the tuberculum impar of the mandibular arches. They are said to occur only in the anterior two-thirds; however, in one review of 46 cases there was no such predilection, and involvement at the base of the tongue occurred in five cases, with extension to the epiglottis in two of them.40,41 Lymphangiomas arising in the superficial submucosa of the tongue generally present as a sessile, papillary nodule that is bluish in color. If located in deeper tissues of the submucosa, the bluish color will be masked, and a pink, smooth or nodular, dome-shaped lesion is found. The irregularity of the surface of the tongue, with grey and pink projections affecting both dorsal and ventral surfaces, is the most common sign of this lesion (Fig. 4-14). Small, single, pale white or pink, soft, fluctuant lesions of the tongue are generally cavernous lymphangiomas and are by far the most common.39 When diffuse, causing macroglossia, the lymphangioma can lead to impairment

174

Cardiorespiratory Organs

due to lymphangioma may be seen in the 1st year of life or at a later age.42 It generally causes enlargement of the vermilion and is treated by excision. Lymphangioma of the buccal mucosa may be circumscribed and superficial or a deep diffuse mass or nodule. Long-standing lesions are knotty and nodular in consistency, as a result of recurrent trauma, periodic attacks of inflammation, periodic swelling, and subsequent fibrosis. Surgical excision is the treatment of choice, although total resection is often impossible. The lesion has a great tendency to recur.43 Lymphangiomas of the alveolar ridges appear to have a striking predilection for blacks, with a male to female distribution of approximately 2:1.44 One white female has been described.45 Blue-domed, fluid-filled lesions on the alveolar ridges of neonates were noted in 3.7% of black newborns examined in one large study.44 They varied from 1 to 9 mm in size, the majority being 3 to 4 mm. Multiple lesions were more common than single lesions. Lesions were most often found on the posterior crest of the maxillary alveolar ridges and on the posterior lingual surface of the mandibular ridges. The majority of these lesions resolve spontaneously.44,45 The differential diagnosis includes Epstein pearl, Bohn nodule, eruption cyst, dental laminar cyst, mucus retention phenomenon, and congenital epulis of the newborn. Anterior Neck

Fig. 4-14. Diffuse lymphangioma involving the dorsal and ventral surfaces of the tongue. (Reprinted with permission from Postlethwaite KR: Br J Oral Maxillofac Surg 24:63, 1986.41)

of speech, drooling, difficulties in mastication, dysphagia, and dentoalveolar problems, such as an increased maxillomandibular angle with an anterior open bite, mandibular prognathism, and spacing of the teeth.41 There have been reports of periodic enlargement of the tongue during menstruation.41 Rapid enlargement may also accompany inflammatory edema, occurring secondary to upper respiratory tract and pharyngeal infections or to accidental trauma.40 During bouts of acute swelling due to trauma or infection, corticosteroids, together with antibiotics and effective analgesia, are required. In young children, sedation may occasionally be necessary. With episodes of acute enlargement of the tongue, the airway is rarely jeopardized, but feeding may become a problem, requiring intravenous infusion or nasogastric feeding.40 A variety of techniques, including radiotherapy, insulated needle diathermy, electrodesiccation, and cryotherapy, have been described for the removal of lymphangiomas, although surgical excision is the treatment of choice.40,41 Diffuse lesions require horizontal partial wedge resection. Total excision of small, circumscribed lesions is generally possible. Adjunctive therapy may include reduction of sharp incisal edges, early orthodontic treatment for open bite, and orthognathic surgery. A variety of lesions can cause macrocheilia: lymphangiomas, hemangiomas, neurofibromas, lipomas, hamartomas, minor salivary gland hypertrophy, and trauma. These lesions are typically asymmetric. Symmetric macrocheilia as a manifestation of angioneurotic edema is rarely seen without other signs. Macrocheilia

The so-called giant beardlike cystic lymphangioma of the anterior nuchal area is distinctly uncommon (Fig. 4-11). The largest series reported nine cases out of 763 lymphangiomas at a major children’s hospital.46 Giant cystic lymphangiomas are defined less by size than by their tendencies to infiltrate throughout both sides of the neck, to involve multiple structures, and to extend into the mediastinum, pharynx, mouth, and tongue. There are dozens or even hundreds of cysts of various sizes. These lesions invariably present at birth or in the first weeks of life. They completely encircle vessels, nerves, and glands and insinuate between and around muscle fibers. They do not actually invade and destroy other tissues, and cell structure is normal, with no evidence of neoplasia. The diagnosis is usually straightforward. These lesions are quite different from fetal cystic hygroma, which occurs secondary to jugular lymphatic obstruction and is not found postnatally, except as redundant neck skin and aberrant posterior hair patterning. The cysts are characteristically soft and ballotable and the overlying skin is normal, but there may be a faint bluish discoloration over the larger cysts. Inspection and palpation of the tongue and floor of the mouth is necessary. Lateral radiography of the neck is helpful to define the size at the base of the tongue and epiglottis and to demonstrate narrowing of the esophagus and upper airway. Frontal and lateral chest radiographs are important to look for mediastinal extension. Ultrasonography and CT have been of limited value in defining the extent of these lesions. Laryngoscopy is useful to determine whether there is involvement of the mucosal surface of the base of the tongue, epiglottis, posterior pharynx, and larynx. Bronchoscopy may help to show the degree of tracheal compression, but intrinsic involvement of the trachea is rare. Management of giant lymphangiomas is difficult and challenging. Recommendations in the literature range from doing nothing to early radical extirpative surgery. It seems that early conservative surgery, combined with temporary tracheostomy, is appropriate initial treatment.46 Recurrence and extension into adjacent areas is common, and multiple operations over several years are almost always necessary to achieve an optimal result.

Lymphatic System

Injection of sclerosing agents and radiotherapy are ineffective, and spontaneous resolution is rare. As in other areas, dramatic tumor enlargement can occur in the presence of infection or trauma, leading to acute airway obstruction. Despite the extensive nature of these lesions, the impossibility of complete excision because of damage to normal structures, and the need for multiple operations, the long-term results may be satisfactory.46 Dental malocclusion and mandibular abnormalities may be striking accompaniments of anterior nuchal cystic lymphangiomas. They require complex maxillofacial evaluation and surgical treatment.47 Thorax

Intrathoracic lesions make up less than 10% of the total number of lymphangiomas. Fewer than 1% are totally within the thorax, and most of these develop in adults (75%), with less than 8% in children under age 1 year.48 Lymphangiomas account for 0.7–4.5% of mediastinal tumors. The most common intrathoracic lesion is a mediastinal extension of a preexisting cervical cystic lymphangioma, which occurs in approximately 10% of the latter lesions. Masses in the superior mediastinum constitute about one-half of all intrathoracic lymphangiomas and are generally described in young patients.49 There is a tendency for them to recur because of the infiltrative growth pattern, incomplete resection, and subsequent cystic dilation of remnants. Approximately one-third of intrathoracic lymphangiomas involve the anterior mediastinum and are found in middle-age. They are often asymptomatic. Presenting features include a mass seen on routine radiograph examination, chest discomfort, chylothorax, obstruction of the superior vena cava, cough, wheezing, and pain. In young children, respiratory symptoms may be dramatic. When intrathoracic lesions are part of generalized lymphangiomatosis, there are additional problems. Cystic lymphangiomas have a predilection for local infiltration of tissue planes and occasional widespread extension. The axilla and chest wall may be particularly prone to this behavior due to local prevalence of major muscular and neurovascular bundles loosely embedded in fat. Muscle atrophy, neural impairment, and tracheal or esophageal obstruction may result from local compression. Conventional radiograph findings are nonspecific. The round contour, sharp border, and uniform density may differentiate the lesion from a malignant neoplasm; however, CT contributes to diagnosis by clear delineation of the anatomic location, demonstration of its molding by and compression of the surrounding structures, confirmation of its cystic nature with a homogeneous content of low density, and assurance of lack of calcium deposition.50 Arteriogram may reveal displacement of the adjacent arterial branches, without neovascularization. Real-time ultrasound can facilitate diagnosis and has also allowed prenatal diagnosis of axillary cystic lymphangioma with mediastinal extension.51,52 Differential diagnosis includes substernal goiter, teratoma, thymoma, lymphoma, bronchial-esophageal cyst, aneurysm, pericardial cyst, neurenteric and thoracic duct cysts, retropharyngeal and mediastinal abscess, and granulomatous disease.53 Treatment is early surgical excision, although rare cases, after multiple recurrences, have responded to radiotherapy. Lymphangiomas of the lung may cause hemoptysis and distortion and circumferential compression of airways.54 These lesions may be similar to those found in lobar pulmonary lymphangiectasia (Section 4.2). Esophageal lymphangiomas are whitishyellow lesions, often in the middle to lower part of the esophagus, and cavernous in nature. They cause achalasia, with dysphagia and

175

vomiting after meals. The differential diagnosis includes esophageal varices, hemangioma, and leiomyoma.55 Intrathoracic lymphangiomas lying outside the mediastinum have been described in the pericardium and just above the diaphragm.48 Abdomen

Intraabdominal lymphangiomas make up only 1% of the total number of lymphangiomas and are usually found incidentally through lymphangiography, during elective abdominal surgery, in an acute surgical abdomen, or at postmortem examination. The incidence ranges from one per 27,000 to 100,000 hospital admissions.56 Seventy percent are found in the mesentery (usually juxtaintestinal, ileal, or ileocecal), where they are the most common cystic masses. Five percent are retroperitoneal.57 They occur in the spleen, liver, uterus, rectum, pancreas, esophagus, and bowel. Approximately 25% come to attention in the 1st decade of life, with up to 20% in each subsequent 4 decades. Fewer than 13% have been reported in patients over age 50 years. There is a significant male predilection. There are few clinical features that help to differentiate retroperitoneal lymphangioma from other retroperitoneal masses. The most common clinical manifestation is that of a soft, palpable, cystic mass that usually enlarges slowly. It may cause a ‘‘dragging sensation’’ or may be asymptomatic. It may remain occult until pressure occurs or until the mass has become visible or palpable. Pressure symptoms depend largely on location and may produce partial intestinal obstruction, displacement of the kidneys and ureters, ureteric obstruction, and displacement of the middle colic artery.56 The cysts seldom cause acute clinical symptoms, and diagnosis is often entirely accidental. Acute symptoms, due to hemorrhage, inflammation, infection, perforation, torsion, volvulus, or rupture, include abdominal pain, tenderness, guarding, and fever, mimicking appendicitis. There are several imaging techniques that afford a preoperative diagnosis. Radiographs, intravenous urography, and barium enema may demonstrate organ displacement. The typical sonographic picture is a cystic mass with multiple thin septa containing anechoic fluid. Thicker septa occur with inflammation and/or accumulations of fatty tissue. Chylous or creamy fluid displays fine diffuse echoes, whereas hemorrhage results in coarse echoes and/or solid masses. Magnetic resonance imaging signal intensities can be used to distinguish between the composition of cystic fluids. Lymphangiography is only useful in rare cases where the lymphangioma communicates with major lymphatic trunks. Of all the above methods, ultrasound and CT appear to be the most efficacious. The differential diagnosis includes mesenteric cyst, ovarian teratoma, mucinous cystadenoma, pancreatic pseudocyst, multilocular cystic nephroma, lymphoma, hematoma, foregut cyst, enteric duplication cyst, polycystic kidney disease, cystic dysplasia of the kidney, epidermoid cyst of the spleen, mesenchymal hamartoma of the liver, cystic hepatoblastoma, hemangioendothelioma of the liver, choledochal cyst, and embryonal sarcoma. The clinical setting may indicate which condition is more likely.58 Ultrasonography has also been used prenatally to demonstrate a fetal abdominal cystic lymphangioma with associated soft tissue enlargement of the lower extremities. Diagnosis was made by 19 weeks gestation.59 Complete excision is the treatment of choice; it is usually carried out with relative ease and rarely followed by recurrence. Occasionally, retroperitoneal cystic lymphangiomas will be found incidentally and can be managed conservatively. Aspiration of larger cysts lessens the difficulty with exposure. If the cyst has

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invaded an abdominal organ, such as the small bowel, spleen, or tail of the pancreas, total excision with resection of the involved organ is indicated.56 Juxtaintestinal cysts may require intestinal resection with removal of adjacent mesentery, because simple excision is impossible without damaging the bowel. If complete excision is technically impossible, since there is no need to sacrifice normal structures, excision of most of the mass, with internal marsupialization, results in apparent cure with minimal morbidity. Most lesions are unicentric and benign, but 10% of cases show an associated diffuse mesenteric or extraabdominal lymphatic dysplasia.60 The latter has a tendency to recur locally or to exhibit extradigestive manifestations, such as chylothorax and intraosseous lymphangiectasia. Lymphangiomas have been described in both small and large bowel, but they are an uncommon lesion at either site. Raiford reported 88 benign gastrointestinal tumors, including only one jejunal lymphangioma, in a retrospective analysis of 11,500 autopsies and 4500 surgical specimens.61 Another series of 292 tumors of the colon and rectum included only four lymphangiomas. Perzin and Bridge reported 21 cases of small bowel lymphangioma, accounting for 10% of the tumors and pseudotumors of the small bowel.62 Average age of onset is 51 years, with a range of 22 to 77 years. Over 30% of patients present in the 7th decade. Some authors report a predominant occurrence in females.63 The lesion originates in the lymphatic plexus within the submucosa, into which the lacteals of the villi empty. Some lesions extend to the mucosa and present as a pedunculated, sessile, or polypoidal lesion.63 Lymphangiomas have been reported more frequently since the development of widespread use of fiberoptic instruments. It is possible to diagnose lymphangiomas endoscopically, because they are lustrous and smooth on the surface and pliable on compression, and half of them have a stalk or waist at the base. They are pinkish and translucent and change shape with peristalsis, compression, and the patient’s position. The most common presentations are abdominal pain and intestinal bleeding. Abdominal mass and diarrhea are rare. Protein-losing enteropathy is uncommon. Lymphangiomas range from 5 to 100 mm in diameter; they are generally single and unilocular or bilocular. Differential diagnosis includes lymphatic cysts, which are common, occurring in up to 20% of autopsies.64 Lymphatic cysts may be associated with aging; they usually appear as yellowish nodules on the proximal small intestinal wall, often protruding on the serosal and mucosal surfaces. Other rare benign colonic and rectal neoplasms include lipoma, leiomyoma, hemangioma, mesothelioma, fibroma, ganglioneuroma, and teratoma. In the past, treatment has focused on segmental resection, but snare-polypectomy and electrocautery, since their development, have become the preferred treatment of smaller lymphangiomas.65 The spleen is the least common intraabdominal site. Fowler reviewed the world literature from 1940 to 1952 and found 27 cases among 265 splenic cysts.66 The spleen is also one of the sites involved in cystic (multifocal) lymphangiomatosis. If this latter condition is suspected, evaluation should also be directed toward the lungs, skeleton, and liver. Sixty percent of splenic cysts occur in women, and 75% present between ages 10 and 50 years. The differential diagnosis of splenic cysts has been reviewed by Pearl and Nassar67 and includes parasitic cysts (taenia echinococcus), endothelial-lined cysts (hemangioma, lymphangioma), epithelial-lined cysts (dermoid, epidermoid), transitional celllined cysts, and secondary or traumatic cysts, which do not have a true cellular lining and account for 80% of the total. When

symptoms are present, splenic cysts most commonly produce pain or discomfort in the left upper quadrant and are in some cases accompanied by weight loss, nausea and vomiting, portal hypertension, and varices. Of the various radiographic studies available for the evaluation of splenic masses, angiography and ultrasound are probably the most useful. However, straight radiographs and radionuclide scanning may occasionally be used. The treatment of choice—splenectomy—is indicated when there is significant enlargement or discomfort, portal hypertension, and varices. Hepatic lymphangioma usually occurs as part of multiorgan lymphangiomatosis. It is occasionally observed alone, usually in children and adolescents. It presents as an abdominal mass, with occasional pain, diarrhea, and weight loss. Diagnosis is made with ultrasound. Gross pathology demonstrates multiple whitish nodules that are soft and release chylous milky fluid on puncture biopsy.68 The differential diagnosis includes mesenchymal hamartoma, hemangiomatosis, and necrotic metastases. Twenty-one cases of renal lymphangioma have been described, with a male to female ratio of 1:2. Presenting features include dull local discomfort, mass, and hematuria. Age range at presentation has been 6 months to 76 years. Differential diagnosis includes hydronephrosis, polycystic kidney disease (both adult and infantile types), neoplasia, and infiltrative disorders such as leukemia and glycogen storage disease.69 Renal malignancy, such as Wilms tumor, should also be considered. Pericalyceal, peripelvic, and hilus lymphatic cysts are more common than lymphangioma. The majority develop in the 5th decade, often following a history of inflammation, obstruction, or calculus. These may be secondary cysts occurring after acquired blockage of the lymphatics.70 Two sisters were described with multiple lymphatic cysts in the renal cortex and medulla, renal sinus, and paranephric tissues.71 Both sisters, during pregnancy, developed collections of perinephric fluid and ascites, with mild impairment of renal function and hypertension. This is the only familial case of lymphangiomatosis involving the kidneys. It may be part of widespread lymphatic dysplasia, although this alternative was not specifically explored. Two or three lymphangiomas of the pancreas have been described, presenting as a mass in the upper abdomen or picked up by a gastrointestinal series or alternative imaging technique. The differential diagnosis includes carcinoma and cystadenoma.72 Adrenal cysts are relatively infrequent lesions that usually are asymptomatic. Most cases are diagnosed at surgery or autopsy. Forty-two percent of adrenal cysts are lymphangiomatous.73 The vast majority are of minute size and may be noted on CT scans performed for other reasons. Bladder lymphangioma has only been reported in one 13- year-old child who presented with microscopic, painless hematuria.74 The lesion was diagnosed by intravenous pyelography and cystoscopy and treated by partial cystectomy. Lymphangioma of the vulva or labia minora is rare.75 In one case, genital ambiguity was the mode of presentation. The lymphangioma was capillary in type and similar to those seen on the lips and tongue. Optimal treatment is complete surgical excision, without damage to surrounding vital structures, with care to include all affected tissue, since involved margins have been shown to increase the recurrence rate. Injection of sclerosing agents, irradiation, and laser therapy are rarely beneficial. Less than 30 cases of scrotal lymphangiomas have been reported. They arise in the skin of the scrotum and cannot be separated from it, although they are distinctly separate from the testis and spermatic cord.76 Definitive treatment requires surgical excision.

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One unusual case of cystic lymphangioma of the scrotum has been reported.77 A right scrotal mass had been present since early childhood, in association with several large lymph nodes in the groin, nonpitting edema of the right lower extremity, and multiple vesicles of the skin of the right lower extremity and scrotum. The lymph nodes and scrotal masses were found to be cystic lymphangioma. There was no evidence of cysts in the pelvis. It seems likely that the lymphangiomatous involvement of the lymph nodes in the inguinal region and scrotum caused lymphatic obstruction with secondary lymphedema of the lower limb. Lymphangioma of the tunica vaginalis has been reported 11 times. It is difficult to distinguish clinically from either an encysted hydrocele of the cord or a communicating hydrocele. The mass is in the anterosuperior portion of the scrotum, is separate from both testicle and scrotal skin, and transilluminates. Lymphangiomas involving the female internal genitalia are noted usually as incidental findings, but occasionally may attain a size sufficient to cause symptoms by displacement, compression, or involvement of adjacent structures.78 Most are isolated ovarian masses, although they can be seen as part of peritoneal lymphangiomatosis. Treatment of choice is total surgical excision. If neighboring vital structures are involved, precluding total resection, marsupialization may be performed. Radiotherapy is infrequently necessary as an adjunct to prevent recurrence. Bone

Solitary intraosseous lymphangioma is a very rare lesion. It has been located in the medullary cavity of long bones (Fig. 4-15), tibia, mandible, calvaria, and the small bones of the hand.79,80 Solitary lymphangioma of bone shares histologic features with systemic lymphangiomatosis and massive osteolysis.79 Metastatic disease, histiocytosis X, Gaucher disease, fibrous dysplasia, congenital fibromatosis, and neurofibromatosis are also part of the differential diagnosis.80 The lesion is frequently indolent, although it may encroach on the bone, producing pressure atrophy, destruction, and pathologic fracture. Curettage is an effective cure. Systemic Lymphangiomatosis

Systemic lymphangiomatosis is an uncommon disease characterized by multicentric angiomatous malformations of the skeletal system, with concomitant skin, soft tissue, and visceral involvement in over 50% of cases (Fig. 4-16).81 It is believed to be due to a generalized maldevelopment of the lymphatic system and has been reported with cystic outpouching of the thoracic duct.82 Synonyms include cystic angiomatosis, skeletal hemangiomatosis, multiple lymphangiectasis of bone, cystic lymphangiomatosis of bone, and cystic angiomatosis of bone. Radiographically, the long bone lesions are described as lucent areas, with or without reactive borders, with a multiloculated soap bubble appearance. In vertebrae, an area of rarefaction may be traversed by thick bony trabeculae. The under 30-year age group is most often affected, and there is no apparent sex predilection.81,82 The course of the disease appears to be benign and often self-limited in those patients without extraskeletal involvement. However, if extraskeletal involvement, especially chylous effusions, is present, the prognosis is poor.83 Management of generalized lymphangiomatosis can be challenging.84 Recurrent chylothorax and multiple pleural aspirations often result in marked protein loss, lymphocytopenia, and critically low levels of humoral and cell-mediated immunity with inherent complications. Chylopericardium with tamponade and cardiac failure can also occur. Limited success has been achieved

Fig. 4-15. A multicystic solitary intraosseous lymphangioma involving the left humerus of a 3-year-old girl. (Reprinted with permission from Jumbelic M, et al.: J Bone Joint Surg 66-A:1479, 1984.79)

with a diet of medium-chain triglycerides. Radiation of skeletal lesions may induce temporary remission. Chemotherapy has failed to control massive accumulation of chylothorax, although pleurectomy, excision of lymphatic lakes, and ligation of the thoracic duct above the diaphragm have been more successful. Systemic lymphangiomatosis is closely related to Gorham massive osteolysis, also known as acute spontaneous absorption of bone, phantom bone disease, and disappearing bone disease.81 In Gorham disease, patients typically have involvement of contiguous bones and soft tissue in the general vicinity of the bony changes. By contrast, in systemic lymphangiomatosis, the bone and visceral involvement is of a noncontiguous type. However, large soft tissue lymphangiomas can occur in Gorham disease, blurring the distinction between the two entities. The cause of Gorham disease is unknown, the clinical progression and prognosis are unpredictable, and treatment is uncertain.85 Although the angiomas themselves are benign, absorption of bone can be relentlessly progressive, and widespread involvement of the ribs and vertebrae can ultimately lead to death.81 The factors that transform a benign, localized lesion into one that causes massive bone destruction are poorly understood. Some authors speculate that the bony lesions might be embryonic rests, responsive to a stimulating growth factor or hormone, as in endometriosis or trophoblast embolism.82 Edwards et al. have reviewed this overlapping group of conditions.86

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Fig. 4-16. Giant lymphangioma involving the legs, perineum, left pelvis, and left abdomen of a fetus (27 weeks gestation). The left leg and perineum are overgrown by nodular, subcutaneous, cystic, blood-filled, tumor masses. Histologic studies confirmed the mixed lymphatic and angiomatous nature of the neoplasm. (Courtesy of Dr. Will Blackburn, Fairhope, AL.)

Skin

Lymphangiomas are mainly found in the neck and axilla, breasts and chest, and buttocks and thighs, but may occur on almost any area of skin. The highest frequency occurs during infancy, and the majority are present by age 5 years, but they may appear spontaneously in adolescence or adult life.87 No family recurrences are known. Cutaneous lymphangiomas can be capillary or cavernous. Treatment modalities include surgery, liquid nitrogen, carbon dioxide snow, local cautery, irradiation, incision and drainage, and sclerotherapy.88–90 In one review, single surgical excision cured 75% of cases and re-excision cured an additional 12%. Recently, carbon dioxide and argon lasers have been used effectively.88 References (Lymphangioma) 1. Bill AH, Sumner OS: A unified concept of lymphangioma and cystic hygroma. Surg Gynecol Obstet 120:70, 1965. 2. Landing BH, Farber S: Tumors of the Cardiovascular System. Atlas of Tumor Pathology. Armed Forces Institute of Pathology, Washington, DC, 1956. 3. Stal S, Hamilton S, Spira M: Hemangiomas, lymphangiomas, and vascular malformations of the head and neck. Otolaryngol Clin North Am 19:769, 1986. 4. Wisnicki JL: Hemangiomas and vascular malformations. Ann Plast Surg 12:41, 1984. 5. Williams HB: Hemangiomas and lymphangiomas. Adv Surg 15:317, 1981. 6. Thomson H: Cutaneous hemangiomas and lymphangiomas. Clin Plast Surg 14:341, 1987. 7. Ninh TN, Ninh TX: Cystic hygroma in children: a report of 126 cases. J Pediatr Surg 9:191, 1974.

8. Singh S, Baboo ML, Pathak IC: Cystic lymphangioma in children: report of 32 cases including lesions at rare sites. Surgery 64:947, 1971. 9. Siegel MJ, McAlister WH, Askin FN: Lymphangiomas in children: report of 121 cases. J Can Assoc Radiol 30:99, 1979. 10. Saijo M, Munro IR, Mancer K: Lymphangioma: a long term follow-up study. Plast Reconstr Surg 56:642, 1975. 11. Bhattacharyya NC, Yadav K, Mitra SK, et al.: Lymphangiomas in children. Aust N Z J Surg 51:296, 1981. 12. Van Cauwelaert P, Oruwez JA: Experience with lymphangioma. Lymphology 11:43, 1978. 13. Tatu WF, Pope TL Jr, Daniel TM, et al.: Computed tomography of mediastinal cystic hygroma in an adult: case report and review of the literature. J Comput Assist Tomogr 9:233, 1985. 14. Anderson DH: Tumours of infancy and childhood. Cancer 4:890, 1951. 15. Sheth S, Nussbaum AR, Hutchins OM, et al.: Cystic hygromas in children: sonographic-pathologic correlation. Radiology 162:821, 1987. 16. Woods D, Young JEM, Filice R, et al.: Late onset cystic hygromas: the role of CT. J Can Assoc Radiol 40:159, 1984. 17. Brock ME, Smith RJH, Parey SE, et al.: Lymphangioma. An otolaryngologic perspective. Int J Pediatr Otorhinolaryngol 14: 133, 1987. 18. Benacerraf BR, Frigoletto FD: Prenatal sonographic diagnosis of isolated congenital cystic hygroma, unassociated with lymphedema or other morphologic abnormality. J Ultrasound Med 6:63, 1987. 19. Goetsch E: Hygroma colli cysticum and hygroma axillare: pathologic and clinical study and report of 12 cases. Arch Surg 36:394, 1938. 20. Willis RA: Pathology of Tumors, ed 4. Butterworths, London, 1967, p 728. 21. Sabin FR: The origin and development of the lymphatic system. Johns Hopkins Hosp Rep 17:347, 1916. 22. Van der Putte SCJ: The early development of the lymphatic system in mouse embryos. Acta Morphol Neerl Scand 13:245, 1975. 23. Broomhead IW: Cystic hygroma of the neck. Br J Plast Surg 17:225, 1964.

Lymphatic System 24. Grabb WC, Dingman RO, Oneal RM, et al.: Facial hamartomas in children: neurofibroma, lymphangioma, and hemangioma. Plast Reconstr Surg 66:509, 1980. 25. Vistnes LM: Treatment of lymphangiomas and cystic hygromas. In: Symposium on Vascular Malformations and Melanotic Lesions. Williams HB, ed. CV Mosby, St. Louis, 1983, p 186. 26. Ravitch MM, Rush BF Jr: Cystic hygroma. In: Pediatric Surgery, ed 3. MM Ravitch, KJ Welch, CD Benson, et al., eds. Year Book Medical Publishers, Chicago, 1979, p 368. 27. Whimster IW: The pathology of lymphangioma circumscriptum. Br J Dermatol 94:473, 1976. 28. Ogita S, Tsuto T, Tokiwa K, et al.: Treatment of cystic hygroma in children with special reference to OK-432 therapy. Z Kinderchir 42:279, 1987. 29. Rootman J, Hay E, Graeb D, et al.: Orbital-adnexal lymphangiomas. A spectrum of hemodynamically isolated vascular hamartomas. Ophthalmology 93:1558, 1986. 30. Iliff WJ, Green WR: Orbital lymphangiomas. Ophthalmology 86:914, 1979. 31. Hemmer KM, Marsh JL, Milder B: Orbital lymphangioma. Plast Reconstr Surg 82:340, 1988. 32. Wilson ME, Parker PL, Chavis RM: Conservative management of childhood orbital lymphangioma. Ophthalmology 95:484, 1989. 33. Chelsky MP, Magnus DE: Conjunctival hemorrhagic lymphangiectasis. J Am Optometr Assoc 59:676, 1988. 34. Crawford AP: Lymphangioma of the parotid gland. Med J Aust 2:141, 1981. 35. Noone RB, Brown HJ: Cystic hygroma of the parotid gland. Am J Surg 120:404, 1979. 36. Myer CM, Bratcher GO: Laryngeal cystic hygroma. Head Neck Surg 6:706, 1983. 37. Cohen SR, Thompson JW: Lymphangiomas of the larynx in infants and children. A study of pediatric lymphangioma. Ann Otol Rhinol Laryngol 127(suppl):1, 1986. 38. Kahn A, Blum D, Hoffman A, et al.: Obstructive sleep apnea induced by a parapharyngeal cystic hygroma in an infant. Sleep 8:363, 1985. 39. White MA: Lymphangioma of the tongue: report of case. J Dent Child 54:280, 1987. 40. Goldberg MH, Nemarich AN, Danielson P: Lymphangioma of the tongue: medical and surgical therapy. J Oral Surg 35:841, 1977. 41. Postlethwaite KR: Lymphangiomas of the tongue. Br J Oral Maxillofac Surg 24:63, 1986. 42. Welsh F, Fahmy A, Shadid EA: Macrocheilia due to lymphangiectasia. South Med J 69:485, 1976. 43. Zachariades N, Koundouris I: Lymphangioma of the oral cavity: report of a case. J Oral Med 39:33, 1984. 44. Levin LS, Jorgenson RJ, Jarvey BA: Lymphangiomas of the alveolar ridges in neonates. Pediatrics 58:881, 1976. 45. Josephson P, Van Wyk CW: Bilateral symmetrical lymphangiomas of the gingiva. A case report. J Periodontol 55:47, 1984. 46. Seashore JH, Gardiner U, Ariyan S: Management of giant cystic hygromas in infants. Am J Surg 149:459, 1985. 47. Osborne TE, Levin LS, Tilghman DM, et al.: Surgical correction of mandibulofacial deformities secondary to large cervical cystic hygromas. J Oral Maxillofac Surg 45:1015, 1987. 48. Pike MG, Wood AJ, Corrin B, et al.: Intrathoracic extramediastinal cystic hygroma. Arch Dis Child 59:75, 1984. 49. Brown LR, Reiman HM, Rosenow EC III, et al.: Intrathoracic lymphangioma. Mayo Clin Proc 61:882, 1986. 50. Shin MS, Berland LL, Ho KJ: Mediastinal cystic hygromas: CT characteristics and pathogenetic consideration. J Comput Assist Tomogr 9:297, 1985. 51. de Orbe Rueda A, Prieto Arellano C, Diaz de Rojas F, et al.: Ultrasound diagnosis of mediastinal cystic hygroma. J Clin Ultrasound 12:180, 1984. 52. Hoffman Tretin J, Koenigsberg M, Ziprkowski M: Antenatal detection of axillary cystic hygroma. J Ultrasound Med 7:233, 1988. 53. Feutz EP, Yune HY, Mandelbaum I, et al.: Intrathoracic cystic hygroma. Radiology 108:61, 1973.

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54. Holden WE, Morris JF, Antonovic R, et al.: Adult intrapulmonary and mediastinal lymphangioma causing hemoptysis. Thorax 42:635, 1987. 55. Tamada R, Sugimachi K, Yaita A, et al.: Lymphangioma of the esophagus presenting symptoms of achalasia—a case report. Jpn J Surg 10:59, 1980. 56. Roisman I, Manny J, Fields S, et al.: Intra-abdominal lymphangioma. Br J Surg 76:485, 1989. 57. Galifer RB, Pous JG, Juskiewenski S, et al.: Intra-abdominal cystic lymphangiomas in childhood. Prog Pediatr Surg 11:173, 1978. 58. Blumhagen JD, Wood BJ, Rosenbaum DM: Sonographic evaluation of abdominal lymphangiomas in children. J Ultrasound Med 6:487, 1987. 59. Kozlowski KJ, Frazier CN, Quirk JG: Prenatal diagnosis of abdominal cystic hygroma. Prenat Diagn 8:405, 1988. 60. Axiotis CA, Zeman RK, Chuong JJH, et al.: Intra-abdominal lymphangiectatic cysts: an uncommon abdominal lesion in children and young adults. J Clin Gastroenterol 5:541, 1983. 61. Raiford TS: Tumors of the small intestine. Arch Surg 25:122, 1932. 62. Perzin KH, Bridge MF: Adenomas of the small intestine: a clinicopathologic review of 51 cases and a study of their relationship to carcinoma. Cancer 48:799, 1981. 63. Lawson JP, Myerson PJ, Myerson DA: Colonic lymphangioma. Gastrointest Radiol 1:85, 1976. 64. Davis M, Fenoglio-Preiser C, Haque AK: Cavernous lymphangioma of the duodenum: case report and review of the literature. Gastrointest Radiol 12:10, 1987. 65. Kuramoto S, Sakai S, Tsuda K, et al.: Lymphangioma of the large intestine: report of a case. Dis Colon Rectum 31:900, 1988. 66. Fowler RH: Non-parasitic benign cystic tumors of the spleen. Int Abstr Surg 96:209, 1953. 67. Pearl GS, Nassar VH: Cystic lymphangioma of the spleen. South Med J 72:667, 1979. 68. Van Steenbergen W, Joosten E, Marchal G, et al.: Hepatic lymphangiomatosis. Report of a case and review of the literature. Gastroenterology 88:1968, 1985. 69. Singer DRJ, Miller JDB, Smith G: Lymphangioma of kidney. Scott Med J 28:293, 1983. 70. Kutcher R, Rosenblatt R, Mahadevia P, et al.: Renal peripelvic multicystic lymphangiectasia. Urology 30:177, 1987. 71. Meredith WT, Levine E, Ahlstrom NG, et al.: Exacerbation of familial renal lymphangiomatosis during pregnancy. Am J Radiol 151:965, 1988. 72. Gregory IL: Lymphangioma of pancreas. N Y State J Med 76:289, 1976. 73. Foster DG: Adrenal cysts. Review of literature and report of case. Arch Surg 92:131, 1966. 74. Bolkier M, Ginesin Y, Lichtig C, et al.: Lymphangioma of bladder. J Urol 129:1049, 1983. 75. Abu-Hamad A, Provencher D, Ganjei P, et al.: Lymphangioma circumscriptum of the vulva: case report and review of the literature. Obstet Gynecol 73:496, 1989. 76. MacMillan RW, MacDonald BR, Alpern HD: Scrotal lymphangioma. Urology 23:79, 1984. 77. Merka ST, Bhatt KS, Wood FW: Cystic lymphangioma of the scrotum: a case report. J Urol 131:1179, 1984. 78. Aristizabal SA, Galindo JH, Davis JR, et al.: Lymphangiomas involving the ovary. Report of a case and review of the literature. Lymphology 10:219, 1977. 79. Jumbelic M, Feuerstein IM, Dorfman HD: Solitary intraosseous lymphangioma. J Bone Jt Surg Am 66:1479, 1984. 80. Kopperman M, Antoine JE: Primary lymphangioma of the calvarium. Am J Radiol 121:118, 1974. 81. Griffin GK, Tatu WF, Fisher LM, et al.: Systemic lymphangiomatosis: a combined diagnostic approach of lymphangiography and computed tomography. J Comput Tomogr 10:335, 1986. 82. Bowman CA, Witte MH, Witte CL, et al.: Cystic hygroma reconsidered: hamartoma or neoplasm? Primary culture of an endothelial cell line from a massive cervicomediastinal hygroma with bony lymphangiomatosis. Lymphology 17:15, 1984.

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83. Ellis GL, Brannon RB: Intraosseous lymphangiomas of the mandible. Skeletal Radiol 5:253, 1980. 84. Bhatti MAK, Ferrante JW, Gielchinsky I, et al.: Pleuropulmonary and skeletal lymphangiomatosis with chylothorax and chylopericardium. Ann Thorac Surg 40:398, 1985. 85. Canady AI, Chou SN: Cervical lymphangiomatosis with progressive craniospinal deformity. Neurosurgery 6:422, 1980. 86. Edwards WH Jr, Thompson RC, Yarsa EW: Lymphangiomatosis and massive osteolysis of the cervical spine. Clin Orthop 177:222, 1983. 87. Flanagan BP, Helwig EB: Cutaneous lymphangioma. Arch Dermatol 113:24, 1977. 88. Eliezra Y, Sklar JA: Lymphangioma circumscriptum: review and evaluation of carbon dioxide laser vaporization. J Dermatol Surg Oncol 14:357, 1988. 89. Karmody CS, Fortson JK, Calcaterra YE: Lymphangiomas of the head and neck in adults. Otolaryngol Head Neck Surg 90:283, 1982. 90. Giguere CM, Bauman NM, Sato Y, et al.: Treatment of lymphangiomas with OK-432 (picibanil) sclerotherapy. Arch Otolaryngol Head Neck Surg 128:1137, 2002.

4.5 Lymphangioleiomyomatosis Definition

Lymphangioleiomyomatosis is a benign, often multicentric, tumorlike malformation or hamartoma involving the major lymphatic trunks of the mediastinum and retroperitoneum, the lymph nodes, and pulmonary lymphatics. The terminology for the disease has evolved from lymphangiomyoma to lymphangiomyomatosis to lymphangioleiomyomatosis. To date, more than 300 cases have been described, and it is estimated that the worldwide occurrence is more than 100 new cases per year.1,2 Diagnosis

First described by Enterline and Roberts,3 lymphangioleiomyomatosis is characterized by one or more nodules of tumorlike proliferation of smooth muscle fascicles, separated from each other by lymphatic channels. Lymphangioleiomyomatosis involves the walls of preexisting lymphatic channels of all calibers, from the major lymphatic trunks in the mediastinum and retroperitoneum to small sinusoids. Occasionally, mediastinal and retroperitoneal lymph nodes are involved. In two-thirds of cases the lymphatics of the lungs are affected, causing the principal features of progressively worsening dyspnea and cyanosis, often followed by chylothorax. Proliferation of smooth muscle tissue occurs to a lesser extent in bronchioles and blood.4 Pulmonary venule obstruction causes intrapulmonary hemorrhage, pulmonary siderosis, and hemoptysis. Bronchiolar obstruction results in hyperinflation, air trapping, and frequent formation of cysts and bullae, leading to spontaneous pneumothorax in 40% of cases. Respiratory distress can thus be caused by chylous effusions, pulmonary involvement of lymphangioleiomyomatosis, and/or pneumothorax. Abdominal signs and symptoms include retroperitoneal mass, abdominal pain, swelling, and associated weight loss. There may also be chylous ascites, chylopericardium, chyluria, or lymphedema of the extremities, depending on the site(s) of lymphatic vessel involvement.5 In many cases the chest radiograph shows a diffuse, coarse, reticulonodular pattern similar to that seen in fibrosing alveolitis or pulmonary fibrosis, with or without a pleural effusion. Pulmonary function testing demonstrates a combined obstructive and restrictive ventilatory defect, with reduction in vital capacity

and gas transfer. Lymphangiography may show blockage to the flow of dye at various levels, fistulas between the thoracic duct and the pleural cavity, replacement of the thoracic duct by multiple irregular mediastinal lymphatic vessels, attenuation of retroperitoneal lymph trunks with mesenteric backflow, or lymphaticovenous communication in the pelvis.4,6 Computed tomography, magnetic resonance imaging, and radioisotope studies may be employed to define the lesion further. Occasionally, surgery or needle biopsy of the lung has been required to make the diagnosis. Lymphangioleiomyomatosis appears to present almost exclusively in women of reproductive age. In the largest reported series, the age at presentation ranged from 17 to 41 years, with rare onset of symptoms after menopause.7 Wolff found the average age to be 40.8 years, with a range of 18 to 69 years.4 Microscopic examination reveals plump clusters of spindleshaped cells coursing in various directions, forming interanastomosing trabeculae with spaces between the clusters that are lined by flattened cells. The spindle-shaped cells have regular bland nuclei without mitoses. Fine reticulin fibers surround the separate cells of the cluster and also support the endothelial cells lining the vascular spaces. The cystic spaces, with varying amounts of smooth muscle in the walls, are lymphatic channels. Electron microscopy reveals immature elongated smooth muscle cells with nuclei containing prominent small nucleoli, sparse chromatin, numerous mitochondria and small vesicles, and abundant cytoplasm. The cells are separated into groups by vascular channels lined by endothelial cells. Pulmonary lymphangioleiomyomatosis must be distinguished from other conditions in which abnormal quantities of smooth muscle are present in the lungs, including chronic bronchiectasis, emphysema, and secondary pulmonary hypertension. Smooth muscle proliferation is also a feature of benign metastasizing leiomyoma, which can present with pulmonary involvement in women of reproductive age and can be difficult to distinguish from lymphangioleiomyomatosis; of intravenous leiomyomatosis, which is characterized by direct extension of leiomyoma into the pelvic veins; and of leiomyomatosis peritonealis disseminata, a rare peritoneal seeding of benign smooth muscle nodules, often seen in association with pregnancy or gonadotropin therapy. Diffuse lung disease, histologically resembling lymphangioleiomyomatosis, has also been described in tuberous sclerosis.8 However, in tuberous sclerosis, chylothorax is conspicuously absent. The lymph nodes may be involved in both conditions. Renal angiomyolipomas occur in about half of the individuals with lymphangioleiomyomatosis and 70% of individuals with tuberous sclerosis.9 This overlap in features is particularly intriguing since tuberous sclerosis is also a hamartomatous condition, and pulmonary disease in tuberous sclerosis almost always affects women.8 Recent evidence suggests that the proliferative and invasive nature of lymphangioleiomyomatosis cells may be due, in part, to somatic mutations in TSC2, the second tuberous sclerosis gene to be identified.10 Etiology and Distribution

Although more than 100 cases of lymphangioleiomyomatosis have been described, the etiology is obscure. Hamartoma formation seems most likely, while alternative theories include reactive muscular proliferation; trauma to the thoracic duct, causing chylomediastinum and chylothorax with subsequent inflammation and secondary muscular proliferation; and neoplasia.3 The role of hormones in this condition remains unclear. This is exclusively a disease of women of reproductive age, and the onset or exacerbation of symptoms may be coincident with pregnancy.11 A

Lymphatic System

menstrual periodicity of symptoms, including dyspnea, chest pain, and even pneumothorax, has also been described. Onset of symptoms has followed chorionic gonadotropin therapy. While normal lung tissue contains no demonstrable estrogen or progesterone receptors, tissue from patients with pulmonary lymphangioleiomyomatosis has been shown on occasion to have significant receptor levels.11 Prognosis, Treatment, and Prevention

Cases with predominantly respiratory symptoms usually have a poor prognosis. Abdominal symptoms herald a more favorable course. The best outcome appears to occur with caudal involvement of the lumbar trunks and isolated peripheral lymphedema.12 Several large cohorts have been reported with survival up to 27 years, with an average survival of 9 years.4,13,14 Patients usually succumb to metabolic disturbance secondary to continuing loss of fluid, lipids, and protein in the chylous fluid leading to cachexia, hypotension, and renal failure, or to severe progressive dyspnea with recurrent chylous effusions leading to respiratory insufficiency. Surgery, with excision of the lesion in combination with ligation of the thoracic duct or lymphatic chain, and postoperative radiotherapy have been successful modes of treatment.4 Pleurectomy and pleurodesis by installation of sclerosing agents such as nitrogen mustard into the pleural cavity have been used when thoracentesis and/or diuretics have failed to limit the formation of chylous effusions.15 Peritoneal-jugular shunt has been performed, and low-fat diet has been used.5,16 Because of the presence of progesterone and, to a lesser extent, estrogen receptors, hormonal manipulation has been used with mixed results. Oophorectomy, progestational agents, and antiestrogenic compounds have been successful in some cases. Lung transplantation can be valuable therapy for end-stage lymphangiomyomatosis.17 References (Lymphangioleiomyomatosis) 1. Kelly J, Moss J: Lymphangioleiomyomatosis. Am J Med Sci 321:17, 2001.

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2. Hancock E, Osborne J: Lymphangioleiomyomatosis: a review of the literature. Respir Med 96:1, 2002. 3. Enterline HT, Roberts B: Lymphangiopericytoma. Cancer 8:582, 1955. 4. Wolff M: Lymphangiomyoma: clinicopathologic study and ultrastructural confirmation of its histogenesis. Cancer 31:988, 1973. 5. Frack MD, Simon L, Dawson BH: The lymphangiomyomatosis syndrome. Cancer 22:428, 1968. 6. Collard M, Fievez M, Godart S, et al.: The contribution of lymphography in the study of diffuse lymphangiomyomatosis. Am J Roentgenol 102:466, 1968. 7. Cornog GL, Enterline HT: Lymphangiomyoma-benign lesions of chyliferous lymphatics synonymous with lymphangiopericytoma. Cancer 19:1909, 1966. 8. Jao J, Gilbert S, Messer R: Lymphangiomyoma and tuberous sclerosis. Cancer 29:1188, 1972. 9. Smolarek TA, Wessner LL, McCormack FX, et al.: Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. Am J Hum Genet 62:810, 1998. 10. Pacheco-Rodriguez G, Kristof AS, Stevens LA, et al.: Genetics and gene expression in lymphangioleiomyomatosis. Chest 121:56S, 2002. 11. Hughes E, Hodder RV: Pulmonary lymphangiomyomatosis complicating pregnancy: a case report. J Reprod Med 32:553, 1987. 12. Abe R, Kimura M, Hirosaki A, et al.: Retroperitoneal lymphangiomyomatosis with lymphedema of the legs. Lymph 13:62, 1980. 13. Taylor JR, Ryu J, Colby TV, et al.: Lymphangioleiomyomatosis. N Engl J Med 323:1254, 1990. 14. Seyama K, Kira S, Takahashi H, et al.: Longitudinal follow up study of 11 patients with pulmonary lymphangioleiomyomatosis: diverse clinical courses of LAM allow some patients to be treated without antihormone therapy. Respirology 6:331, 2001. 15. Bush JL, McLean RL, Sicker HO: Diffuse lung disease due to lymphangiomyoma. Am J Med 46:645, 1969. 16. Joliat G, Stalder H, Kapanci Y: Lymphangiomyomatosis: a clinicoanatomical entity. Cancer 31:455, 1973. 17. Boehler A, Speich R, Russi EW, et al.: Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 335:1275, 1996.

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5 Spleen Arthur S. Aylsworth

he spleen forms during the 5th week (when the embryo is 8– 10 mm) as a local mesodermal condensation in an area of tissue on the left side of the dorsal mesogastrium. It is the only organ that is left-sided at its inception.1 The splanchnopleuric epithelium thickens to form a ridge of mesoderm that extends along the dorsolateral border of the developing stomach. The ridge lies between areas of tissue that eventually will form the gastrosplenic and pancreaticosplenic portions of the dorsal mesentery and extends to the region of the developing mesonephros (Fig. 5-1).2 Several genes involved in spleen development have been identified in the mouse. These include Hox11, Wt1, Bapx1, and capsulin. The orphan homeobox gene Hox11 is expressed in the splenic anlage arising from the splanchnic mesoderm. The human homologue, HOX11, is the T-cell acute leukemia gene that maps to 10q24. Homozygous Hox11-deficient mice have asplenia but are otherwise normal with no defects in the development of other splanchnic derivatives.3 Spleen formation begins normally in these homozygous embryos, but the splenic anlage subsequently undergoes rapid and complete resorption.4 Rudimentary spleen cells fail to organize, proliferate, or differentiate, and hematopoietic cells do not populate the tissue.5 The Wilms tumor supressor gene, Wt1, is also necessary for spleen development, as demonstrated in a homozygous Wt1-deficient mouse model.6 In these mice, the normal expression of Hox11 was not affected by the inactivation of Wt1. On the other hand, Wt1 mRNA is significantly reduced in the splenic anlage of Hox11-null mice, suggesting that Wt1 functions downstream from Hox11 in the pathway of normal spleen development.7 The human homologue, WT1, maps to 11p13. Bapx1 expression in the mouse is detected in the splanchnic mesoderm adjacent to the prospective gut endoderm and in the sclerotomal portion of the somites. The human homologue maps to 4p16.1. Targeted disruption of Bapx1 produced homozygous mice with no identifiable splenic tissue, in addition to a lethal skeletal dysplasia with defects in the axial skeleton and base of the skull.8 In addition, Hox11 expression was absent in the splanchnic mesoderm where it is normally found during spleen development. An increase in apoptosis was found in all affected tissues.9 The drosophila homologue bap also plays an important role in gut mesoderm development.

T

Human capsulin, or transcription factor 21 (TCF21), maps to 6q23-q24. In the mouse, it is expressed at sites of epithelialmesenchymal interactions in mesenchyme that encapsulates the epithelial primordia of the kidney, lung, intestine, and pancreas.10 It is also expressed in the epicardium and in the mesoderm that gives rise to the spleen. Mice homozygous for a capsulin (also called Pod1) null mutation have asplenia along with a lethal combination of lung and kidney hypoplasia.11,12 As in the Hox11and Bapx1-deficient animals, early spleen development was initiated, but there was no subsequent proliferation or differentiation of precursor cells. The spleen is intraperitoneal and freely movable. Position and fixation are related to the phrenicocolic ligament, which runs between the left flexure of the colon and the left hemidiaphragm and limits downward displacement of the spleen. The splenic artery develops from a branch of the celiac artery that passes through the dorsal mesogastrium, supplying the greater curvature of the stomach. Vascularization of the spleen occurs early in the 3rd month of development, although red pulp cords may be present as early as the 6th week. B cells and T cells appear during the 4th month and a distinction between the red and white pulp is possible by the 6th month, but germinal centers are not usually seen until the perinatal or postnatal period. Based on research in nonhuman mammals, it is assumed that the spleen plays a role in hematopoiesis during the 4th and 5th months of gestation, with decreasing importance as intramedullary hematopoiesis develops. Studies using sensitive immunohistologic techniques, however, fail to demonstrate a significant collection of true precursors of myelopoiesis in the human fetal spleen, and it has been suggested that the few precursor cells found can be accounted for by trapping from the peripheral blood.13 As in the liver, hematopoietic activity is found only occasionally at birth. References 1. Van Mierop LHS, Gessner IH, Schiebler GL: Asplenia and polysplenia syndromes. Birth Defects Orig Artic Ser VIII(5):36, 1972. 2. Sulik KK: Development of the gut with special reference to the liver, gallbladder, pancreas, and spleen: a review. Proc Greenwood Genet Center 8:91, 1989. 3. Roberts CW, Shutter JR, Korsmeyer SJ: Hox11 controls the genesis of the spleen. Nature 368:747, 1994. 183

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Fig. 5-1. A,B. Scanning electron micrographs illustrating a cut at the level of the stomach in gestational day 11 (49 somite pair) mouse embryos, corresponding to 6-week human embryos. Note the dorsal mesentery (mesogastrium, arrowheads) extending from the dorsal midline to the lateral (left) border of the stomach (S). H, hindlimb bud; G, gonadal ridge; N, neural tube; M, midgut. C. The dorsal mesentery, visualized from its dorsal side following removal of the posterior (dorsal) body wall. Note the thickened ridge of mesoderm, which represents the initial formation of the spleen (arrows). As

development proceeds, the spleen becomes suspended between the stomach and pancreas by the gastrosplenic (asterisk) and pancreaticosplenic ligaments (star), respectively. P, pancreas. D. Human, day 67. A horizontal cut was made through the stomach, spleen, and pancreas. By the time the human conceptus reaches 9 weeks, the gross morphology of this region is similar to that in the adult. P, pancreas; Sp, spleen. (From Proceedings of the Greenwood Genetic Center, vol. 8, 1989, Greenwood Genetic Center. Used by permission.)

4. Dear TN, Colledge WH, Carlton MB, et al.: The Hox11 gene is essential for cell survival during spleen development. Development 121:2909, 1995. 5. Kanzler B, Dear TN: Hox11 acts cell autonomously in spleen development and its absence results in altered cell fate of mesenchymal spleen precursors. Dev Biol 234:231, 2001. 6. Herzer U, Crocoll A, Barton D, et al.: The Wilms tumor suppressor gene Wt1 is required for development of the spleen. Curr Biol 9:837, 1999. 7. Koehler K, Franz T, Dear TN: Hox11 is required to maintain normal Wt1 mRNA levels in the developing spleen. Dev Dyn 218:201, 2000. 8. Lettice LA, Purdie LA, Carlson GJ, et al.: The mouse bagpipe gene controls development of axial skeleton, skull, and spleen. Proc Natl Acad Sci U S A 96:9695, 1999.

9. Tribioli C, Lufkin T: The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen. Development 126:5699, 1999. 10. Quaggin SE, Vanden Heuvel GB, Igarashi P: Pod-1, a mesoderm-specific basic-helix-loop-helix protein expressed in mesenchymal and glomerular epithelial cells in the developing kidney. Mech Dev 71:37-48, 1998. 11. Lu J, Chang P, Richardson JA, et al.: The basic helix-loop-helix transcription factor capsulin controls spleen organogenesis. Proc Natl Acad Sci U S A 97:9525, 2000. 12. Patterson M: A mean spleen gene. Nat Rev Genet 1:8, 2000. 13. Wolf BC, Luevano E, Neiman RS: Evidence to suggest that the human fetal spleen is not a hematopoietic organ. Am J Clin Pathol 80:140, 1983.

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Most parts of the human body are structurally symmetric about the sagittal plane. Asymmetric organs include the heart and great vessels, the lungs, the liver, the gallbladder and biliary tract, the gastrointestinal tract, and the spleen. The usual or ‘‘normal’’ positioning of the asymmetric organs is called situs solitus, and a mirror-image reversal of this arrangement is called situs inversus.

Figure 5-2A shows the ‘‘normal’’ or usual configuration of thoracic and abdominal organs. The right lung usually has three lobes, and the right mainstem bronchus is shorter and deviates from the midline by a smaller angle than the left. The right superior lobe bronchus arises and passes above the pulmonary artery and is called an eparterial bronchus, in contrast to the right middle and lower lobe bronchi, which are called hyparterial. The left mainstem bronchus is approximately twice as long as the right and narrower in diameter. It extends above the pulmonary artery but then passes below the aorta and pulmonary artery before branching into hyparterial bronchi to the superior and inferior lobes. Figure 5-2B shows situs inversus, the mirror-image reversal of the normal configuration. Total situs inversus is usually asymptomatic. Approximately 20–25% will have an immotile cilia syndrome (primary ciliary dyskinesia) and less than 10% have associated structural malformations. A normal, right-sided spleen is present. Some patients have what appears to be a combination of situs solitus and situs inversus—some organs are in their usual position and some are reversed. These individuals usually have major birth defects involving one or more of the asymmetric organs, especially malformations of the heart and great vessels, anomalies of the liver and biliary tract, and malrotation of the bowel. These patients usually have either congenital asplenia or polysplenia. Isomerism refers to the duplication of structures typical of one side of the body on the other side, a situation also described by the terms bilateral right-sidedness and bilateral left-sidedness. Asplenia has been called bilateral right-sidedness (dextroisomerism) because of the apparent bilateral duplication of right-sided

Fig. 5-2. A. Situs solitus. A schematic representation of situs solitus showing the eparterial bronchus on the right with the trilobed right lung (RL). On the left, there is a hyparterial bronchus because the pulmonary artery crosses over the bronchus. The left lung (LL) has two lobes. The left bronchus is longer than the right by about a 1.7 to 2.1 ratio. The right atrium (RA) is on the patient’s right side and the left atrium (LA) is on the left side. The abdominal viscera are normal, with the liver on the right and the spleen and stomach on the left. The inferior vena cava is to the right of the spine, and

the aorta descends to the left of the spine in the normal or situs solitus situation. B. Situs inversus. In the schematic representation of situs inversus, there is a mirror image, with the trilobed lung and eparterial bronchus on the left, a bilobed lung and hyparterial bronchus on the right, dextrocardia, and reversal of the abdominal organs and vessels. (Illustration and legend from Tonkin ILD: The definition of cardiac malpositions with echocardiography and computed tomography, in Pediatric Cardiac Imaging, WF Friedman, CB Higgins, eds, WB Saunders Company, Philadelphia, 1984. Used by permission.)

5.1 Polyasplenia Definition

A composite term that includes asplenia (absence of the spleen) and polysplenia (multiple spleens). Historically, asplenia and polysplenia (and their accompanying anomalies) have been treated as separate entities and the terms asplenia syndrome and polysplenia syndrome widely used to refer to the complex of malformations and heterotaxy that is associated with each splenic anomaly. However, because they are both associated with similar malformations in other organ systems and occasional families include cases of both, polysplenia and asplenia can be thought of as different manifestations of a common set of morphogenetic errors.1–6 Opitz coined the term polyasplenia to indicate the likelihood that asplenia and polysplenia are part of a single spectrum of malformation.7 This spectrum does not constitute a specific malformation syndrome but represents a collection of nonrandom associations with more than one causally specific syndrome. The polyasplenia spectrum includes phenotype labels such as Ivemark asplenia syndrome, polysplenia syndrome, situs ambiguus, heterotaxia, partial or complete situs inversus, isomerism, and laterality defect.8 Diagnosis

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structures, such as bilateral trilobed lungs in association with absent spleen. Polysplenia has been called bilateral left-sidedness because of the apparent bilateral duplication of left-sided structures, such as bilateral bilobed lungs in association with multiple spleens.9 In polyasplenia there is an unusual spatial arrangement of the thoracic and/or abdominal organs in relationship to each other called visceral heterotaxia or heterotaxy, as well as malformations in one or more organ systems. Note that polyasplenia with associated anomalies is sometimes incorrectly referred to as ‘‘situs inversus.’’ This term should be reserved for situations where there is a mirror-image reversal of organ relationships, that is, so-called ‘‘complete’’ situs inversus. The terms ‘‘partial’’ or ‘‘incomplete’’ situs inversus have also been used for polyasplenia, but situs ambiguus is less confusing and preferred. Figure 5-3 shows the situs ambiguus configurations associated with polyasplenia. Asplenia is found in association with right isomerism (Fig. 5-3A), and polysplenia occurs with left isomerism (Fig. 5-3B). Patients with situs ambiguus usually have lifethreatening structural malformations that can involve any organ system. Evidence that situs ambiguus and complete, mirror-image situs inversus (thoracic and/or abdominal, with or without ciliary abnormality) may be parts of the same spectrum of malformationassociation is suggested by families where both occur.4,10 Although patients with situs inversus usually have a low incidence of other structural malformations, occasional families have a high frequency of other anomalies.11 Some families have had recurrence of the malformations that are typically associated with situs

ambiguus, such as congenital heart disease with only variable occurrence of complete situs inversus or polyasplenia.11–15 One should suspect situs ambiguus in any child who has cyanotic congenital heart disease and an apparently symmetric liver, with the edge palpable across the entire upper abdomen, or an inverted liver with the left lobe larger than the right. Most visceroatrial situs abnormalities can be diagnosed with a combination of chest radiography, abdominal ultrasonography, echocardiography, and either computed tomography (CT) or magnetic resonance imaging (MRI).16 Radiography of the chest and upright abdomen will allow determination of heart malposition and mainstem bronchial anatomy, an indicator of atrial situs.17–19 Asplenia is suggested by the observation of Heinz bodies or Howell-Jolly bodies in a peripheral blood smear. Hepatobiliary radionuclide imaging may identify liver symmetry and shape.20 Radionuclide spleen scanning may also be used to identify spleen position but not spleen number, because in polysplenia the splenules may be so closely situated that they form a multilobulated mass that appears, on scan, to be a single spleen (Fig. 5-4).21,22 In polysplenia, the multiple spleens are typically, but not invariably, found along the greater curvature of the stomach.9 The electrocardiogram and echocardiogram are helpful in cases with cardiac malposition, inversion, or other malformation. Abdominal CT and MRI can be very useful when combined with ultrasonographic studies.16,23 Patients with asplenia or polysplenia usually have other, severe malformations that are life-threatening. The list of associated malformations is extensive and involves virtually every thoracic and abdominal organ system24 (Table 5-1). Most commonly,

Fig. 5-3. A. With situs ambiguus, there may be bilateral right isomerism with bilateral trilobed lungs and eparterial bronchi of the same short length. In the instance of right atrial isomerism, the atrial appendages are usually symmetric and resemble a broad-based right atrial appendage. The liver is frequently in the midline, as may be the stomach with absence of the spleen. The abdominal aorta and inferior vena cava cross to the same side of the spine in the abdomen with inferior vena cava–right atrial continuity. B. In left isomerism or polysplenia syndrome, there are bilateral hyparterial bronchi, bilobed lungs, and bilateral left atria or a

common atrium. By definition, at least two spleens are along the greater curvature of the stomach. Left isomerism frequently involves interruption of the inferior vena cava with azygos or hemiazygos continuation to a superior vena cava. Heart disease is less severe in this syndrome, with a 5–10% incidence of no congenital heart disease. (Illustration and legend from Tonkin ILD: The definition of cardiac malpositions with echocardiography and computed tomography, in Pediatric Cardiac Imaging, WF Friedman, CB Higgins, eds, WB Saunders Company, Philadelphia, 1984. Used by permission.)

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Fig. 5-4. Anatomic specimen from 2-month-old girl with polysplenia, dextrocardia, double-outlet right ventricle, ventricular septal defect, partial anomalous venous return, absent inferior vena cava with azygous continuation, patent ductus, inverted liver with left lobe larger than right, midline gallbladder, left-sided stomach, and bilateral bilobed lungs with symmetric bronchial anatomy. A. Location of spleens on

greater curvature of the left-sided stomach (arrows indicate extent of splenic mass; liver has been reflected upward). B. Multiple small spleens form a multilobulated splenic mass, the total size of which is appropriate for the age of the infant. (Illustrations courtesy of F. Dalldorf and K. Willits, Department of Pathology, University of North Carolina.)

cardiovascular anomalies predominate. As many as 90% of patients with polysplenia and 99% of patients with asplenia have congenital heart disease.16 Numerous reports of patients with situs ambiguus who have central nervous system anomalies or defects of the axial skeleton suggest that such malformations are also nonrandomly associated with the polyasplenia spectrum (Table 5-1). It should be noted that since many patients and reported series are ascertained by malformations in single organ systems (for example, congenital heart disease), prevalence data for associated anomalies may be biased.

lungs, both with eparterial bronchi). Abdominal heterotaxy also occurs, often with bowel malrotation and a symmetric liver. The stomach is frequently located on the right side. Extracardiac malformations are common and frequently involve the gastrointestinal, genitourinary, bronchopulmonary, skeletal, and central nervous systems (Table 5-1). Cardiovascular malformations are usually conotruncal anomalies and tend to be more severe than those associated with polysplenia. They include malposition, common atrium, bilateral superior vena cavae, total anomalous pulmonary venous return, transposition of the great vessels, and pulmonary stenosis or atresia (Table 5-1). The inferior vena cava and the abdominal aorta have an anomalous relationship, both lying on the same side of the spine, regardless of the side occupied by the vena cava. This relationship seemed pathognomonic for the asplenia complex until Freedom34 observed it in a patient with malformations typical of polysplenia, another example supporting the concept of a polyasplenia spectrum of malformation.

Asplenia Phenotype

Adult presentations of asplenia have been described.25 Asplenia occurs rarely in individuals with situs solitus without other severe malformations.21,26–30 Many of these have been familial cases consistent with an autosomal dominant mode of inheritance.30 Two patients with isolated agenesis of the spleen presented with secondary thrombocytosis mimicking essential thrombocythemia.29 Isolated asplenia is also a rare cause of sudden unexpected death in childhood.31 Asplenia with heterotaxy but without cardiac malformation seems to be very rare.32 A significant relationship between asplenia, cardiac malformations, and other visceral anomalies was noted by Polhemus and Schafer1 in 1952 and by Ivemark in 1955.33 Asplenia became known as bilateral right-sidedness (dextroisomerism) because of the apparent bilateral duplication of right-sided structures (for example, asplenia is commonly associated with bilateral trilobed

Polysplenia Phenotype

One or more small, accessory spleens are found commonly in individuals with situs solitus. This normal variant should not be confused with true polysplenia. Accessory spleens are usually asymptomatic but may be associated with other malformations such as splenogonadal fusion and limb reduction (see Section 5.3).

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Table 5-1. Malformations associated with asplenia and polysplenia Pulmonary42,118–120

Pulmonary isomerism (bilateral trilobed lungs with eparterial bronchi in asplenia, bilateral bilobed lungs with hyparterial bronchi in polysplenia), four-lobed lungs, anomalous (absent or extra) major fissures, pulmonary situs inversus, tracheoesophageal fistula, tracheal agenesis with bronchoesophageal fistula, total tracheopulmonary agenesis

Cardiovascular1,9,16,22,23,26,33–37,42,79,119,121–124

Malposition, single atrium, bilateral superior vena cavae, anomalous pulmonary venous return (including a rare variant with intrapulmonary drainage of one lung by the other), transposition of the great vessels, pulmonic stenosis or atresia, atrial septal defect, ventricular septal defect, atrioventricular canal, intrahepatic interruption of the inferior vena cava with azygous continuation of the superior vena cava, persistent left superior vena cava to coronary sinus, double outlet right ventricle, subaortic stenosis, hypoplastic left heart with malformed aortic and mitral valves, endocardial cushion defect, right-sided aortic arch

Skeletal125,126

Vertebral malformation (hypoplasia, dysplasia, hemivertebrae, spina bifida), scoliosis, hypoplastic sternum, radial and/or ulnar hypoplasia

Nervous2,26,36,40,42,44,95,118,119,125,127–129

Neural tube defects (anencephaly, spina bifida and encephalocele, especially craniocervical), iniencephaly, holoprosencephaly, microphthalmia, hydrocephalus, third ventricle hypoplasia, septum pellucidum abnormality, cerebellar dysplasia or hypoplasia, Dandy-Walker malformation, arteriovenous malformation, porencephaly, hydranencephaly

Craniofacial36,125,126

Cleft lip with or without cleft palate, cleft palate without cleft lip, microphthalmia

Gastrointestinal36,40,42,44,125,126,130–133

Esophageal atresia with tracheoesophageal fistula, esophageal varices, liver midline, symmetrical or inverted (left lobe larger than right), extrahepatic biliary atresia, hypoplastic or absent gallbladder with or without biliary atresia, annular or semiannular pancreas, hypoplastic pancreas, duplication of the stomach, microgastria, tubular stomach, duodenal or jejunal atresia, malrotation of the bowel, short bowel, intestinal web, duplication of the hindgut, aganglionosis, imperforate anus, rectal stenosis

Urinary26,125,126

Renal agenesis, renal hypoplasia, horseshoe kidney, double ureters, hydronephrosis, renal cysts, posterior urethral valves

Endocrine125,126,134

Fused adrenal glands, absence of one adrenal, adrenal hyperplasia

Genital125,126

Undescended testicles, testicular hypoplasia, bicornuate uterus and other unspecified uterine anomalies, ovarian cysts

Other26,125

Diaphragmatic hernia or agenesis, single umbilical artery, inguinal hernia, premature birth, fetal hydrops

In 1967, Moller and colleagues9 described similarities between patients with asplenia and polysplenia, giving the latter the term bilateral left-sidedness (levoisomerism). Two or more spleens are usually present along the greater curvature of the stomach. Patients with polysplenia typically have bilateral bilobed lungs with hyparterial bronchi, abdominal heterotaxy with bowel malrotation, and a liver that is symmetric or inverted with the larger lobe on the left. The stomach is usually right-sided. Extracardiac malformations are common as in asplenia and also involve the gastrointestinal, genitourinary, bronchopulmonary, skeletal, and central nervous systems (Table 5-1). Cardiovascular malformations most commonly include malposition, atrial septal defects, ventricular septal defects, bilateral superior vena cavae, partial anomalous pulmonary venous return, and intrahepatic interruption of the inferior vena cava with connection to the azygous or hemiazygous vein (Table 5-1). One patient with a complex of anomalies otherwise typical of the polysplenia spectrum had a single, hypoplastic, ectopic spleen.35 Adult presentations of polysplenia have been delineated.25 Unlike the situation with asplenia, a number of cases of polysplenia with heterotaxia but without severe or complex heart malformation have been observed, and rarely the diagnosis is first made in adult life.25,32,36–39 Extrahepatic biliary atresia (EHBA) occurs in a subgroup of patients who have polysplenia with other typical extracardiac anomalies but a relatively low frequency of congenital heart disease.40 It is estimated that between 6% and 23% of EHBA patients

have polysplenia and 31–50% of patients with polysplenia present with EHBA.41 Etiology and Distribution

The minimal incidence of polysplenia and asplenia was estimated by Rose and colleagues to be 1 of 40,000 live births.42 Gatrad and colleagues found 1 of 24,000 affected in an English population and 1 of 2700 affected in a highly inbred Asian population.5 Lin and colleagues found a heterotaxy prevalence of approximately 1 per 10,000 total births in Boston.43 Asplenia is more commonly reported than is polysplenia. There seems to be a male predominance in asplenia and an equal sex distribution among cases with polysplenia.16,22,26,42,44 The polyasplenia-situs ambiguus spectrum of malformation appears to be associated with errors in the early embryonic determination of body asymmetry. The genetic controls and embryologic events involved in determining situs solitus are becoming better understood as the result of elegant research in model organisms. The pathogenetic mechanisms leading to situs inversus and the polyasplenia spectrum are still largely unknown, although some causative factors and genes in the pathways of normal laterality determination have been elucidated (see Chapter 33, Introduction and Section 33.1).45–51 In asplenia, there appears to be incomplete or aberrant development of left-sided structures, and in polysplenia, bilateral development of left-sided structures. Visceral heterotaxies seem to be related to interruption of normal early embryonic morphogenetic processes, which results in

Spleen

retention of some symmetrical embryonic organization and structure.34 For example, the presence of bilateral superior vena cavae represents persistence of the normally paired anterior cardinal veins, and atrial isomerism is the result of incomplete incorporation of the left horn of sinus venosus into the coronary sinus. In asplenia, one often finds no coronary sinus and the connection of the left anterior cardinal vein (persistent left superior vena cava) to the left horn of sinus venosus (into the left atrium). Numerous abnormalities in the ciliary apparatus have been associated with the immotile cilia syndrome or primary ciliary dyskinesia.52–54 These appear to be caused by autosomal mutations that are recessively expressed. Among affected homozygotes, one-half have situs solitus and one-half have situs inversus.55 These mutant genes, therefore, seem to release the early embryo from its normal program of situs determination, allowing laterality to be established randomly with regard to situs solitus and situs inversus.55,56 Complete situs inversus usually is not associated with polyasplenia. Therefore, that group of disorders will not be covered in this entry. Immotile cilia have been found in a few individuals with situs ambiguus, however, and polysplenia and Kartagener syndrome have been observed in sibs.10,57,58 Such observations suggested that normal ciliary activity might be a part of the mechanism by which situs solitus is established, and subsequent studies have identified the importance of nodal ciliary activity at the time of gastrulation in determining normal leftright asymmetry. 51,59,60 Prenatal exposure to retinoic acid produces malformations in many organ systems in hamsters, depending on the time of treatment.61 What was reported as situs inversus was produced by treatment at the earliest times that caused anomalies, stages that are also those of peak embryo sensitivity. Both a deficit and an excess of retinoic acid can produce cardiac defects, which depend on dose and timing. The mechanism proposed was that retinoic acid causes these cardiac defects by disrupting production of the extracellular matrix.62 Subsequent studies have confirmed an important role for retinoic acid in left-right patterning.63–66 Retinoic acid acts in a synergistic manner with the type IIB activin receptor.64 Acvr2b knockout mice die shortly after birth with asplenia, complicated cardiac malformations, renal anomalies, and thoracic hypersegmentation. The human gene, ACVR2B, has been characterized, and two missense mutations have been identified in three patients with situs ambiguus. These were found by screening samples from 112 sporadic and 14 familial cases of laterality defects.67 Maternal diabetes causes fetal anomalies of the neural tube, cardiovascular system, and many other structures. In Kucera’s study of the incidence of birth defects, an anomaly referred to as ‘‘situs inversus’’ was second only to defects of the spine in the offspring of diabetic women compared to controls.68 Because these observations involved congenital anomalies diagnosed in newborns, it seems likely that all probably had some form of situs ambiguus. Subsequent reports continue to support a causative association between maternal diabetes and polyasplenia.69–71 Maternal diabetes is clearly the cause of laterality defects in the offspring of NOD mice, a model of insulin-dependent diabetes mellitus.72 The induction of polyasplenia with heterotaxy and malformation in fetuses of NOD mothers by maternal diabetes is influenced by the fetal genotype.73 The fetal genotype appears to set a level of predisposition to malformation, while the abnormal glucose homeostasis in the environment disrupts normal development in susceptible embryos. Sequence variations in HNF3beta, Lefty1, and Nodal genes have been identified that appear to

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influence the susceptibility to situs abnormalities in this mouse model.74 Most cases of polyasplenia occur sporadically, but numerous familial cases suggest that there are major monogenic factors involved. Observations of affected cousins in families initially suggested an inherited predisposition to polyasplenia.2,13 Parental consanguinity and/or familial recurrences of polyasplenia have been cited as evidence consistent with the hypothesis that some cases are caused by recessively expressed mutations in autosomal genes.1–3,5,6,13–15,33,36,42,75–88 Recessive causation of complete situs inversus without symptoms of ciliary dysfunction is also suggested by an instance of probable pseudodominant inheritance where an affected man married his cousin and had two affected sons.89 Before recognition of the ciliary disorders, Cockayne concluded that complete situs inversus was of autosomal recessive causation.90 He also suggested that different types of ‘‘partial situs inversus’’ (situs ambiguus) were of monogenic origin and that these conditions formed a continuous spectrum of malformation with ‘‘an almost perfect gradation leading up to complete transposition.’’ A significant paternal age effect for ‘‘situs inversus’’ was found among malformed babies in the Metropolitan Atlanta Congenital Defects Program, leading to the conclusion that a proportion is due to new, dominantly expressed mutations.91 Because the study ascertained babies with malformations, this group probably had situs ambiguus rather than total situs inversus. A father with complete situs inversus has had two children with different manifestations of the situs ambiguus spectrum.4 One had asplenia and the other polysplenia, both manifesting typical associated lethal anomalies. An apparent autosomal dominant predisposition to laterality defects has been described over three generations of a family.92 Two individuals had asplenia with heterotaxy (situs ambiguus), while two others had apparent complete mirror-image situs inversus without other malposition or malformation. Several other reports also suggest the existence of either straightforward autosomal dominant inheritance of situs inversus and situs ambiguus, or at least a monogenic predisposition to laterality defects running through families.4,58,93 It is unclear whether father-to-son transmission of nonsyndromic asplenia is caused by genes involved in laterality determination.94 Mathias and colleagues described a family with X-linked situs ambiguus affecting 11 males.95 Both asplenia and polysplenia occurred, with cardiac, CNS, and vertebral malformations, including sacral dysplasia with anorectal anomalies. Another X-linked family also featured caudal anomalies in the affected males and genitourinary anomalies in carrier females (bicornuate uterus, uterine septum, septate vagina and uterus), one of which also had anal stenosis.96 The causes of this phenotype of X-linked situs ambiguus with caudal dysplasia are various mutations in the X-linked gene, ZIC3.97,98 Zic3 is also the gene deleted in the X-linked mouse mutation Bent Tail. Kinked tails in these mice are due to aberrant tail bone development. Some have exencephaly. Both the hemizygous males and heterozygous females may have situs ambiguus.99,100 The Zic3 knockout mouse has a phenotype similar to the human ZIC3 mutations, including situs ambiguus, CNS malformations (exencephaly), and axial skeletal anomalies (vertebral dysplasia, fusion, and duplication).101,102 One X-linked family with a ZIC3 mutation has the unique finding of situs inversus in carrier females and situs ambiguus in males.97 The affected males had lethal malformation syndromes associated with situs ambiguus, while carrier females have mirror-image situs inversus or situs solitus. Anal anomalies occur in both affected

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males and carrier females. Most reported familial recurrences of situs inversus or situs ambiguus with caudal dysplasia are compatible with X-linked inheritance. Therefore, caudal dysplasia appears to be a clinical finding highly associated with heterotaxies caused by mutations in ZIC3. Several other nonfamilial cases of situs ambiguus with caudal dysgenesis have been described; it is not clear whether they also have ZIC3 mutations.36,103,104 Situs abnormalities are occasionally found in patients with chromosome abnormalities. Since these patients may have overexpression of duplicated genes, deficiency of deleted gene products,

or disruption of single genes, they may be useful in identifying genes involved in left-right axis determination. It should be remembered that associations reported in only a single subject may be coincidental or nonspecific. On the other hand, involvement of the same chromosomal region in more than one patient with heterotaxy may suggest a true association and support a search for candidate genes in the region. Reports of situs inversus or situs ambiguus with chromosome abnormalities are summarized in Table 5-2. Other non-chromosomal syndromes syndromes reported with asplenia or polysplenia are summarized in Table 5-3.

Table 5-2. Chromosome abnormalities associated with laterality defects Phenotype

Chromosome Abnormality 135

Situs inversus abdominus, complex congenital heart disease

dup(2)(pter-p24) and del(2)(q34-qter)

Situs ambiguus and familial split hand/foot malformation136,137

Familial, apparently balanced, reciprocal t(2;7)(q21.1;q22.1) (baby with situs ambiguus not karyotyped)

Situs inversus, malrotation, duodenal and jejunal atresia, short stature, mental retardation, seizures138

Microdeletion of 2q37.3

Adult with mild mental retardation, heterotaxy, malrotation and malposition of large and small bowel, with most of the bowel above the liver and spleen, malrotation and malposition of the right kidney, hypoplastic male genitalia138

Microdeletion of 2q37.3

Situs ambiguous139

Partial trisomy 3p(mat); [maternal translocation t(3:4)(p23;q35)]

Absent left arm, short bowel, malrotation, pseudo-obstruction, dextrocardia with situs solitus, patent ductus arteriosus, and a tiny atrophic spleen140

Mosaic ring 4 with partial trisomy of 4pter to q22.3 and partial monosomy 4q22.3 to qter

Agnathia, holoprosencephaly, situs solitus141

dup(6)(pter-p24) and del(18)(pter-p11.21)

[Similarly affected sister had apparent situs solitus but also cardiac malformations, renal hypoplasia, and malrotation] Inversely located heart, stomach, duodenum, and cecum; cerebral atrophy, hypertelorism, severe mental retardation142

46,XX,t(6;18)(q21;q21.3)

Atrioventricular septal defect, left atrial isomerism, large atrial septal defect, right-sided aorta, left inferior vena cava, persistent left superior vena cava, abdominal situs inversus with right stomach and spleen, left liver, malrotation143

46,XX,t(6;20)(q21.1;p13)

Holoprosencephaly (HPE), sacral anomalies, abdominal situs ambiguus144

46,XY,der(7)t(2;7)(p23.2;q36.1)—hemizygosity for SHH and HLXB9 probably caused the HPE and sacral anomalies, respectively

Complete situs inversus, cystic fibrosis, normal cilia by electron microscopy145

Paternal isodisomy of chromosome 7 (see iv mouse)

146

Situs ambiguus, polysplenia, bilateral split hand malformation

46,XY,ins(7;8)(q22;q12q24); insertion of 8q12q24 into 7q22

Situs inversus, volvulus with duodenal obstruction, patent ductus arteriosus, abnormal origin of the carotid artery, absent lung lobation, annular pancreas147

46,XX,t(7;16)(p22;q24)

Situs ambiguus, omphalocele, cleft lip and palate148

46,XX,del(10)(q21q23)

Asplenia, pulmonic stenosis, Hirschsprung disease, minor anomalies, mental retardation149

46,XX,t(11;20)(q13.1;q13.13)(pat)

Situs ambiguus, polysplenia [Father phenotypically normal]150

inv(11)(q13.5;q25)(pat)

Situs ambiguus, asplenia [Mother phenotypically normal]151

46,XX,t(12;13)(q13.1;p13)(mat)

Situs ambiguus [Mother phenotypically normal]46

46,XX,inv(12)(q12;q24.3)(mat)

Situs ambiguus, microcephaly, absent thumbs148

46,XX,del(13)(q31qter)

Polysplenia, hydrocephalus, intrauterine growth retardation, single umbilical artery, agenesis of the corpus callosum152

Confined placental mosaicism 47,XXX,þ16

Situs ambiguus and other features of del 18p phenotype153

del(18)(p11.21)

Dextrocardia24

22q11 deletion

Left isomerism sequence24

22q11 deletion 45,X/46,X þ mar (80%/20%)

Primary ciliary dyskinesia, situs inversus154,155 155

Mirror-image dextrocardia, complete situs inversus, 19 week fetus

45,X/46,XY

Spleen

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Table 5-3. Syndromes with asplenia or polysplenia Causation Gene/Locus

Syndrome

Major Findings

X-linked laterality syndrome95–97,99,156,157

A variable spectrum of asplenia and polysplenia, situs inversus and situs ambiguus, congenital heart disease, arrhinencephaly, meningomyelocele, sacral dysgenesis, cerebellar hypoplasia, and extrahepatic biliary atresia. In at least one family, carriers had complete, mirror-image situs inversus without other heterotaxy, but with variable degrees of caudal dysplasia such as anal atresia or stenosis

XLR (304750) ZIC3

Maternal diabetes, prenatal68,69

Situs inversus or ambiguus, sacral dysgenesis, neural tube defects, congenital heart malformation, arthrogryposis, and an extremely wide and variable spectrum of malformations involving the genitourinary tracts, gastrointestinal tract, nervous system, craniofacies, and skeleton

Multifactorial

Agnathia and/or holoprosencephaly158–168

Agnathia, holoprosencephaly, situs inversus, situs ambiguus, genitourinary anomalies

Unknown

Absence/hypoplasia of the tongue165,169–173

Microglossia or aglossia, situs inversus, situs ambiguus (possibly related to agnathia association above)

Unknown

Cumming campomelia syndrome174,175,181,182

Polysplenia, campomelia, cervical lymphocele, short bowel, multicystic/polycystic dysplasia of kidneys, liver, and/or pancreas, abnormal lung lobation (bilateral left bronchial morphology), dextrocardia, total anomalous pulmonary venous return, left superior vena cava, right aortic arch, short pancreas with absence of the body and tail

AR probable

Rare patients/families are described with polyasplenia and features of the Carpenter syndrome,176,177 Johanson-Blizzard syndrome,178 Meckel syndrome,179,180 and the autosomal recessive ciliary dyskinesia syndromes with immotile cilia.10,57,58

Prognosis, Prevention, and Treatment

Children with polyasplenia usually have other severe malformations that cause death in the newborn period or during the 1st year. Malformations associated with asplenia are more commonly lethal than those occurring with polysplenia, but rare cases have been reported of prolonged survival in patients who have asplenia and situs ambiguus with cardiac malformation.32,39,105–107 Patients with asplenia have a risk of dying from sepsis, because they lack the normal splenic functions that protect against bacterial infection, and arrhythmias.27,108 Pneumococcal and other bacterial vaccines should be considered, in conjunction with antibiotic prophylaxis, for treatment of patients with congenital asplenia.13,109 Some patients with polysplenia have cardiovascular malformations for which surgery is feasible. A suggestion has been made that heart transplantation is a viable therapy for high-risk patients with polyasplenia, and that it may offer better survival than standard surgical management for some patients with complex heart malformations.110 Orthotopic liver transplantation procedures tend to be much more complex in individuals with abdominal heterotaxy than in patients with situs solitus, initially resulting in excessive postoperative complications and poor survival rates. This is because the associated complex vascular anomalies such as interrupted inferior vena cava, preduodenal portal vein, and anomalous origin of the hepatic artery increase the technical difficulties of the operation. In spite of the need for significant technical modifications, however, polysplenia with abdominal heterotaxy is not a contraindication to liver transplantation, and good results have been obtained.111 Living-related donor grafts are now being used successfully to treat end-stage liver disease due to biliary atresia in children with polysplenia.112–114 A French national study concluded that early performance of a Kasai operation appears to

provide children with biliary atresia the best chance of survival without the need for liver transplantation.115 Prenatal diagnosis by ultrasonography is feasible and appears to be accurate.116 In pregnancies with no family history to suggest heterotaxy, affected babies can be identified by the presence of cardiac malformation, malposition, or dysrhythmia associated with other organ malposition and malformations of the skeleton, urinary tract, or central nervous system. In those with a previous history, a single anomaly in any organ system suggests recurrence. The spleen can usually be detected by 20 weeks gestation, and nonvisualization has led to the prenatal diagnosis of asplenia in fetuses with cardiac malformation and dysrhythmia.117 Berg et al. concluded that left isomerism is suggested by two or more of the following: (1) complete atrioventricular septal defect or other structural heart disease; (2) interruption of inferior vena cava with azygos continuation; (3) early fetal heart block; or (4) viscerocardiac heterotaxy. Right isomerism should be suspected when finding at least two of the following: (1) structural heart disease, namely complete atrioventricular septal defect; (2) juxtaposition of inferior vena cava and descending aorta; or (3) viscerocardiac heterotaxy.116 References (Polyasplenia) 1. Polhemus DW, Schafer WB: Congenital absence of the spleen; syndrome with atrioventricularis and situs inversus. Pediatrics 9:696, 1952. 2. Chen SC, Monteleone PL: Familial splenic anomaly syndrome. J Pediatr 91:160, 1977. 3. Zlotogora J, Elian E: Asplenia and polysplenia syndromes with abnormalities of lateralisation in a sibship. J Med Genet 18:301, 1981. 4. Niikawa N, Kohsaka S, Mizumoto M, et al.: Familial clustering of situs inversus totalis, and asplenia and polysplenia syndromes. Am J Med Genet 16:43, 1983. 5. Gatrad AR, Read AP, Watson GH: Consanguinity and complex cardiac anomalies with situs ambiguus. Arch Dis Child 59:242, 1984.

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6. De la Monte SM, Hutchins GM: Sisters with polysplenia. Am J Med Genet 21:171, 1985. 7. Opitz JM: Editorial comment on the paper by de la Monte and Hutchins on familial polyasplenia. Am J Med Genet 21:175, 1985. 8. Aylsworth AS: Clinical aspects of defects in the determination of laterality. Am J Med Genet 101:345, 2001. 9. Moller JH, Nakib A, Anderson RC, et al.: Congenital cardiac disease associated with polysplenia. A developmental complex of bilateral ‘‘left-sidedness.’’ Circulation 36:789, 1967. 10. Schidlow DV, Katz SM, Turtz MG, et al.: Polysplenia and Kartagener syndromes in a sibship: association with abnormal respiratory cilia. J Pediatr 100:401, 1982. 11. Zlotogora J, Schimmel MS, Glaser Y: Familial situs inversus and congenital heart defects. Am J Med Genet 26:181, 1987. 12. Silver W, Steier M, Chandra N: Asplenia syndrome with congenital heart disease and tetralogy of Fallot in siblings. Am J Cardiol 30:91, 1972. 13. Katcher AL: Familial asplenia, other malformations, and sudden death. Pediatrics 65:633, 1980. 14. Arnold GL, Bixler D, Girod D: Probable autosomal recessive inheritance of polysplenia, situs inversus and cardiac defects in an Amish family. Am J Med Genet 16:35, 1983. 15. Distefano G, Romeo MG, Grasso S, et al.: Dextrocardia with and without situs viscerum inversus in two sibs. Am J Med Genet 27:929, 1987. 16. Tonkin ILD: The definition of cardiac malpositions with echocardiography and computed tomography. In: Pediatric Cardiac Imaging. Friedman WF, Higgins CB, eds. WB Saunders Co, Philadelphia, 1984, p 157. 17. Van Mierop LH, Eisen S, Schiebler GL: The radiographic appearance of the tracheobronchial tree as an indicator of visceral situs. Am J Cardiol 26:432, 1970. 18. Soto B, Pacifico AD, Souza AS Jr, et al.: Identification of thoracic isomerism from the plain chest radiograph. AJR Am J Roentgenol 131:995, 1978. 19. Furlonger BJ: High kV filtered beam technique for demonstrating bronchial situs. Radiography 48:197, 1982. 20. Polga JP, Spencer RP: Hepatobiliary imaging as an aid in determining situs in a case of polysplenia. Clin Nucl Med 9:159, 1984. 21. Muir CS: Splenic agenesis and multilobulate spleen. Arch Dis Child 34:431, 1969. 22. Van Mierop LHS, Gessner IH, Schiebler GL: Asplenia and polysplenia syndromes. Birth Defects Orig Artic Ser VIII:36, 1972. 23. Winer-Muram HT, Tonkin IL: The spectrum of heterotaxic syndromes. Radiol Clin North Am 27:1147, 1989. 24. Splitt MP, Burn J, Goodship J: Defects in the determination of leftright asymmetry. J Med Genet 33:498, 1996. 25. Winer-Muram HT: Adult presentation of heterotaxic syndromes and related complexes. J Thorac Imaging 10:43, 1995. 26. Putschar WGJ, Manion WC: Congenital absence of the spleen and associated anomalies. Am J Clin Pathol 26:429, 1956. 27. Waldman JD, Rosenthal A, Smith AL, et al.: Sepsis and congenital asplenia. J Pediatr 90:555, 1977. 28. Hauser GJ, Silberman C: Incidental discovery of asplenia syndrome, with situs inversus and a normal heart by radionuclide biliary imaging. A case report. Clin Nucl Med 7:543, 1982. 29. Chanet V, Tournilhac O, Dieu-Bellamy V, et al.: Isolated spleen agenesis: a rare cause of thrombocytosis mimicking essential thrombocythemia. Haematologica 85:1211, 2000. 30. Gilbert B, Menetrey C, Belin V, et al.: Familial isolated congenital asplenia: a rare, frequently hereditary dominant condition, often detected too late as a cause of overwhelming pneumococcal sepsis. Report of a new case and review of 31 others. Eur J Pediatr 161:368, 2002. 31. Kanthan R, Moyana T, Nyssen J: Asplenia as a cause of sudden unexpected death in childhood. Am J Forensic Med Pathol 20:57, 1999. 32. Fulcher AS, Turner MA: Abdominal manifestations of situs anomalies in adults. Radiographics 22:1439, 2002. 33. Ivemark BI: Implications of agenesis of the spleen on the pathogenesis of cono-truncus anomalies in childhood: analysis of the heart malformations in the splenic agenesis syndrome, with fourteen new cases. Acta Pediatr 44(suppl 104):1, 1955.

34. Freedom RM: Aortic valve and arch anomalies in the congenital asplenia syndrome. Case report, literature review and re-examination of the embryology of the congenital asplenia syndrome. J Hopkins Med J 135:124, 1974. 35. Majeski JA, Upshur JK: Polysplenic syndrome in association with a rudimentary spleen. South Med J 69:378, 1976. 36. Peoples WM, Moller JH, Edwards JE: Polysplenia: a review of 146 cases. Pediatr Cardiol 4:129, 1983. 37. Winer Muram HT, Tonkin IL, Gold RE: Polysplenia syndrome in the asymptomatic adult: computed tomography evaluation. J Thorac Imaging 6:69, 1991. 38. Gayer G, Apter S, Jonas T, et al.: Polysplenia syndrome detected in adulthood: report of eight cases and review of the literature. Abdom Imaging 24:178, 1999. 39. Abut E, Arman A, Guveli H, et al.: Malposition of internal organs: a case of situs ambiguous anomaly in an adult. Turk J Gastroenterol 14:151, 2003. 40. Chandra RS: Biliary atresia and other structural anomalies in the congenital polysplenia syndrome. J Pediatr 85:649, 1974. 41. Varela-Fascinetto G, Castaldo P, Fox IJ, et al.: Biliary atresiapolysplenia syndrome: surgical and clinical relevance in liver transplantation. Ann Surg 227:583, 1998. 42. Rose V, Izukawa T, Moes CAF: Syndromes of asplenia and polysplenia. A review of cardiac and noncardiac malformations in 60 cases with special reference to diagnosis and prognosis. Br Heart J 37:840, 1975. 43. Lin AE, Ticho BS, Houde K, et al.: Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genet Med 2:157, 2000. 44. Mishalany H, Mahnovski V, Woolley M: Congenital asplenia and anomalies of the gastrointestinal tract. Surgery 91:38, 1982. 45. Casey B: Two rights make a wrong: human left-right malformations. Hum Mol Genet 7:1565, 1998. 46. Kosaki K, Casey B: Genetics of human left-right axis malformations. Semin Cell Dev Biol 9:89, 1998. 47. Bisgrove BW, Morelli SH, Yost HJ: Genetics of human laterality disorders: insights from vertebrate model systems. Annu Rev Genomics Hum Genet 4:1, 2003. 48. Otto EA, Schermer B, Obara T, et al.: Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 34:413, 2003. 49. Przemeck GK, Heinzmann U, Beckers J, et al.: Node and midline defects are associated with left-right development in Delta1 mutant embryos. Development 130:3, 2003. 50. Raya A, Kawakami Y, Rodriguez-Esteban C, et al.: Notch activity induces nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos. Genes Dev 17:1213, 2003. 51. Tabin CJ, Vogan KJ: A two-cilia model for vertebrate left-right axis specification. Genes Dev 17:1, 2003. 52. Afzelius BA, Mossberg B: Immotile-cilia syndrome (primary ciliary dyskinesia), including Kartagener syndrome. In: The Metabolic Basis of Inherited Disease, ed 6. Scriber CR, Beaudet AL, Sly WS, et al., eds. McGraw-Hill, NY, 1989, p 2739. 53. Meeks M, Bush A: Primary ciliary dyskinesia (PCD). Pediatr Pulmonol 29:307, 2000. 54. Cowan MJ, Gladwin MT, Shelhamer JH: Disorders of ciliary motility. Am J Med Sci 321:3, 2001. 55. Moreno A, Murphy EA: Inheritance of Kartagener syndrome. Am J Med Genet 8:305, 1981. 56. Afzelius BA: Genetical and ultrastructural aspects of the immotile-cilia syndrome. Am J Hum Genet 33:852, 1981. 57. Teichberg S, Markowitz J, Silverberg M, et al.: Abnormal cilia in a child with the polysplenia syndrome and extrahepatic biliary atresia. J Pediatr 100:399, 1982. 58. Gershoni-Baruch R, Gottfried E, Pery M, et al.: Immotile cilia syndrome including polysplenia, situs inversus, and extrahepatic biliary atresia. Am J Med Genet 33:390, 1989. 59. McGrath J, Brueckner M: Cilia are at the heart of vertebrate left-right asymmetry. Curr Opin Genet Dev 13:385, 2003.

Spleen 60. McGrath J, Somlo S, Makova S, et al.: Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114:61, 2003. 61. Shenefelt RE: Morphogenesis of malformations in hamsters caused by retinoic acid: relation to dose and stage at treatment. Teratology 5:103, 1972. 62. Sinning AR: Role of vitamin A in the formation of congenital heart defects. Anat Rec 253:147, 1998. 63. Kim SH, Son CS, Lee JW, et al.: Visceral heterotaxy syndrome induced by retinoids in mouse embryo. J Korean Med Sci 10:250, 1995. 64. Oh SP, Li E: The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev 11:1812, 1997. 65. Schneider A, Mijalski T, Schlange T, et al.: The homeobox gene NKX3.2 is a target of left-right signalling and is expressed on opposite sides in chick and mouse embryos. Curr Biol 9:911, 1999. 66. Wasiak S, Lohnes D: Retinoic acid affects left-right patterning. Dev Biol (Orlando) 215:332, 1999. 67. Kosaki R, Gebbia M, Kosaki K, et al.: Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet 82:70, 1999. 68. Kucera J: Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 7:61, 1971. 69. Gonzalez A, Krassikoff N, Gilbert-Barness EF: Polyasplenia complex with mesocardia and renal agenesis in an infant of a diabetic mother. Am J Med Genet 32:457, 1989. 70. Slavotinek A, Hellen E, Gould S, et al.: Three infants of diabetic mothers with malformations of left-right asymmetry—further evidence for the aetiological role of diabetes in this malformation spectrum. Clin Dysmorphol 5:241, 1996. 71. Martinez-Frias ML: Heterotaxia as an outcome of maternal diabetes: an epidemiological study. Am J Med Genet 99:142, 2001. 72. Morishima M, Ando M, Takao A: Visceroatrial heterotaxy syndrome in the NOD mouse with special reference to atrial situs. Teratology 44:91, 1991. 73. Morishima M, Yasui H, Ando M, et al.: Influence of genetic and maternal diabetes in the pathogenesis of visceroatrial heterotaxy in mice. Teratology 54:183, 1996. 74. Maeyama K, Kosaki R, Yoshihashi H, et al.: Mutation analysis of leftright axis determining genes in NOD and ICR, strains susceptible to maternal diabetes. Teratology 63:119, 2001. 75. Schonfeld EA, Frischman B: Syndrome of spleen agenesis, defects of the heart and vessels and situs inversus. Report of a case suggesting heredity as an aetiological factor. Helv Paediatr Acta 13:636, 1958. 76. Badr-El-Din M: Syndrome of levocardia, multiple cardiac defects, situs inversus, and absent spleen. Am Heart J 63:115, 1962. 77. Neimann N, Pernot C, Gentin G, et al.: Le syndrome d’Ivemark: cardiopathie congenitale cyanogene severe, heterotaxie thoracoabdominale complexe et asplenie ou polysplenie. Pediatrie 21:511, 1966. 78. Simpson J, Zellweger H: Familial occurrence of Ivemark syndrome with splenic hypoplasia and asplenia in sibs. J Med Genet 10:303, 1973. 79. Hallett JJ, Gang DL, Holmes LB: Familial polysplenia and cardiovascular defects. Pediatr Res 13:344, 1979. 80. Kawagoe K, Hara K, Jimbo T, et al.: Occurrence of Ivemark syndrome with polysplenia in sibs of a family. Proc Jpn Acad 56:633, 1980. 81. Hurwitz RC, Caskey CT: Ivemark syndrome in siblings. Clin Genet 22:7, 1982. 82. Neill CA: Congenital cardiac malformations and syndromes. In: Genetics of Cardiovascular Disease. Pierpont ME, Moller JH, eds. Martinus Nijhoff, Boston, 1986, p 95. 83. Toriello HV, Kokx N, Higgins JV, et al.: Sibs with the polyasplenia developmental field defect. Am J Med Genet (suppl)2:31, 1986. 84. Czeizel A: Familial situs inversus and congenital heart defects [letter]. Am J Med Genet 28:227, 1987. 85. McChane RH, Hersh JH, Russell LJ, et al.: Ivemark’s ‘‘asplenia’’ syndrome: a single gene disorder. South Med J 82:1312, 1989. 86. Cesko I, Hajdu J, Toth T, et al.: Ivemark syndrome with asplenia in siblings. J Pediatr 130:822, 1997.

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87. Cesko I, Hajdu J, Marton T, et al.: Polysplenia and situs inversus in siblings. Case reports. Fetal Diagn Ther 16:1, 2001. 88. Eronen M, Kajantie E, Boldt T, et al.: Right atrial isomerism in four siblings. Pediatr Cardiol 2003. 89. Chib P, Grover DN, Shahi BN: Unusual occurrence of dextrocardia with situs inversus in succeeding generations of a family. J Med Genet 14:30, 1977. 90. Cockayne EA: The genetics of transposition of the viscera. Quart J Med 7:479, 1938. 91. Lian ZH, Zack MM, Erickson JD: Paternal age and the occurrence of birth defects. Am J Hum Genet 39:648, 1986. 92. Casey B, Cuneo BF, Vitali C, et al.: Autosomal dominant transmission of familial laterality defects. Am J Med Genet 61:325, 1996. 93. Alonso S, Pierpont ME, Radtke W, et al.: Heterotaxia syndrome and autosomal dominant inheritance. Am J Med Genet 56:12, 1995. 94. Lindor NM, Smithson WA, Ahumada CA, et al.: Asplenia in two father-son pairs. Am J Med Genet 56:10, 1995. 95. Mathias RS, Lacro RV, Jones KL: X-linked laterality sequence: situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:111, 1987. 96. Mikkila SP, Janas M, Karikoski R, et al.: X-linked laterality sequence in a family with carrier manifestations. Am J Med Genet 49:435, 1994. 97. Gebbia M, Ferrero GB, Pilia G, et al.: X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 17:305, 1997. 98. Ferrero GB, Gebbia M, Pilia G, et al.: A submicroscopic deletion in Xq26 associated with familial situs ambiguus. Am J Hum Genet 61:395, 1997. 99. Klootwijk R, Franke B, van der Zee CEEM, et al.: A deletion encompassing Zic3 in bent tail, a mouse model for X-linked neural tube defects. Hum Mol Genet 9:1615, 2000. 100. Carrel TL, Purandare SM, Harrison W, et al.: The X-linked mouse mutation bent tail is associated with a deletion of the Zic3 locus [abstract & notes]. Am J Hum Genet 67(suppl 2):66, 2000. 101. Purandare SM, Gebbia M, Bassi MT, et al.: Zic3-deficient mice manifest defects in left-right axis development. Am J Hum Genet 67(suppl 2): 173, 2000. 102. Purandare SM, Ware SM, Kwan KM, et al.: A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129:2293, 2002. 103. Fullana A, Garcia-Frias E, Martinez-Frias ML, et al.: Caudal deficiency and asplenia anomalies in sibs. Am J Med Genet (suppl)2:23, 1986. 104. Rodriguez JI, Palacios J, Omenaca F, et al.: Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am J Med Genet 38:99, 1991. 105. Wolfe MW, Vacek JL, Kinard RE, et al.: Prolonged and functional survival with the asplenia syndrome. Am J Med 81:1089, 1986. 106. Vanhoenacker FM, De Ruysscher D, De Backer AI, et al.: Heterotaxy syndrome in an adult, with polysplenia, visceral and cardiovascular malposition. JBR-BTR 84:1, 2001. 107. Brandenburg VM, Krueger S, Haage P, et al.: Heterotaxy syndrome with severe pulmonary hypertension in an adult. South Med J 95:536, 2002. 108. Wu MH, Wang JK, Lue HC: Sudden death in patients with right isomerism (asplenism) after palliation. J Pediatr 140:93, 2002. 109. Biggar WD, Ramirez RA, Rose V: Congenital asplenia: immunologic assessment and a clinical review of eight surviving patients. Pediatrics 67:548, 1981. 110. Larsen RL, Eguchi JH, Mulla NF, et al.: Usefulness of cardiac transplantation in children with visceral heterotaxy (asplenic and polysplenic syndromes and single right-sided spleen with levocardia) and comparison of results with cardiac transplantation in children with dilated cardiomyopathy. Am J Cardiol 89:1275, 2002. 111. Farmer DG, Shaked A, Olthoff KM, et al.: Evaluation, operative management, and outcome after liver transplantation in children with biliary atresia and situs inversus. Ann Surg 222:47, 1995. 112. Maggard MA, Goss JA, Swenson KL, et al.: Liver transplantation in polysplenia syndrome: use of a living-related donor. Transplantation 68:1206, 1999. 113. Srinivasan P, Heaton ND, Rela M: Liver transplantation in polysplenia syndrome. Transplantation 71:818, 2001.

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114. Hasegawa T, Kimura T, Sasaki T, et al.: Living-related liver transplantation for biliary atresia associated with polysplenia syndrome. Pediatr Transplant 6:78, 2002. 115. Chardot C, Carton M, Spire-Bendelac N, et al.: Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996. Hepatology 30:606, 1999. 116. Berg C, Geipel A, Smrcek J, et al.: Prenatal diagnosis of cardiosplenic syndromes: a 10-year experience. Ultrasound Obstet Gynecol 22:451, 2003. 117. Chitayat D, Lao A, Wilson RD, et al.: Prenatal diagnosis of asplenia/ polysplenia syndrome. Am J Obstet Gynecol 158:1085, 1988. 118. Devi B, More JRS: Total tracheopulmonary agenesis associated with asplenia, agenesis of umbilical artery and other anomalies. Acta Paediatr Scand 55:107, 1966. 119. Majeski JA, Upshur JK: Asplenia syndrome. A study of congenital anomalies in 16 cases. JAMA 240:1508, 1978. 120. Bates AW: Variation in major pulmonary fissures: incidence in fetal postmortem examinations and a review of significant extrapulmonary structural abnormalities in sixty cases. Pediatr Dev Pathol 1:289, 1998. 121. Phoon CK, Neill CA: Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 73:581, 1994. 122. Chung JH, Suh YL, Lee HJ, et al.: Rare variant of total anomalous pulmonary venous connection: intrapulmonary drainage of one lung by the other—a case report and review of the literature. Pediatr Pathol Lab Med 17:133, 1997. 123. Campbell M, Deuchar DC: Absent inferior vena cava, symmetrical liver, splenic agenesis, and situs inversus, and their embryology. Br Heart J 29:268, 1967. 124. Ruttenberg HD, Neufeld HN, Lucas RV Jr, et al.: Syndrome of congenital cardiac disease with asplenia. Distinction from other forms of congenital cyanotic cardiac disease. Am J Cardiol 13:387, 1964. 125. Freedom RM: The asplenia syndrome: a review of significant extracardiac structural abnormalities in 29 necropsied patients. J Pediatr 81:1130, 1972. 126. Ticho BS, Goldstein AM, Van Praagh R: Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures. Am J Cardiol 85:729, 2000. 127. Pantke OA, Gorlin RJ, Burke BA: Polysplenia syndrome with skeletal and central nervous system anomalies. Birth Defects Orig Artic Ser XI(2):252, 1975. 128. Jones MC, Jones KL, Chernoff GF: Possible mesodermal origin for axial dysraphic disorders. J Pediatr 101:845, 1982. 129. Aylsworth AS, Laco JM: The association of central nervous system malformations with defects in determination of laterality. Proc Greenwood Genet Center 8:154, 1989. 130. Paddock RJ, Arensman RM: Polysplenia syndrome: spectrum of gastrointestinal congenital anomalies. J Pediatr Surg 17:563, 1982. 131. Sullivan RF, Madell SJ, Oates E, et al.: A case of biliary atresia and polysplenia. Evaluation by hepatobiliary scintigraphy. Clin Nucl Med 12:55, 1987. 132. Hernaiz D, Gohlich-Ratmann G, Konig R, et al.: Congenital microgastria, growth hormone deficiency and diabetes insipidus. Eur J Pediatr 156:37, 1997. 133. Kobayashi H, Kawamoto S, Tamaki T, et al.: Polysplenia associated with semiannular pancreas. Eur Radiol 11:1639, 2001. 134. Coen RW, Aase JM: Fusion of the adrenal glands in association with asplenia. J Pediatr 88:152, 1976. 135. Schinzel A: Catalogue of Unbalanced Chromosome Aberrations in Man, ed 2. Walter de Gruyter, Inc., Hawthorne, NY, 2001. 136. Genuardi M, Pomponi MG, Sammito V, et al.: Split hand/split foot anomaly in a family segregating a balanced translocation with breakpoint on 7q22.1. Am J Med Genet 47:823, 1993. 137. Genuardi M, Gurrieri F, Neri G: Genes for split hand/split foot and laterality defects on 7q22.1 and Xq24-q27.1. Am J Med Genet 50:101, 1994. 138. Reddy KS, Flannery D, Farrer RJ: Microdeletion of chromosome subband 2q37.3 in two patients with abnormal situs viscerum. Am J Med Genet 84:460, 1999.

139. Schinzel A, Hanson JW, Pagon RA, et al.: Trisomy 3 (p23-pter) resulting from maternal translocation, t(3;4)(p23;q35). Ann Genet 21:168, 1978. 140. Hou JW, Wang TR: Amelia, dextrocardia, asplenia, and congenital short bowel in deleted ring chromosome 4. J Med Genet 33:879, 1996. 141. Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255, 1989. 142. Kato R, Yamada Y, Niikawa N: De novo balanced translocation (6;18) (q21;q21.3 or q22) [corrected] in a patient with heterotaxia [published erratum appears in Am J Med Genet 70(1):104]. Am J Med Genet 66: 184, 1996. 143. Peeters H, Debeer P, Groenen P, et al.: Recurrent involvement of chromosomal region 6q21 in heterotaxy. Am J Med Genet 103:44, 2001. 144. Nowaczyk MJ, Huggins MJ, Tomkins DJ, et al.: Holoprosencephaly, sacral anomalies, and situs ambiguus in an infant with partial monosomy 7q/trisomy 2p and SHH and HLXB9 haploinsufficiency. Clin Genet 57:388, 2000. 145. Pan Y, McCaskill CD, Thompson KH, et al.: Paternal isodisomy of chromosome 7 associated with complete situs inversus and immotile cilia [letter]. Am J Hum Genet 62:1551, 1998. 146. Koiffmann CP, Wajntal A, de Souza DH, et al.: Human situs determination and chromosome constitution 46,XY,ins(7;8)(q22;q12q24). Am J Med Genet 47:568, 1993. 147. Warburton D: De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49:995, 1991. 148. Carmi R, Boughman JA, Rosenbaum KR: Human situs determination is probably controlled by several different genes. Am J Med Genet 44:246, 1992. 149. Freeman SB, Muralidharan K, Pettay D, et al.: Asplenia syndrome in a child with a balanced reciprocal translocation of chromosomes 11 and 20 [46,XX,t(11;20)(q13.1;q13.13)]. Am J Med Genet 61:340, 1996. 150. Iida A, Emi M, Matsuoka R, et al.: Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient with left-right axis malformation. Hum Genet 106:277, 2000. 151. Wilson GN, Stout JP, Schneider NR, et al.: Balanced translocation 12/ 13 and situs abnormalities: homology of early pattern formation in man and lower organisms? Am J Med Genet 38:601, 1991. 152. Sanchez JM, Lopez D, Panal MJ, et al.: Severe fetal malformations associated with trisomy 16 confined to the placenta. Prenat Diagn 17:777, 1997. 153. Digilio MC, Marino B, Giannotti A, et al.: Heterotaxy with left atrial isomerism in a patient with deletion 18p. Am J Med Genet 94:198, 2000. 154. Oggiano N, Kantar A, Fabbrizi E, et al.: Respiratory distress in a newborn with primary ciliary dyskinesia, situs inversus and Turner syndrome. Minerva Pediatr 46:153, 1994. 155. Ortiga DJ, Chiba Y, Kanai H, et al.: Antenatal diagnosis of mirrorimage dextrocardia in association with situs inversus and Turner’s mosaicism. J Matern Fetal Med 10:357, 2001. 156. Carrel T, Purandare SM, Harrison W, et al.: The X-linked mouse mutation bent tail is associated with a deletion of the Zic3 locus. Hum Mol Genet 9:1937, 2000. 157. Ware SM, Peng J, Zhu L, et al.: Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet 74:93, 2004. 158. Pauli RM, Graham JM Jr, Barr M Jr: Agnathia, situs inversus, and associated malformations. Teratology 23:85, 1981. 159. Leech RW, Bowlby LS, Brumback RA, et al.: Agnathia, holoprosencephaly, and situs inversus: report of a case. Am J Med Genet 29:483, 1988. 160. Hersh JH, McChane RH, Rosenberg EM, et al.: Otocephaly-midline malformation association. Am J Med Genet 34:246, 1989. 161. Robinson HB Jr, Lenke R: Agnathia, holoprosencephaly, and situs inversus. Am J Med Genet 34:266, 1989. 162. Meinecke P, Padberg B, Laas R: Agnathia, holoprosencephaly, and situs inversus: a third report. Am J Med Genet 37:286, 1990.

Spleen 163. Persutte WH, Yeasting RA, Kurczynski TW, et al.: Agnathia malformation complex associated with a cystic distention of the oral cavity and hydranencepahly. J Craniofac Genet Dev Biol 10:391, 1990. 164. Stoler JM, Holmes LB: A case of agnathia, situs inversus, and a normal central nervous system. Teratology 46:213, 1992. 165. Chabrolle JP, Labenne M, Cailliez D, et al.: [Hypoglossia, situs inversus and absence of the pituitary in a neonate: teratogenic effect of maternal hyperthermia?]. [French]. Archives de Pediatrie 5:163, 1998. 166. Ozden S, Ficicioglu C, Kara M, et al.: Agnathia-holoprosencephalysitus inversus. Am J Med Genet 91:235, 2000. 167. Tohma T, Asato Y, Chinen Y, et al.: An infant of agnathia, situs inversus, and no brain malformation. Am J Hum Genet 67(suppl 2):129, 2000. 168. Ozden S, Bilgic R, Delikara N, et al.: The sixth clinical report of a rare association: agnathia-holoprosencephaly-situs inversus. Prenat Diagn 22:840, 2002. 169. Hussels IE: Microglossia, hypodontia, micrognathia, situs inversus. Birth Defects Orig Artic Ser VII(7):282, 1971. 170. Oulis CJ, Thornton JB: Severe congenital hypoglossia and micrognathia with other multiple birth defects. J Oral Pathol 11:276, 1982. 171. Dunham ME, Austin TL: Congenital aglossia and situs inversus. Int J Pediatr Otorhinolaryngol 19:163, 1990. 172. Jang GY, Lee KC, Choung JT, et al.: Congenital aglossia with situs inversus totalis—a case report. J Korean Med Sci 12:55, 1997. 173. Amor DJ, Craig JE: Situs inversus totalis and congenital hypoglossia. Clin Dysmorphol 10:47, 2001. 174. Cumming WA, Ohlsson A, Ali A: Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:783, 1986. 175. Ming JE, McDonald-McGinn DM, Markowitz RI, et al.: Heterotaxia in a fetus with campomelia, cervical lymphocele, polysplenia, and multicystic dysplastic kidneys: expanding the phenotype of Cumming syndrome. Am J Med Genet 73:419, 1997. 176. McLoughlin TG, Krovetz LJ, Schiebler GL: Heart disease in the Laurence-Moon-Biedl-Bardet syndrome. J Pediatr 65:388, 1964. 177. Temtamy SA: Carpenter’s syndrome: acrocephalopolysyndactyly. An autosomal recessive syndrome. J Pediatr 69:111, 1966. 178. Helin I, Jodal U: A syndrome of congenital hypoplasia of the alae nasi, situs inversus, and severe hypoproteinemia in two siblings. J Pediatr 99:932, 1981. 179. Moerman P, Verbeken E, Fryns JP, et al.: Association of Meckel syndrome with M-anisosplenia in one patient. Clin Genet 22:143, 1982. 180. Shen-Schwarz S, Dave H: Meckel syndrome with polysplenia: case report and review of the literature. Am J Med Genet 31:349, 1988. 181. Urioste M, Arroyo A, Martinez-Frias ML: Campomelia, polycystic dysplasia, and cervical lymphocele in two sibs. Am J Med Genet 41:475, 1991. 182. Perez del Rio MJ, Fernandez-Toral J, Madrigal B, et al.: Two new cases of Cumming syndrome confirming autosomal recessive inheritance. Am J Med Genet 82:340, 1999.

5.2 Positional Alterations of the Spleen Definition

Positional alterations of the spleen is the positioning of the spleen outside of the left upper quadrant of the abdomen. It includes wandering spleen, floating spleen, excessive mobility of the spleen, ectopic spleen, and splenic ptosis. Diagnosis

Ectopic or ‘‘wandering’’ spleens are found in both children and adults, and symptoms may or may not be present at the time of diagnosis.1–5 An enlarged spleen with an elongated pedicle may present as an asymptomatic abdominal or pelvic mass. It often occurs in women who have no complaints other than mild, episodic abdominal pain. Torsion of the elongated pedicle causes

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acute, severe abdominal pain due to splenic congestion and/or infarction. When symptomatic, an ectopic spleen may be misdiagnosed as appendicitis, ovarian cyst, diverticulitis, cholecystitis, bowel obstruction, peritonitis, or lymphoma.3,6 In his review, Robinson7 points out that although the first postmortem description of wandering spleen was by Van Horne in 1667, it was a condition that had been recognized by Hippocrates, Pliny, Herophilus, and Galen. Abdominal palpation reveals a mass with a notched border. The mass is usually mobile, with painless movement toward the left upper quadrant and painful, limited movement in other directions. A number of imaging techniques are potentially helpful.3,4,8–11 Abdominal plain-film radiography may show a notched abdominal or pelvic mass and left upper quadrant bowel loops. Ultrasonography can detect an enlarged, ectopic, disoriented, coarsely hyperechoic spleen with characteristic vascular pulsations. This technique has the advantages of noninvasiveness, relative convenience, and lack of radiation exposure. Angiography will identify the location of the spleen, can aid in diagnosing pancreatic involvement, and is useful in demonstrating vascular compromise associated with torsion. 99mTc-sulfur colloid liver-spleen scanning can be useful in identifying and locating a splenic ectopia; significant torsion of the pedicle can interfere with uptake, resulting in a negative scan. Computed tomography (CT) may reveal an enlarged, ectopic, disoriented, radiolucent spleen and has the advantage of also allowing noninvasive assessment of the pancreatic tail. Torsion of the pedicle can also interfere with CT enhancement. A combination of two or more of these techniques may be required for accurate delineation of the anomaly. Etiology and Distribution

The spleen is normally fixed in the left upper quadrant by a combination of neighboring structures and peritoneal reflections called supporting ligaments. A combination of congenital and acquired factors is probably necessary to cause or allow location of the spleen outside of the left upper quadrant in an individual who otherwise has normal situs solitus abdominal organ positioning. Evidence for underlying, predisposing, or causative genetic factors includes observations that splenic ligamentous supports (gastrosplenic, splenorenal, splenophrenic, splenocolic, splenopancreatic, presplenic fold, pancreaticocolic, and phrenocolic) may be lax, hypoplastic, or absent. Some patients have had hypermobility or congenital anomalies of other abdominal structures, including prune belly (hypoplasia or absence of abdominal musculature, usually associated with dilation of the urinary tract and undescended testicles),12,13 renal agenesis,14,15 gastric volvulus,16–18 diaphragmatic eventration,19,20 and congenital diaphragmatic hernia.18 The lack of reported familial recurrences, however, suggests that genetic factors play a relatively minor role in causation. Acquired factors appear to include splenomegaly and abdominal laxity. Wandering spleen has been associated with splenomegaly due to chronic disease21 and multiparity.22 Early reports emphasized the association of splenic ectopia with splenomegaly (most notably hypertrophy due to malaria) and suggested that an enlarged spleen allows increased mobility by stretching and elongating the supporting structures.7,23,24 Prevalence data for wandering spleen are variable.7 In a review of 708 patients undergoing splenectomy prior to 1908, Johnston found that 139 of them (20%) had ectopic spleens.23 Of these, 52 were associated with malarial disease and 87 had idiopathic splenomegaly. On the other hand, Whipple25 does not mention

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splenic ectopia in his series of 1457 patients evaluated in a combined medical-surgical spleen clinic. Subsequent reviews suggest that the condition is probably rare.7,26 In a series of 1413 children having splenectomy between 1956 and 1965, wandering spleen is not mentioned, but four patients had torsion of the spleen.27 Estimates of the male to female ratio vary widely. There appears to be a male predominance of patients presenting in the 1st year of life but a female predominance after the age of 1.4,7,24,28 Prognosis, Prevention, and Treatment

Torsion of an elongated splenic pedicle can cause acute congestion or infarction. Mortality rates are greatest in patients who present with acute abdominal findings, especially when this occurs during pregnancy. An enlarged, congested spleen is also at increased risk of being ruptured by trauma. Early diagnosis and treatment are essential for the prevention of morbidity and mortality. Surgical options include splenectomy or splenopexy to shorten the pedicle and prevent future torsion by fixation. Originally, these were done as open procedures, but now both can be performed using laparoscopic techniques with less postoperative recovery time and fewer complications.29–36 Splenectomy, when necessary, should be accompanied by the use of pneumococcal vaccine. References (Positional Alterations of the Spleen) 1. Rodkey ML, Macknin ML: Pediatric wandering spleen: case report and review of literature. Clin Pediatr (Phila) 31:289, 1992. 2. Dawson JH, Roberts NG: Management of the wandering spleen. Aust N Z J Surg 64:441, 1994. 3. Desai DC, Hebra A, Davidoff AM, et al.: Wandering spleen: a challenging diagnosis. South Med J 90:439, 1997. 4. Brown CV, Virgilio GR, Vazquez WD: Wandering spleen and its complications in children: a case series and review of the literature. J Pediatr Surg 38:1676, 2003. 5. Dalpe C, Cunningham M: Wandering spleen as an asymptomatic pelvic mass. Obstet Gynecol 101:1102, 2003. 6. Moll S, Igelhart JD, Ortel TL: Thrombocytopenia in association with a wandering spleen. Am J Hematol 53:250, 1996. 7. Robinson AP: Wandering spleen: case report and review. Mt Sinai J Med 55:428, 1988. 8. Freeman JL, Jafri SZ, Roberts JL, et al.: CT of congenital and acquired abnormalities of the spleen. Radiographics 13:597, 1993. 9. Murray KF, Ryan SP, Hough MC: Radiological case of the month. Pancreatitis associated with a wandering spleen. Arch Pediatr Adolesc Med 149:460, 1995. 10. Paterson A, Frush DP, Donnelly LF, et al.: A pattern-oriented approach to splenic imaging in infants and children. Radiographics 19:1465, 1999. 11. Gayer G, Zissin R, Apter S, et al.: CT findings in congenital anomalies of the spleen. Br J Radiol 74:767, 2001. 12. Heydenrych JJ, du Toit DF: Torsion of the spleen and associated ‘‘prune belly syndrome.’’ A case report and review of the literature. S Afr Med J 53:637, 1978. 13. Teramoto R, Opas LM, Andrassy R: Splenic torsion with prune belly syndrome. J Pediatr 98:91, 1981. 14. Pearson JB: Torsion of the spleen associated with congenital absence of the left kidney. Br J Surg 51:393, 1964. 15. Boschert MT, Helikson MA: Splenic torsion in the presence of renal agenesis. Pediatr Surg Int 13:426, 1998. 16. Uc A, Kao SC, Sanders KD, et al.: Gastric volvulus and wandering spleen. Am J Gastroenterol 93:1146, 1998. 17. Spector JM, Chappell J: Gastric volvulus associated with wandering spleen in a child. J Pediatr Surg 35:641, 2000. 18. Pelizzo G, Lembo MA, Franchella A, et al.: Gastric volvulus associated with congenital diaphragmatic hernia, wandering spleen, and intrathoracic left kidney: CT findings. Abdom Imaging 26:306, 2001.

19. Melikoglu M, Colak T, Kavasoglu T: Two unusual cases of wandering spleen requiring splenectomy. Eur J Pediatr Surg 5:48, 1995. 20. Ratan SK, Grover SB, Kulsreshtha R, et al.: Left diaphragmatic eventration with a suprapubic spleen: report of a case. Surg Today 31:184, 2001. 21. Carswell JW: Wandering spleen: 11 cases from Uganda. Br J Surg 61:495, 1974. 22. Miller EI: Wandering spleen and pregnancy: case report. J Clin Ultrasound 3:281, 1975. 23. Johnston GB: Splenectomy. Ann Surg 48:50, 1908. 24. Abell I: Wandering spleen with torsion of the pedicle. Ann Surg 98:722, 1933. 25. Whipple AO: The medical-surgical splenopathies. Bull N Y Acad Med 15:174, 1939. 26. Pugh HL: Splenectomy, with special reference to its historical background. Int Abstr Surg 83:209, 1946. 27. Eraklis AJ, Filler RM: Splenectomy in childhood: a review of 1413 cases. J Pediatr Surg 7:382, 1972. 28. Allen KB, Andrews G: Pediatric wandering spleen—the case for splenopexy: review of 35 reported cases in the literature. J Pediatr Surg 24:432, 1989. 29. Cohen MS, Soper NJ, Underwood RA, et al.: Laparoscopic splenopexy for wandering (pelvic) spleen. Surg Laparosc Endosc 8:286, 1998. 30. Gurski RR, Schirmer CC, Fischer CA, et al.: Laparoscopic approach to wandering spleen: a case report and an update to the question. Surg Laparosc Endosc Percutan Tech 8:363, 1998. 31. Hirose R, Kitano S, Bando T, et al.: Laparoscopic splenopexy for pediatric wandering spleen. J Pediatr Surg 33:1571, 1998. 32. Haj M, Bickel A, Weiss M, et al.: Laparoscopic splenopexy of a wandering spleen. J Laparoendosc Adv Surg Tech A 9:357, 1999. 33. Nomura H, Haji S, Kuroda D, et al.: Laparoscopic splenopexy for adult wandering spleen: sandwich method with two sheets of absorbable knitted mesh. Surg Laparosc Endosc Percutan Tech 10:332, 2000. 34. Peitgen K, Majetschak M, Walz MK: Laparoscopic splenopexy by peritoneal and omental pouch construction for intermittent splenic torsion (‘‘wandering spleen’’). Surg Endosc 15:413, 2001. 35. Benevento A, Boni L, Dionigi G, et al.: Emergency laparoscopic splenectomy for ‘‘wandering’’ (pelvic) spleen: case report and review of the literature on laparoscopic approach to splenic diseases. Surg Endosc 16:1364, 2002. 36. Rosin D, Bank I, Gayer G, et al.: Laparoscopic splenectomy for torsion of wandering spleen associated with celiac axis occlusion. Surg Endosc 16:1110, 2002.

5.3 Accessory Spleens, Structural Variation, and Fusion to Other Organs Definition

Accessory spleens are small nodules of splenic tissue that are present in addition to a main spleen that is usually of normal size. Structural variations include splenic notches, clefts, and lobulation. The main spleen or accessory spleen may fuse with gonads or other organs. Polysplenia with situs ambiguus is discussed in Section 5.1. Diagnosis Accessory Spleens

One or more asymptomatic accessory spleens are found in at least 10% of the human population and usually diagnosed at surgery or incidentally at autopsy. The location of accessory splenic tissue is variable. The most common sites are the hilum of the spleen and the tail of the pancreas. Other frequent sites include the gastrosplenic ligament near the tail of the pancreas, the splenocolic

Spleen

ligament, the splenorenal ligament, the pancreaticosplenic ligament, the greater omentum, along the splenic artery, and in the connective tissue under the left diaphragm.1,2,3 They may also be found scattered on the peritoneal surface, on the transverse colon, imbedded in the liver, in the body or tail of the pancreas, in the inguinal canal, and in the scrotum. Although usually associated with a normal size spleen, a number of accessory spleens have been observed in a patient with only a very small ‘‘walnut-sized’’ main spleen.1 Approximately 15% of accessory spleens found at autopsy are located at sites sufficiently far enough from the hilum of the spleen that they would be difficult to find at routine splenectomy without a specific search being made.3 Abdominal computed tomography, ultrasound, magnetic resonance imaging, angiography, and splenic scintigraphy have been used successfully to detect accessory spleens preoperatively.4–12 A symptomatic accessory spleen usually presents as an abdominal mass with or without pain. The abdominal mass may be caused by epidermoid cyst formation.10,13–16 Accessory spleens may have long attachments causing torsion, giving rise to the term wandering accessory spleen.7,9,17–22 Since accessory spleens are found commonly as ‘‘normal’’ variant structures in individuals without other malformations, their presence in patients with other malformation associations and syndromes usually can be thought of as coincidental. The principal malformation associations that specifically involve accessory or ectopic splenic tissue are those in which fusion occurs between splenic and gonadal tissue. Structural Variation

Structural variations include splenic notches, clefts, thinning, and lobulation. These appear to be nonspecific normal variants. Splenic Fusion to Other Organs

Fusion can involve a single main spleen or accessory spleens. Splenorenal fusion occurs rarely.23,24 Accessory spleens are commonly found in the pancreas.5,25–27 Presentation as a cystic abdominal mass seems to be associated with those accessory spleens that are associated with the pancreas.10,13–15 The gonad may be attached to the spleen by a fibrous cord containing splenic tissue (continuous fusion), or ectopic rests of splenic tissue may be attached to the gonad without an intervening attachment to the spleen (discontinuous fusion).28 Pain is caused by torsion of accessory splenic tissue or obstruction of the bowel by the fibrous cord present in continuous splenogonadal fusion. When an accessory spleen is fused to a testicle in the scrotal sac, it may be mistaken for a hernia or third testicle. Patients may be aware of a testicular or scrotal mass for years prior to diagnosis.29 If a diagnosis can be made prior to or during surgery, it may be possible to avoid orchiectomy. Diagnostic techniques include radiocolloid spleen scintigraphy, angiography, ultrasound, and laparascopy.30–36 Splenogonadal fusion may be associated with other anomalies such as inguinal hernia, hydrocele, congenital heart disease, transverse limb reduction anomalies, cryptorchism, micrognathia, cleft palate, and anal anomalies. Microgastria, a rare anomaly that is sometimes seen in association with asplenia, has been noted.37 Limb anomalies, cryptorchism, and micrognathia are much more commonly associated with continuous fusion than with discontinuous fusion.29,38 The presence of any of these associated anomalies should suggest the possibility that a scrotal mass is actually benign splenic tissue rather than testicular cancer.

197

Most patients with associated limb anomalies are severely affected but not invariably so. Pauli and Greenlaw reviewed 14 cases and pointed out that the legs are usually more severely affected than the arms and, while both sides can be involved, there may be a slight predilection for the right side to be more frequently and more severely affected (Fig. 5-5).39 Most reported patients have had terminal transverse reduction anomalies. Two exceptions to this were patients with apparent absence of the femur and fibula, maintenance of a bone or bones that appeared to be tibia, severe arm reduction anomalies, and the additional atypical finding of significant central nervous system involvement.39 The combination of splenogonadal fusion with transverse limb reduction anomalies constitutes a memorable phenotype and, as such, is sometimes considered to be a separate, distinct entity (MIM No. 183300). There is obvious similarity to and overlap with phenotypes in the spectrum known as the oromandibularlimb hypogenesis syndromes.40–42 Micrognathia occurs commonly in both groups, and splenogonadal fusion has been observed in patients with normal limbs and paucity of facial expression diagnosed as ‘‘Moebius syndrome,’’ part of the oromandibular limb hypogenesis phenotypic spectrum.41,43 Etiology and Distribution Accessory Spleens

The spleen forms by a merging of the hillocks that have formed in the left side of the dorsal mesogastrium during the 5th week of development. Accessory spleens probably represent hillocks or centers of mesenchymal cell proliferation that fail to fuse with the main mass and usually remain in the gastrosplenic ligament, which eventually becomes a narrow band of mesentery attaching at the hilus of the spleen. Occasionally, peritoneal accessory spleens are found in patients after abdominal trauma or spleen surgery, suggesting that in these cases small splenic particles released by trauma or surgery find implantation sites and grow (‘‘peritoneal splenosis’’).1,33 Because accessory spleens may be difficult to detect and because they are usually studied in patients with symptoms who go on to have surgery, the true incidences of both accessory spleens and splenosis are unknown.44 One or more accessory spleens is a common variant in humans, occurring in 10–19% of patients at surgery or autopsy.2,3,25 In other animals, estimates of incidence include 23.8% in Chinese hamsters, 27% in golden hamsters, 8.9% in rabbits, and 51% in New Hampshire pigs.45 As expected for a variant that is common in the general population, accessory spleens are commonly found in patients with chromosomal abnormalities. Although not a characteristic feature of either syndrome, accessory spleens have been observed in as high as 30–50% of patients with trisomy 13 and trisomy 18 who have had thorough anatomic studies.46–48 Structural Variation

The spleen forms by a merging of the mesenchymal cell clusters that have formed in the left side of the dorsal mesogastrium during the 5th week of development. It seems likely that some spleens appear to be cleft or lobulated because of incomplete fusion of these embryonic hillocks. Splenic Fusion to Other Organs

Proximity between the developing spleen and other organs appears to predispose to abnormal connections being formed. Accessory spleens are commonly found fused to the pancreas.3,25

198

Cardiorespiratory Organs

Fig. 5-5. Drawings summarizing the limb and long bone abnormalities in 14 cases of splenogonadal fusion with limb reduction. Question mark (?) indicates cases with vaguely described limb anomalies. The cases in the box at lower right, m and n, are the two with nonterminal defects. (From Pauli RM, Greenlaw A, Am J Med Genet 13:81, 1982. John Wiley and Sons, Inc. Used by permission.)

At the time the splenic centers are growing and fusing in the dorsal mesogastrium, the mesonephros or Wolffian body is separated from them by two layers of peritoneum. During the next 5 weeks, the gonad ‘‘migrates’’ caudally, the gut tube rotates, and the splenic anlage is in close proximity to the left urogenital fold. Fusion presumably can take place at any time during this period. This anatomic relationship explains why splenogonadal fusion usually involves the left-sided gonad. Splenogonadal fusion occurs sporadically, without evidence of genetic or environmental (teratogenic) causation. The syndrome of splenogonadal fusion with limb defects also occurs sporadically. Splenogonadal fusion occurs rarely. A literature review in 1988 summarized 93 cases.29 The male to female ratio was approximately 12:1, but ascertainment was probably biased by the relative likelihood of male genital complications coming to medical attention. Fifty-one cases (45 males and six females) had the continuous type and 42 had discontinuous fusion (41 males and one female). Only two cases (2.2%) involved the right side, and both were male. Limb reduction occurred in 16 with the continuous type, but in only one of those with the discontinuous type. The cause of splenogonadal fusion with limb defects (SGFLD) is unknown, but recent reviews have pointed out similarities with syndromes in the oromandibular-limb hypogenesis spectrum, for which vascular causes have been proposed.42,49 SGFLD occurs sporadically. Associated anomalies include man-

dibular hypoplasia, cleft palate, microglossia, anal atresia, diaphragmatic hernia, and complex congenital heart malformations. Prognosis, Treatment, and Prevention Accessory Spleens

Accessory spleens are usually found coincidentally at autopsy and, therefore, are probably asymptomatic and of no clinical importance most of the time. The fibrous cord present in continuous splenogonadal fusion may cause obstruction of the bowel. When accessory spleens occur in the scrotal sac, they may be mistaken for a hernia, a third testicle, or testicular cancer. Torsion may occur, causing acute abdominal symptoms requiring surgical intervention. Undetected accessory spleens may be the underlying cause of patients with hypersplenism failing to respond to splenectomy, in which case a second surgical exploration may be necessary.50,51 For example, recurrence of idiopathic thrombocytopenic purpura years after splenectomy has been reported numerous times as the result of one or more accessory spleens not identified at the time of initial surgery. Since accessory spleens may be missed, a specific search should be made prior to or during surgery. Preoperative and intraoperative imaging techniques such as computed tomography and scintigraphy may be useful, especially in the case where a patient has failed to respond to initial splenectomy and reoperation is being considered.

Spleen

Splenogonadal Fusion

Often it is difficult to avoid orchiectomy when the patient has splenogonadal fusion and testicular cancer is in the original differential diagnosis. When a testicle is intraabdominal, the presence of splenogonadal fusion does not necessarily eliminate the possibility of cancer.52 The association of splenogonadal fusion with transverse limb reduction anomalies is usually, but not universally, a lethal combination of severe malformations. Most patients have other associated anomalies and die during early infancy. One boy, however, with severe deficiency of all limbs, splenogonadal fusion, mild developmental delay, and micrognathia had otherwise good health at age 10 years.39 Ultrasonography and spleen scintigraphy are recommended for all patients with the Hanhart phenotype and the femoral-facial syndrome, because of their associated anomalies and similarities to patients with the SGFLD phenotype.34,39,42,49 References (Accessory Spleens, Structural Variation, and Fusion to Other Organs) 1. Robertson RF: The clinical importance of accessory spleens. Can Med Assoc J 39:222, 1938. 2. Eraklis AJ, Filler RM: Splenectomy in childhood: a review of 1413 cases. J Pediatr Surg 7:382, 1972. 3. Wadham BM, Adams PB, Johnson MA: Incidence and location of accessory spleens. N Engl J Med 304:111, 1981. 4. Koyanagi N, Kanematsu T, Sugimachi K: Preoperative computed tomography and scintigraphy to facilitate the detection of accessory spleen in patients with hematologic disorders. Jpn J Surg 18:101, 1988. 5. Harris GN, Kase DJ, Bradnock H, et al.: Accessory spleen causing a mass in the tail of the pancreas: MR imaging findings. AJR Am J Roentgenol 163:1120, 1994. 6. Marchant LK, Levine MS, Furth EE: Splenic implant in the jejunum: radiographic and pathologic findings. Abdom Imaging 20:518, 1995. 7. Jans R, Vanslembrouck R, Van Hoe L, et al.: Torsion of accessory spleen in an adult patient: imaging findings at CT, MRI and angiography. J Belge Radiol 80:229, 1997. 8. Barawi M, Bekal P, Gress F: Accessory spleen: a potential cause of misdiagnosis at EUS. Gastrointest Endosc Clin N Am 52:769, 2000. 9. Perez Fontan FJ, Soler R, Santos M, et al.: Accessory spleen torsion: US, CT and MR findings. Eur Radiol 11:509, 2001. 10. Yokomizo H, Hifumi M, Yamane T, et al.: Epidermoid cyst of an accessory spleen at the pancreatic tail: diagnostic value of MRI. Abdom Imaging 27:557, 2002. 11. Miyayama S, Matsui O, Yamamoto T, et al.: Intrapancreatic accessory spleen: evaluation by CT arteriography. Abdom Imaging 28:862, 2003. 12. Ota T, Ono S: Intrapancreatic accessory spleen: diagnosis using contrast enhanced ultrasound. Br J Radiol 77:148, 2004. 13. Tsutsumi S, Kojima T, Fukai Y, et al.: Epidermoid cyst of an intrapancreatic accessory spleen—a case report. Hepatogastroenterology 47:1462, 2000. 14. Horibe Y, Murakami M, Yamao K, et al.: Epithelial inclusion cyst (epidermoid cyst) formation with epithelioid cell granuloma in an intrapancreatic accessory spleen. Pathol Int 51:50, 2001. 15. Sonomura T, Kataoka S, Chikugo T, et al.: Epidermoid cyst originating from an intrapancreatic accessory spleen. Abdom Imaging 27:560, 2002. 16. Mori M, Ishii T, Iida T, et al.: Giant epithelial cyst of the accessory spleen. J Hepatobiliary Pancreat Surg 10:118, 2003. 17. Grunspan M, Wechsler U, Weintraub S: Torsion of an accessory spleen simulating acute appendicitis. Isr J Med Sci 17:458, 1981. 18. Seo T, Ito T, Watanabe Y, et al.: Torsion of an accessory spleen presenting as an acute abdomen with an inflammatory mass. US, CT, and MRI findings. Pediatr Radiol 24:532, 1994.

199 19. Dahlin LB, Anagnostaki L, Delshammar M, et al.: Torsion of an accessory spleen in an adult. Case report. Eur J Surg 161:607, 1995. 20. Erden A, Karaalp G, Ozcan H, et al.: Wandering accessory spleen. Surg Radiol Anat 17:89, 1995. 21. Valls C, Mones L, Guma A, et al.: Torsion of a wandering accessory spleen: CT findings. Abdom Imaging 23:194, 1998. 22. Kaniklides C, Wester T, Olsen L: Accessory wandering spleen associated with short pancreas. A pediatric case report. Acta Radiol 40:104, 1999. 23. Rosenthal JT, Bedetti CD, Labayen RF, et al.: Right splenorenal fusion with associated hypersplenism. J Urol 126:812, 1981. 24. Obley DL, Slasky BS, Bron KM: Right-sided splenorenal fusion with arteriographic, ultrasonic, and computerized tomographic correlation. Urol Radiol 4:221, 1982. 25. Halpert B, Gyorkey F: Accessory spleen in the tail of the pancreas. Arch Pathol 64:266, 1957. 26. Lauffer JM, Baer HU, Maurer CA, et al.: A rare cause of a pancreatic mass. Int J Pancreatol 25:65, 1999. 27. Weiand G, Mangold G: Accessory spleen in the pancreatic tail—a neglected entity? A contribution to embryology, topography and pathology of ectopic splenic tissue. Chirurg 74:1170, 2003. 28. Putschar WGJ, Manion WC: Splenic-gonadal fusion. Am J Pathol 32:15, 1956. 29. Walther MM, Trulock TS, Finnerty DP, et al.: Splenic gonadal fusion. Urology 32:521, 1988. 30. Guarin U, Dimitrieva Z, Ashley SJ: Splenogonadal fusion—a rare congenital anomaly demonstrated by 99mTc-sulfur colloid imaging: case report. J Nucl Med 16:922, 1975. 31. Heloury Y, Valayer J, Leborgne J, et al.: Spleno-gonadal fusion: anatomic and angiographic study of a case. Surg Radiol Anat 8:147, 1986. 32. McLean GK, Alavi A, Ziegler MM, et al.: Splenic-gonadal fusion: identification by radionuclide scanning. J Pediatr Surg 16:649, 1981. 33. Sty JR, Conway JJ: The spleen: development and functional evaluation. Sem Nucl Med 15:276, 1985. 34. Steinmetz AP, Rappaport A, Nikolov G, et al.: Splenogonadal fusion diagnosed by spleen scintigraphy. J Nucl Med 38:1153, 1997. 35. Braga LH, Braga MM, Dias MA: Laparoscopic diagnosis and treatment of splenogonadal fusion associated with intra-abdominal cryptorchidism in a child. Pediatr Surg Int 15:465, 1999. 36. Rubenstein RA, Dogra VS, Seftel AD, et al.: Benign intrascrotal lesions. J Urol 171:1765, 2004. 37. Mandell GA, Heyman S, Alavi A, et al.: A case of microgastria in association with splenic-gonadal fusion. Pediatr Radiol 13:95, 1983. 38. Le Roux PJ, Heddle RM: Splenogonadal fusion: is the accepted classification system accurate? BJU Int 85:114, 2000. 39. Pauli RM, Greenlaw A: Limb deficiency and splenogonadal fusion. Am J Med Genet 13:81, 1982. 40. Barr M: Amelia-splenogonadal fusion and Hanhart syndrome: the same or different conditions? Proc Greenwood Genet Center 6:180, 1987. 41. Lammens M, Moerman P, Fryns JP, et al.: Neuropathological findings in Moebius syndrome. Clin Genet 54:136, 1998. 42. Bonneau D, Roume J, Gonzalez M, et al.: Splenogonadal fusion limb defect syndrome: report of five new cases and review. Am J Med Genet 86:347, 1999. 43. Sieber WK: Splenotesticular cord (splenogonadal fusion) associated with inguinal hernia. J Pediatr Surg 4:208, 1969. 44. Targarona EM, Espert JJ, Lomena F, et al.: Inadequate detection of accessory spleens and splenosis with laparoscopic splenectomy: a shortcoming of the laparoscopic approach in hematological diseases. Surg Endosc 13:196, 1999. 45. Yoon YS, Shin JW, Park CB, et al.: Morphological structure of accessory spleen in Chinese hamsters. J Vet Sci 1:73, 2000. 46. Mottet NK, Jensen H: The anomalous embryonic development associated with trisomy 13-15. Am J Clin Pathol 43:334, 1965. 47. Warkany J, Passarge E, Smith LB: Congenital malformations in autosomal trisomy syndromes. Am J Dis Child 112:502, 1966. 48. Hashida Y, Jaffe R, Yunis EJ: Pancreatic pathology in trisomy 13. Pediatr Pathol 1:169, 1983.

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49. McPherson F, Frias JL, Spicer D, et al.: Splenogonadal fusion-limb defect ‘‘syndrome’’ and associated malformations. Am J Med Genet 120A:518, 2003. 50. Walters DN, Roberts JL, Votaw M: Accessory splenectomy in the management of recurrent immune thrombocytopenic purpura. Am Surg 64:1077, 1998.

51. MacDonald JK, Wilke RA, Jacobs WE: Accessory spleens in the thoracic and abdominal cavities after a relapse of idiopathic thrombocytopenic purpura: a case report. J Nucl Med Technol 28:49, 2000. 52. Imperial SL, Sidhu JS: Nonseminomatous germ cell tumor arising in splenogonadal fusion. Arch Pathol Lab Med 126:1222, 2002.

6 The Lower Respiratory Organs Laurie H. Seaver

T

he lower respiratory organs consist of the larynx (including the epiglottis), trachea, bronchi, and lungs. The diaphragm, although not a respiratory tract organ per se, is included here because malformations of this organ impact the developing respiratory tract. The frequency of congenital lung and airway anomalies is reported to comprise approximately 7–19% of all congenital malformations, although this may be an underestimate since some malformations are asymptomatic or delayed in presentation.1 The malformations discussed in this chapter are presented because they frequently come to the attention of those interested in the field of birth defects, because they impact prenatal, perinatal, or neonatal management, or because they are frequently associated with other respiratory tract and nonrespiratory tract malformations. The pertinent embryology is discussed within each section. Little is known about molecular developmental pathways of the respiratory tract. Hepatocyte nuclear factor-3ß (HNF-3ß) is a transcription factor important in early embryonic development, including the endoderm of the foregut from which the respiratory tract is derived.2 Another transcription factor, thyroid transcription factor-1 (TTF-1) is also critical in early lung embryogenesis, specifically regulating genes involved in the development of the respiratory epithelium.2 Successive stages of lung growth and differentiation include branching and the development of pulmonary parenchyma, cartilage and pulmonary vessels. A variety of growth factors, including fibroblast growth factors, plateletderived growth factors, and vascular endothelial growth factors are required. There are now animal models, and a few human examples, of developmental lung defects associated with disruption of specific genes and pathways.2

6.1 Bifid Epiglottis Definition

Bifid epiglottis is an epiglottis with two distinct cartilaginous halves and a midline cleft extending at least two-thirds of its length.1 Excluded are minor defects, including notching, indentation, or a submucosal bifid appearance, which are much more frequent. Diagnosis

Symptoms of a bifid epiglottis are often present in the neonatal period or infancy and include stridor, aspiration, and/or failure to thrive. Some cases, however, are asymptomatic.2,3 The diagnosis is made by direct laryngoscopy (Fig. 6-1). Etiology and Distribution

Bifid epiglottis is a rare defect, with less than 50 cases reported in the literature.1,3 In a review of 21 cases, Stroh et al. reported 13 males and 8 females of various racial backgrounds, primarily Caucasian (90%).1 It may be an isolated finding but more commonly is associated with other anomalies. Polydactyly, facial clefts, hypopituitarism, hypothalamic hamartoma, genitourinary defects, Fig. 6-1. Bifid epiglottis in a patient with Bardet-Biedl syndrome. Courtesy of Drs. Cathy Stevens and Joel C. Ledbetter, T.C. Thompson Children’s Hospital, Chattanooga, TN.

References 1. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby Inc., St. Louis, 1999, p 1106. 2. Whitsett JA, Wert SE: Molecular determinants of lung development. In: Kendig’s Disorders of the Respiratory Tract in Children, ed 6. Chernick V, Boat TF, Kendig EL Jr, eds. WB Saunders Company, Philadelphia, 1998, p 3. The author acknowledges the important contributions of Gary M. Albers and Robert E. Wood to the first edition of this text, which provided the basis for this chapter.

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202

Cardiorespiratory Organs Table 6-1. Syndromes with bifid epiglottis Syndrome

Significant Features

Causation Gene/Locus

Pallister-Hall

Hypothalamic hamartoma, postaxial polydactyly, imperforate anus, genital and cardiac defects

AD (146510) GLI3, 7p13

Bardet-Biedl

Mental retardation, pigmentary retinopathy, polydactyly, obesity, hypogenitalism

AR (209900) BBS1, 11q13 BBS2, 16q21 BBS4, 15q22.3-q23 BBS6, 20p12 BBS7, 4q27 Also 3p13-p12, 2q31

McKusick-Kaufman

Hydrometrocolpos, polydactyly, hypospadias, obesity, retinal dystrophy

AR (236700) BBS6, 20p12

Hirschsprung disease, heart defects, laryngeal anomalies, preaxial polydactyly5

Cleft lip/palate, hallux duplication, postaxial polydactyly, cardiac defect, Hirschsprung disease

AR (604211)

Hypothyroidism, spiky hair, cleft palate6

Athyroidal hypothyroidism, choanal atresia, cleft palate, abnormal hair

AR (241850) FKHL15/TTF2, 9q22

Joubert7

Episodic hyperpnea, abnormal eye movements, retinal coloboma, macrocephaly, prominent forehead, cerebellar vermis hypoplasia, ‘‘molar tooth’’ sign on cranial imaging

AR (213300) 9q34.3

Weyers acrofacial dysostosis8

Postaxial polydactyly, mandibular hypoplasia, short limbs, teeth and nail defects

AD (193530) EVC, 4p16

gastrointestinal defects, and cardiac defects are common.1,3 Fifty percent of patients with bifid epiglottis have a potentially lethal central nervous system lesion, and therefore cranial magnetic resonance imaging and endocrine evaluation are important.1 Bifid epiglottis should strongly be considered in a patient with polydactyly who presents with stridor and/or aspiration.1 Syndromes associated with bifid epiglottis are reported in Table 6-1. The embryology of the epiglottis is not well-understood. The epiglottis arises from the hypobranchial eminence (third and fourth branchial arches), but it is less clear whether this is a midline structure or a bilateral structure. Based on an example of a tricleft epiglottis, Sturgis and Howell proposed that the hypobranchial eminence arises from two midline swellings that fuse separately from the fourth branchial arch.4 The lateral portions of the epiglottis are derived from the fourth branchial arch, which fuses to the hypobranchial eminence. This hypothesis would explain midline, off-midline, and both narrow and wide clefts of the epiglottis.1,4 Prognosis and Treatment

Treatment of bifid epiglottis is dependent on the degree of symptomatology. There are few reports of surgical correction. Microlaryngoscopy with carbon dioxide laser and epiglottectomy with tracheostomy have been attempted in cases with severe symptoms of aspiration or airway compromise.9,10 References (Bifid Epiglottis) 1. Stroh B, Rimmell FL, Mendelson N: Case report: bifid epiglottis. Int J Pediatr Otorhinolaryngol 47:81, 1999. 2. Ondrey F, Griffth A, Van Waes C, et al.: Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome. Am J Med Genet 94:64, 2000.

3. Stevens CA, Ledbetter JC: The significance of bifid epiglottis. Presented at the 24th Annual David W. Smith Workshop on Malformations and Morphogenesis, Vancouver, British Columbia, 2003. 4. Sturgis EM, Howell LL: Bifid epiglottis syndrome. Int J Pediatr Otorhinolaryngol 33:149, 1995. 5. Huang T, Elias ER, Mulliken JB, et al.: A new syndrome: heart defects, laryngeal anomalies, preaxial polydactyly and colonic aganglionosis in sibs. Genet Med 1:104, 1999. 6. Bamforth JS, Hughes IA, Lazarus JH, et al.: Congenital hypothyroidism, spiky hair, and cleft palate. J Med Genet 26:49, 1989. 7. Sung MW, Kim JW, Kim KH: Bifid epiglottis associated with Joubert’s syndrome. Ann Otol Rhinol Laryngol 110:194, 2001. 8. Wittig FJ, Hickey SA, Kumar M: Double epiglottis in Weyer’s acrofacial dysostosis. J Laryngol Otol 112:976, 1998. 9. Montreuil F: Bifid epiglottis—report of a case. Laryngoscope 59:194, 1949. 10. Prescott CA: Bifid epiglottis: a case report. Int J Pediatr Otorhinolaryngol 30:167, 1994.

6.2 Laryngeal Atresia, Webs, and Stenosis Definition

Laryngeal atresia, webs, and stenosis are a spectrum of anomalies of arrested development of the larynx resulting in various combinations of supraglottic, glottic, and subglottic obstruction or hypoplasia. This excludes acquired forms of subglottic stenosis. Diagnosis

The clinical presentation of this category of laryngeal anomalies depends on the severity of the obstruction. Complete laryngeal atresia presents immediately upon delivery of the infant with severe respiratory distress and cyanosis, no audible cry, and inability

The Lower Respiratory Organs

to pass an endotracheal tube. If the infant can be successfully resuscitated by emergency tracheotomy, diagnosis can be confirmed by laryngoscopy augmented by computerized tomography. Some infants can be ventilated by mask or esophageal intubation if a tracheoesophageal fistula is present. The diagnosis of laryngeal atresia has been made prenatally by ultrasonography and is characterized by increased echogenicity of large lungs, inverted diaphragms, dilated trachea, ascites, or other signs of fetal hydrops1–3 (Fig. 6-2). Marked immature amniotic fluid lung maturity studies have also been reported near term.4 Laryngeal webs, typically at the level of the glottis, may also present with variable symptom severity, depending on the degree of obstruction, including severe respiratory distress, inspiratory stridor, weak or hoarse voice or cry, and recurrent crouplike illness.5,6 Diagnosis can be suggested by well-penetrated lateral radiograph of the neck, but flexible laryngoscopy and/or rigid endoscopy of the airway are typically required. Barium swallow is used to differentiate from other laryngeal defects, including laryngeal clefts, tracheoesophageal fistula, or vascular rings.5 Congenital subglottic stenosis accounts for approximately 19% of congenital laryngeal abnormalities and is the most common congenital indication for tracheostomy in infants. Acquired subglottic stenosis is more common than congenital, and it is typically more severe than the congenital form.5 Symptoms vary with the degree of obstruction, which can range from mild to severe. Individuals may be asymptomatic, only noted to accept a smaller than expected endotracheal tube placed for an unrelated procedure, or may have recurrent crouplike illnesses. Inspiratory and expiratory stridor and a weak cry may also suggest the diagnosis. The diagnosis may be suspected on a standard anterior-

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posterior view of the neck, although flexible or rigid laryngoscopy is required to fully evaluate the airway.5 Etiology and Distribution

The embryology of the larynx, and the classification of laryngeal obstructive abnormalities based on embryologic principles, has been the subject of numerous reviews.6–8 The larynx begins to develop during the fourth week of development on day 25 with thickening of the epithelium, the respiratory primordium, along the ventral foregut. The respiratory diverticulum, the outpouching of the foregut on the floor of the primitive pharynx, extends into the respiratory primordium and delineates the level of the glottis. The respiratory diverticulum extends caudally as the trachea and separates from the esophagus. Abnormal septation between the primitive respiratory and gastrointestinal tracts gives rise to laryngotracheoesophageal clefting and fistula. The muscular and cartilaginous structures of the larynx derive from the fourth and sixth pharyngeal arches. Rapid proliferation of the surrounding mesenchyme forms the arytenoid swellings, changing the primitive sagittal orifice to a T-shaped opening. The epithelial lining of the posterior pharynx also proliferates rapidly, resulting in near occlusion of the lumen, leaving only a minor dorsal opening, the pharyngoglottic duct. Recanalization progresses cephalocaudally, with the last remnant at the glottis at week 10, and should be complete by week 12.6,8 Laryngeal atresia has been classified into three types depending on the level and degree of obstruction.7,8 Likewise, anterior laryngeal webs have been classified into four types of increasing severity.9 Laryngeal webs and atresias account for approximately 5% of laryngeal defects. The true incidence is not known.

Fig. 6-2. Laryngeal atresia. A. Profile of 20 week gestation hydropic fetus with laryngeal atresia. B. Lung overgrowth associated with laryngeal atresia (top) compared to gestational age matched control. Note the scalloped edges from rib compression.

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Associated malformations of the upper and lower airways, esophagus, and other organ systems are common, especially in the more severe laryngeal lesions.7,10 Familial cases have been reported, typically in an autosomal dominant pattern.11,12 Discordant monozygotic twins have also been reported.13 McElhinney et al. reported a series of 25 patients with laryngeal web and found

deletions by fluorescence in situ hybridization (FISH) of chromosome 22q11.2 (DiGeorge critical region) in 7 of the 12 patients that had cytogenetic analysis. They also reported associated cardiovascular anomalies in 9 of 25 patients, most commonly involving the aortic arch.14 Syndromes associated with laryngeal defects are presented in Table 6-2.

Table 6-2. Patterns of malformation associated with laryngeal abnormalities Syndrome

Significant Features

Causation Gene/Locus

Fraser

LA, LS, cryptophthalmos, frontolateral hair growth, syndactyly, genital abnormality, nasal coloboma, ear abnormality

AR (219000) FRAS1, 4q21

Opitz

LC, LH, hypertelorism, telecanthus, anteverted nares, cleft lip/palate, hypospadias, cryptorchidism, cardiac defect, developmental delay

XLR (300000) Xp22

Pallister-Hall

LC, SGS, hypothalamic hamartoma, postaxial polydactyly, imperforate anus, genital and cardiac defects

AD (146510) GLI3, 7p13

Short rib polydactyly, type II (Majewski)

LH, short ribs, median cleft upper lip, pre- and/or postaxial polydactyly, short ovoid tibiae, fetal hydrops

AR (263520)

Oral-facial-digial, type IV (Baraitser-Burn)

LH, cleft lip, broad nasal root and tip, hypertelorism, micrognathia, brachydactyly, pre- and/or postaxial polydactyly, short tibiae, talipes equinovarus

AR (258860)

Oral-facial-digital, type II (Mohr)

LH, midline cleft of upper lip, cleft tongue, postaxial polydactyly of hands, hallux duplication, mental retardation, other central nervous system defects

AR (252100)

Trisomy 21

LW, LC, SGS, flat facies, upslanted palpebral fissures, small ears, cardiac defect, brachydactyly, clinodactyly, hypotonia

Chromosomal

Velocardiofacial 22q11.2 deletion

LW, long face, malar flattening, tubular nose, micrognathia, cleft palate, conotruncal heart defect

Chromosomal AD (192430) del 22q11.2

Ulnar-mammary

LW, LS, breast and/or nipple hypoplasia, anal defect, genital defect, hypoplasia of ulna/radius/humerus, postaxial polydactyly

AD (181450) TBX3, 12q24.1

Frontometaphyseal dysplasia

SGS, coarse facies, prominent supraorbital ridge, micrognathia, hypertelorism, hearing loss, dental defects, skeletal defects, urinary tract anomalies, mental retardation

XLD (305620) FLNA, Xq28

Larsen18

SGS, LM, short stature, flat facies, prominent forehead, hypertelorsim, low nasal bridge, cardiac defect, multiple joint dislocations, spatulate thumbs

AD (150250) 3p21.1-p14.1

Marshall-Smith19

LH, accelerated skeletal maturation, prominent forehead, prominent eyes, micrognathia, failure to thrive, developmental delay

Sporadic (602535)

Acrofacial dysostosis (Nager)

LH, hypoplasia of zygoma, maxilla, and mandible, radial ray defect, ear anomalies, cleft palate, hearing loss

AD (154400) 9q32

Robin sequence with cleft mandible and limb anomalies20

LH, short stature, Robin sequence, cleft mandible, hypoplastic thumbs, talipes equinovarus

AR (268305)

Laryngeal atresia, encephalocele and limb deformities21

LA, anterior encephalocele, radial defects, tibial defects, oligodactyly, syndactyly, camptodactyly, fetal hydrops

Unknown (607132)

Chondrodysplasia punctata, rhizomelic type22

LA, frontal bossing, flat nasal bridge, microcephaly, cleft palate, cataracts, ichthyosis, rhizomelia

AR (215100) PEX7, 6q22-q34 AR (222765) Chrom 1 AR (600121) AGPS, 2q31

Hirschsprung disease, heart defects, laryngeal anomalies, preaxial polydactyly23

LH, cleft lip/palate, hallux duplication, postaxial polydactyly, cardiac defect, Hirschsprung disease

AR (604211)

Mosaic chromosome 13q deletion24

LC, growth retardation, microcephaly, hypertelorism, ear anomalies, agenesis of corpus callosum, laryngeal cleft, cardiac defect, renal hypoplasia, skeletal anomalies, digital anomalies

Chromosomal

Fraser-like25

SGS, fused eyelids, digital anomalies

AR (229230)

LA: laryngeal atresia, LS: laryngeal stenosis, LC: laryngeal cleft, LH: laryngeal hypoplasia, SGS: subglottic stenosis, LW: laryngeal web, LM: laryngomalacia

The Lower Respiratory Organs

Prognosis and Treatment

Congenital high airway obstruction (CHAOS) due to laryngeal atresia is commonly lethal due to inability to establish an airway and associated defects. A small patent pharyngoglottic duct or tracheoesophageal fistula may allow ventilation until definitive measures to establish an airway can be taken.15 A novel surgical approach, EXIT (ex utero intrapartum treatment), has been successfully utilized in cases where the airway obstruction is diagnosed prenatally.16,17 Laryngeal webs are managed according to the extent and thickness of the web. Small, thin webs are treated endoscopically, while more extensive webs with subglottic extension or associated cricoid abnormality require an open surgical approach.5,6 Temporary tracheostomy is sometimes required for extensive or staged repairs. Congenital subglottic stenosis can often be managed conservatively, as most children improve over several years. Severe cases may require tracheostomy and reconstruction.5 References (Laryngeal Atresia, Webs, and Stenosis) 1. Morrison PJ, Macphail S, Williams D, et al.: Laryngeal atresia or stenosis presenting as second-trimester fetal ascites—diagnosis and pathology in three independent cases. Prenat Diagn 18:963, 1998. 2. Meizner I, Sherizly I, Mashiach R, et al.: Prenatal sonographic diagnosis of laryngeal atresia in association with single umbilical artery. J Clin Ultrasound 28:435, 2000. 3. Onderoglu L, Saygan-Karamursel B, Bulun A, et al.: Prenatal diagnosis of laryngeal atresia. Prenat Diagn 23:277, 2003. 4. Watson MJ, Munson DP: Amniotic fluid analysis in a fetus with laryngeal atresia. Prenat Diagn 15:571, 1995. 5. Wiatrak BJ: Congenital anomalies of the larynx and trachea. Otolaryngol Clin North Am 33:91, 2000. 6. Hartnick CJ, Cotton RT: Congenital laryngeal anomalies. Otolaryngol Clin North Am 33:1293, 2000. 7. Smith II, Bain AD: Congenital atresia of the larynx: a report on nine cases. Ann Otol Rhinol Laryngol 74:338, 1965. 8. Zaw-Tun HI: Development of congenital laryngeal atresias and clefts. Ann Otol Rhinol Laryngol 97:353, 1988. 9. Cohen SR: Congenital glottic webs in children: a retrospective review of 51 patients. Ann Otol Rhinol Laryngol 121(suppl):2, 1985. 10. Smith RJH, Catlin FI: Congenital anomalies of the larynx. Am J Dis Child 138:35, 1984. 11. Howie TO, Ladefoged P, Stark RE: Congenital subglottic bars found in 3 generations of one family. Folia Phoniatr Logop 13:56, 1961. 12. Strakowski SM, Butler MG, Cheek JW, et al.: Familial laryngeal web in three generations with probable autosomal dominant transmission. Dysmorphol Clin Genet 2:9, 1988. 13. Tang PT, Meagher SE, Khan AA, et al.: Laryngeal atresia: antenatal diagnosis in a twin pregnancy. Ultrasound Obstet Gynecol 7:371, 1996. 14. McElhinney DB, Jacobs I, McDonald-McGinn DM, et al.: Chromosomal and cardiovascular anomalies associated with congenital laryngeal web. Int J Pediatr Otorhinolaryngol 66:23, 2002. 15. Hicks BA, Contador MP, Perlman JM: Laryngeal atresia in the newborn: surgical implications. Am J Perinatol 13:409, 1996. 16. Bui TH, Grunewald C, Frenckner B, et al.: Successful EXIT (ex utero intrapartum treatment) procedure in a fetus diagnosis prenatally with congenital high-airway obstruction syndrome due to laryngeal atresia. Eur J Pediatr Surg 10:328, 2000. 17. Lim FY, Crombleholme TM, Hedrick HL, et al.: Congenital high airway obstruction: natural history and management. J Pediatr Surg 38:940, 2003. 18. Hoeve HJ, Joosten KF, Bogers AJ, et al.: Malformation and stenosis of the cricoid cartilage in association with Larsen’s syndrome. Laryngoscope 107:792, 1997. 19. Cullen A, Clarke TA, O’Dwyer TP: The Marshall-Smith syndrome: a review of the laryngeal complications. Eur J Pediatr 156:463, 1997.

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20. Tabith Jr A, Bento-Goncalves CG: Laryngeal malformations in the Richieri-Costa and Pereira form of acrofacial dysostosis. Am J Med Genet 66:399, 1996. 21. Kalache KD, Masturzo B, Scott RJ: Laryngeal atresia, encephalocele, and limb deformities (LEL): a possible new syndrome. J Med Genet 38:420, 2001. 22. Storm W, Fasse M: [Laryngeal atresia in an infant with chondrodysplasia punctata, rhizomelic type]. Monatsschr Kinderheilkd 139:629, 1991. 23. Huang T, Elias ER, Mulliken JB, et al.: A new syndrome: heart defects, laryngeal anomalies, preaxial polydactyly and colonic aganglionosis in sibs. Genet Med 1:104, 1999. 24. Lorentz CP, Jalal SM, Thompson DM, et al.: Mosaic r(13) resulting in large deletion of chromosome 13q in a newborn female with multiple congenital anomalies. Am J Med Genet 111:61, 2002. 25. Mena W, Krassikoff N, Philips JB III: Fused eyelids, airway anomalies, ovarian cysts and digital abnormalities in siblings: a new autosomal recessive syndrome or a variant of Fraser syndrome? Am J Med Genet 40:377, 1991.

6.3 Laryngotracheoesophageal Cleft Definition

Laryngotracheoesophageal cleft is a partial or complete communication between the larynx, subglottis, and trachea with the hypopharynx and/or esophagus due to deficiency of the interarytenoid musculature and cricoid lamina rostrally and/or the membranous trachea caudally. Ventral laryngeal clefts are extremely rare, with less than five reports in the literature, and are excluded from this discussion. Diagnosis

The extent of the cleft determines the severity of presenting symptomatology. Posterior laryngeal clefts are commonly classified according to the scheme set forth by Benjamin and Inglis:1 Type I: Supraglottic interarytenoid cleft Type II: Partial cricoid cleft extending below the vocal cords Type III: Complete cricoid cleft extending into the cervical trachea Type IV: Complete cleft extending into thoracic trachea Patients with type I clefts may present with nonspecific symptoms, including wheezing or asthmalike symptoms, chronic cough, and failure to thrive. More specific symptoms include inspiratory stridor, weak cry, cyanotic spells with feeding, and increased secretions. Affected children often present with recurrent pneumonia.2 The more severe clefts always present with more severe signs and symptoms of aspiration and other evidence of incompetent larynx, including cough and choking with feeding and absent or very weak cry.3 Differential diagnosis includes laryngomalacia for the type I clefts and other laryngeal defects. Accurate and timely diagnosis requires a high index of suspicion. Chest radiograph may show evidence of aspiration pneumonia. Contrast swallow study may also demonstrate laryngeal incompetence and aspiration. The diagnosis is not always obvious during flexible laryngoscopy; definitive diagnosis is made with rigid endoscopy and may require specific instrumentation and techniques to identify the defect.2,4 Etiology and Distribution

Posterior laryngeal clefts occur in approximately 1 in 10,000 to 20,000 live births, accounting for less than 1% of all laryngeal anomalies.5 A recent report, however, found type I clefts in 6.2% of 660 children evaluated by microlaryngoscopy when each case was specifically

206

Cardiorespiratory Organs

evaluated for the possibility of a posterior laryngeal cleft.2 Associated anomalies are common, present in 60–70% of cases.2,3 The more severe clefts are nearly always associated with multiple anomalies.3 Other defects of the upper and lower airway and esophagus are most common and include tracheoesophageal fistula, esophageal atresia, laryngomalacia, bronchomalacia, subglottic stenosis, subglottic cysts, laryngeal hamartomata, tracheal stenosis, and gastroesophageal reflux. Nonrespiratory defects include cleft lip with or without cleft palate, heart defects, and gastrointestinal and genitourinary system anomalies.2–4 Syndromes associated with laryngeal clefts and other laryngeal anomalies are also set forth in Table 6-2. Opitz syndrome and Trisomy 21 are the most commonly recognized conditions associated with posterior laryngeal clefts.2,3 Males are more commonly affected than females, with a 63–66% predominance,2,6 some of which is undoubtedly accounted for by the frequency of laryngeal clefts in Opitz syndrome. Familial cases, without an underlying diagnosis, have been reported.7,8 An interesting kindred of two sibships of double first cousins, each with three affected, was reported by Phelan et al. in 1973.9 Follow-up of the family revealed several affected children of the original patients, suggesting autosomal dominant inheritance.10 Prognosis and Treatment

Type I laryngeal clefts may not require surgical intervention. Speech and feeding therapy are required to control aspiration and gastroesophageal reflux.2–4 Type I clefts that are not responsive to conservative therapy, and all of the more severe clefts, require surgical treatment. Minor repairs may be accomplished endoscopically, but revisions are frequently required; open repair is necessary for the more severe clefts. Repair is accomplished either from an anterior approach, lateral pharyngotomy, or thoracotomy, depending on the extent of the cleft and associated defects.3 Gastroesophageal reflux commonly complicates the management of posterior laryngeal clefts, occurring in up to 44%.2,3 The mortality rate associated with posterior laryngeal clefts was reported by Roth et al. in 1983 as being as high as 40% for type I, 50% for type II, and greater than 90% for type III.11 However, recent advances in diagnosis, anesthesia, and surgical techniques have lowered the mortality rate to as low as 14% in a recent series that included 44 patients with type I to IV clefts. Of note is that many patients died from a cause not attributable to the airway cleft.3 References (Laryngotracheoesophageal Clefts) 1. Benjamin B, Inglis A: Minor congenital laryngeal clefts: diagnosis and classification. Ann Otol Rhinol Laryngol 98:417, 1989. 2. Parsons DS, Stivers E, Giovanetto DR, et al.: Type I posterior laryngeal clefts. Laryngoscope 108:403, 1998. 3. Evans KL, Courteney-Harris R, Bailey CM, et al.: Management of posterior laryngeal and laryngotracheoesophageal clefts. Arch Otolaryngol Head Neck Surg 121:1380, 1995. 4. Hartnick CJ, Cotton RT: Congenital laryngeal anomalies. Otolaryngol Clin North Am 33:1293, 2000. 5. Dubois JJ, Pokorny WJ, Harberg FJ, et al.: Current management of laryngeal and laryngotracheoesophageal clefts. J Pediatr Surg 25:855, 1990. 6. Tyler DC: Laryngeal cleft: report of eight patients and a review of the literature. Am J Med Genet 21:61, 1985. 7. Finlay HVL: Familial congenital stridor. Arch Dis Child 24:219, 1949. 8. Crooks J: Non-inflammatory laryngeal stridor in infants. Arch Dis Child 29:12, 1954. 9. Phelan PD, Stocks JG, Williams HE, et al.: Familial ocurrence of congenital laryngeal clefts. Arch Dis Child 48:275, 1973. 10. Phelan PD, Williams H, Danks D: Familial occurrence of congenital laryngeal clefts (Letter). Arch Dis Child 72:98, 1995. 11. Roth B, Rose KG, Benz-Bohm G, et al.: Laryngotracheoesophageal cleft: clinical features, diagnosis, and therapy. Eur J Pediatr 140:41, 1983.

6.4 Tracheal Agenesis Definition

The terms tracheal agenesis (agenesis meaning absence of an organ) and tracheal aplasia (aplasia meaning lack or failure of development of an organ) may be used interchangeably, although tracheal agenesis appears to be the preferred term in the literature. Tracheal atresia (atresia meaning congenital absence or closure of an opening) is also used to describe discontinuity of the tracheal lumen. All of these terms are used in the literature to describe absence of all or most of the trachea between the larynx and mainstem bronchi. Tracheal agenesis is classified into three anatomic types according to Floyd et al.:1 Type I: Agenesis of the proximal trachea with a normal short segment of distal tracheal and a tracheoesophageal fistula Type II: Agenesis of the entire trachea with normal main stem bronchi fused in the midline at the carina. There is often a fistula between the carina and the esophagus. Type III: Agenesis of the trachea and carina with the mainstem bronchi arising separately from the esophagus1,2 The relative frequencies for types I to III are 13%, 65%, and 22%, respectively.3 Diagnosis

Polyhydramnios, often leading to premature delivery, complicates approximately 50% of cases of tracheal agenesis.2 At birth, there is immediate respiratory distress, lack of air movement, and no audible cry. Endotracheal intubation is impossible, although esophageal intubation may provide some respiratory support via a distal tracheoesophageal fistula. Contrast radiographic studies and computerized tomography may be helpful in the diagnosis if the infant’s respiratory status is stabilized. Etiology and Distribution

Tracheal agenesis is rare, with an incidence of less than 1:50,000.4 Over 100 cases have been reported in the literature and are the subject of recent reviews.2,5 Epidemiologic characteristics of tracheal agenesis are presented in Table 6-3. The embryologic development of embryonic foregut leading to separate respiratory and gastrointestinal tracts is controversial. Recent understanding has been aided by the development of an animal model of aberrant tracheoesophageal development, the adriamycin-exposed rat.6–8 Previously, it was believed that bilateral esophagotracheal ridges divided the ventral (respiratory) from the

Table 6-3. Selected epidemiologic characteristics of tracheal agenesis Characteristic

Summary Information

Incidence

<1:50,0004

Geographic variation

None reported

Race/ethnic differences

None reported

Gender difference

M/F 2:12

Gestation

Prematurity commonly associated with polyhydramnios

Familial patterns

No recurrence reported

The Lower Respiratory Organs

dorsal (gastrointestinal) foregut.9 More recent data have suggested that the respiratory diverticulum, a ventral outgrowth of the foregut during the 4th week of development, elongates, forming a stalk that will develop into the trachea. The surrounding mesenchyme between the primitive trachea and esophagus actually constitutes the septum or tissue dividing the two structures.10 In abnormal foregut development in adriamycin-exposed rats, normal lung buds develop, but the elongation of the trachea does not occur. If ventral development predominates, the foregut develops into a trachea, and the upper esophageal segment is only a pouch from the dorsal foregut (esophageal atresia). If dorsal development predominates, the foregut develops into the esophagus, and the ventral foregut derivative is a blind pouch (tracheal agenesis).8 The mechanism in the adriamycin model is hypothesized to be arrest or delay of normal development due to cytotoxicity and impaired DNA synthesis.8 Greater growth potential of dorsal upper foregut cells compared to ventral cells may explain the relative rarity of tracheal agenesis compared to esophageal atresia.8 In 90–95% of cases, tracheal agenesis is associated with other malformations.2,5 Cardiovascular, gastrointestinal, and genitourinary malformations are the most commonly associated. Although there is some overlap with malformations included in the VATER/ VACTERL association, Evans et al. have noted a distinct difference in the nature and frequency of the associated malformations and concluded that tracheal agenesis is a separate entity.5,11 Analysis of 86 cases of tracheal agenesis with associated malformations suggested four consistent subgroups: (1) anomalies primarily confined to the thorax, including cardiovascular and laryngeal defects and rare unilateral limb and renal defects; (2) complex congenital heart defects and abnormal lung lobation; (3) cardiac and caudal anomalies, including imperforate anus, rectal fistula, renal, bladder, and genital defects; (4) similar to group 3 but with more frequent cardiac and foregut defects. A male excess was noted in groups 1 to 3, while an equal sex ratio characterized group 4.5 No chromosomal, teratogenic, or single gene has been identified as contributing to the development of tracheal agenesis in humans. No familial cases are recorded, although a woman with tetralogy of Fallot and absent pulmonary valve gave birth to a female infant with a similar heart defect associated with tracheal agenesis.12 The pathogenesis is unknown, but Evans et al. have suggested a disturbance of epithelial-mesenchymal interaction, or disruption of a primary developmental field, as potential explanations for tracheal agenesis and the common associated defects.5 Prognosis and Treatment

Complete tracheal agenesis remains a lethal condition.2,5 One child with Floyd’s type I tracheal agenesis, with a distal tracheal segment, survived over 6 years ventilated through a distal tracheostomy.13 No suitable autologous, homologous, or artificial tissue replacement has been successful for long-segment tracheal agenesis.14 References (Tracheal Agenesis) 1. Floyd J, Campbell DC, Dominy DE: Agenesis of the trachea. Am Rev Respir Dis 86:557, 1962. 2. Van Veenendaal MB, Liem KD, Marres HAM: Congenital absence of the trachea. Eur J Pediatr 159:8, 2000. 3. Koltai PJ, Quiney R: Tracheal agenesis. Ann Otol Rhinol Laryngol 101:560, 1992. 4. Manschot HJ, van den Anker JN, Tibboel D: Tracheal agenesis. Anaesthesia 49:788, 1994. 5. Evans JA, Greenberg CR, Erdile L: Tracheal agenesis revisited: analysis of associated anomalies. Am J Med Genet 82:415, 1999.

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6. Thompson DJ, Molello JM, Strebing RJ, et al.: Teratogenicity of adriamycin and daunomycin in the rat and rabbit. Teratology 17:151, 1978. 7. Diez-Pardo JA, Qi B, Navarro C, et al.: A new rodent experimental model of esophageal atresia and tracheoesophageal fistula: preliminary report. J Pediatr Surg 31:498, 1996. 8. Merei JM, Hutson JM: Embryogenesis of tracheoesophageal anomalies: a review. Pediatr Surg Int 18:319, 2002. 9. Sadler TW: Langman’s Medical Embryology, ed 8. Lippincott Williams and Wilkins, Baltimore, 2000, p 260. 10. O’Rahilly R, Mu¨ller F: Respiratory and alimentary relations in staged human embryos, new embryological data and congenital anomalies. Ann Otol Laryngol 93:421, 1984. 11. Evans JA, Reggin J, Greenberg C: Tracheal agenesis and associated malformations: a comparison with tracheoesophageal fistula and the VACTERL association. Am J Med Genet 21:21, 1985. 12. Hirt-Armon K, Pober BR, Holmes LB: Type III tracheal agenesis with familial tetralogy of Fallot and absent pulmonary valve syndrome. Am J Med Genet 65:266, 1996. 13. Soh H, Kawahawa H, Imura K, et al.: Tracheal agenesis in a child who survived for 6 years. J Pediatr Surg 34:1541, 1999. 14. Haben CM, Rappaport JM, Clarke KD: Tracheal agenesis. J Am Coll Surg 194:217, 2002.

6.5 Tracheal Stenosis Definition

Tracheal stenosis is a fixed intrinsic narrowing of the trachea. The narrowing can be localized to a short or long tracheal segment, often due to complete tracheal rings. Alternatively, the tracheal lumen may become progressively narrow caudally. Excluded from this discussion is narrowing caused by extrinsic compression of the trachea, which occurs most commonly due to an aberrant left pulmonary artery ‘‘sling.’’ Congenital tracheal cartilaginous sleeve, with vertical fusion of tracheal rings, occasionally presents with tracheal stenosis and is considered separately. Diagnosis

Tracheal stenosis typically presents in infancy, but may not present until adolescence or adulthood.1,2 Severe forms present at birth with respiratory distress, inspiratory and expiratory stridor, and difficult tracheal intubation.1 Inspiratory stridor characterizes extrathoracic tracheal stenosis, whereas wheezing, with or without stridor, may be present in cases of intrathoracic tracheal stenosis.3 Highly penetrated radiographs may demonstrate the narrowed airway, but bronchoscopy is often required. Computerized tomography is also useful to demonstrate the length and extent of the stenotic lesion and is useful in planning surgical repair. Etiology and Distribution

The etiology of tracheal stenosis is unknown. The C-shaped cartilage, muscle, and connective tissue of the trachea are derived from the surrounding splanchnic mesenchyme and are well-developed by 11 to 12 weeks gestation.4 There is no period during normal development in which the cartilaginous rings completely encircle the trachea. Tracheal stenosis is rare. Albers and Wood reported complete tracheal rings in 5 of 1147 (0.4%) children who underwent bronchoscopy. Associated anomalies were reported in 19 of 21 infants with congenital tracheal stenosis, most commonly involving the respiratory tract and esophagus.1 The specific defects included bronchial stenosis (18 of 21), tracheal bronchus (4 of 21), pulmonary hypoplasia or agenesis (6 of 21), and tracheoesophageal

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Table 6-4. Patterns of malformations associated with tracheal stenosis Causation Gene/Locus

Syndrome

Significant Features

Anterior chamber cleavage disorder, cerebellar hypoplasia, hypothyroidism, tracheal stenosis8

Growth retardation, iris coloboma, congenital hypothyroidism, narrow external auditory canal, cerebellar hypoplasia, short neck, hip dysplasia, dense scalp hair, genital hypoplasia, growth hormone deficiency.

Unknown (601427)

Conradi-Hu¨nermann

Growth retardation, flat facies, prominent forehead, macrocephaly, eye anomalies, ear anomalies, short neck, punctate calcifications, scoliosis, skeletal asymmetry, hydronephrosis, congenital ichthyosiform erythroderma, sparse hair

XLD (302960) EBP, Xp11.23-p11.22

Mosaic chromosome 13q deletion9

Growth retardation, microcephaly, hypertelorism, ear anomalies, agenesis of corpus callosum, laryngeal cleft, cardiac defect, renal hypoplasia, skeletal anomalies, digital anomalies

Chromosomal

Frontometaphyseal dysplasia10

Coarse facies, prominent supraorbital ridge, micrognathia, hypertelorism, hearing loss, dental defects, skeletal defects, urinary tract anomalies, mental retardation

XLD (305620) FLNA, Xq28

Goldenhar11

Facial asymmetry, macrostomia, microtia, preauricular skin tags, hearing loss, epibulbar dermoid, vertebral anomalies, cardiac defects

Sporadic, AD (164210) 14q32

Geleophysic dysplasia

Short stature, round face, thickened helices, short nose, wide mouth, high-pitched voice, cardiac defects, skeletal anomalies including contractures, abnormal skin and nails, developmental delay

AR (231050)

Hydrolethalus

Growth retardation; cleft lip/palate; micrognathia; polydactyly; central nervous system, genitourinary, gastrointestinal, and diaphragmatic defects

AR (236680) 11q23-q25

Keutel12

Midface hypoplasia, low nasal bridge, small alae nasi, hearing loss, peripheral pulmonary stenosis, brachyphalangy, stippled cartilage calcification

AR (245150) 12p13.1-p12.3

Laryngotracheal stenosis, short stature, arthropathy13

Progressive/acquired laryngotracheal stenosis, short stature, joint limitation, minor facial anomalies

Unknown (603391)

Larsen

Short stature, flat facies, prominent forehead, hypertelorism, low nasal bridge, cardiac defect, multiple joint dislocations, spatulate thumbs

AD (150250) 3p21.1-p14.1

Opitz14

Hypertelorism, telecanthus, anteverted nares, cleft lip/palate, hypospadias, cryptorchidism, cardiac defect, developmental delay

XLR (300000) MID1, Xp22

Oral-facial-digital, type II15

Midline cleft of upper lip, cleft tongue, postaxial polydactyly of hands, hallux duplication, mental retardation, other central nervous system defects

AR (252100)

Thoracolaryngopelvic dysplasia16

Thoracic dystrophy, short ribs, wide costochondral junctions, small pelvis

AD (187760)

Trisomy 21

Flat facies, upslanted palpebral fissures, small ears, cardiac defect, brachydactyly, clinodactyly, hypotonia

Chromosomal

VATER/VACTERL17

Vertebral defects, anal atresia, cardiac defect, tracheoesophageal fistula, radial ray defect, renal defect, other limb defects

Sporadic (192350)

fistula (3 of 21). Other defects included congenital lobar emphysema, tracheomalacia, tracheal web, congenital subglottic stenosis, and laryngeal hypoplasia. Cardiac defects were also reported, including common atrioventricular canal, aortic coarctation, and dextrocardia with ventriculoseptal defect. Skeletal defects reported in that series included hemivertebrae, radial ray defects, radioulnar synostosis, and micrognathia. Tracheal stenosis is usually a sporadic defect. Wong et al. reported congenital tracheobronchial stenosis in a pair of monozygotic twin females.5 Lethal tracheal stenosis was reported in two infants of diabetic mothers.7 Syndromes associated with tracheal stenosis are set forth in Table 6-4.

References (Tracheal Stenosis) 1. Benjamin B, Pitkin J, Cohen D: Congenital tracheal stenosis. Ann Otol Rhinol Laryngol 90:364, 1981. 2. Donnelly J: Congenital tracheal stenosis in an adult, complicated by asphyxial pulmonary oedema. Anaesth Intens Care 16:212, 1988. 3. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 4. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology, ed 7. WB Saunders Company, Philadelphia, 2003, p 245. 5. Albers GM, Wood RE: The lower respiratory organs. In: Human Malformations and Related Anomalies, ed 1, vol II. Stevenson RE, Hall JG, Goodman RM, eds. Oxford University Press, New York, 1993, p 347.

The Lower Respiratory Organs 6. Wong KS, Lien R, Lin TY: Congenital tracheobronchial stenosis in monozygotic twins. Eur J Pediatr 157:1023, 1998. 7. Tack E, Perlman J: Tracheal stenosis: lethal malformation in two infants of diabetic mothers. Am J Dis Child 141:77, 1987. 8. Jung C, Wolff G, Back E, et al.: Two unrelated children with developmental delay, short statures and anterior chamber cleavage disorder, cerebellar hypoplasia, endocrine disturbances and tracheostenosis: a new entity? Clin Dysmorphol 4:44, 1995. 9. Lorentz CP, Jalal SM, Thompson DM, et al.: Mosaic r(13) resulting in large deletion of chromosome 13q in a newborn female with multiple congenital anomalies. Am J Med Genet 111:61, 2002. 10. Leggett JM: Laryngo-tracheal stenosis in frontometaphyseal dysplasia. J Laryngol Otol 102:74, 1988. 11. Downing GJ, Kilbride H: An interesting case presentation: pulmonary malformations associated with oculoauriculovertebral dysplasia (Goldenhar anomalad). J Perinatol 11:190, 1991. 12. Meier M, Weng LP, Alexandrakis E, et al.: Tracheobronchial stenosis in Keutel syndrome. Eur Respir J 17:566, 2001. 13. Hopkin RJ, Cotton R, Langer LO, et al.: Laryngotracheal stenosis, progressive with short stature and arthropathy. Am J Med Genet 80:241, 1998. 14. Buckley JG, Hinton AE, Penter G, et al.: Total laryngotracheal hypoplasia in a case of G syndrome. J Laryngol Otol 102:1056, 1988. 15. Steichen-Gersdorf E, Gassner I, Cofi B, et al.: Oral-facial-digital syndrome II. Transitional type between Mohr and Majewski syndrome: report of a new case with congenital stenosis of the trachea. Clin Dysmorphol 3:245, 1994. 16. Wood E, Kearns D: Laryngotracheal stenosis in thoracolaryngopelvic dysplasia: Barnes syndrome. Otolaryngol Head Neck Surg 113:807, 1995. 17. Kairamkonda V, Thorburn K, Sarginson R: Tracheal bronchus associated with VACTERL. Eur J Pediatr 162:165, 2003.

6.6 Congenital Tracheal Cartilaginous Sleeve Definition

Congenital tracheal cartilaginous sleeves are discrete tracheal rings replaced by an uninterrupted cartilaginous cylinder secondary to vertical fusion of the tracheal cartilages. Other terms used to describe this lesion include ‘‘pipe-stem’’ or ‘‘stovepipe trachea’’.1

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Prognosis and Treatment

Most of the patients have respiratory symptoms, for the most part attributable to the upper respiratory tract. The functional significance of tracheal cartilaginous sleeve is unclear. Tracheostomy may be required due to the upper airway obstruction or due to associated tracheal stenosis. Aggressive treatment of respiratory infections and secretions is required in these patients. Tracheal cartilaginous sleeve is compatible with long-term survival.1,2 References (Tracheal Cartilaginous Sleeve) 1. Lin SY, Chen JC, Hotaling AJ, et al.: Congenital tracheal cartilaginous sleeve. Laryngoscope 105:1213, 1995. 2. Davis S, Bove KE, Wells TR, et al.: Tracheal cartilaginous sleeve. Pediatr Pathol 12:349, 1992. 3. Inglis AF Jr, Kokesh J, Seibert J, et al.: Vertically fused tracheal cartilage. An underrecognized anomaly. Arch Otolaryngol Head Neck Surg 118: 436, 1992. 4. Noorily MR, Farmer DL, Belenky WM, et al.: Congenital tracheal anomalies in the craniosynostosis syndromes. J Pediatr Surg 34:1036, 1999. 5. Scheid SC, Spector AR, Luft JD: Tracheal cartilaginous sleeve in Crouzon syndrome. Int J Pediatr Otorhinolaryngol 65:147, 2002. 6. Okajima K, Aoki I, Sagehashi N, et al.: Three craniosynostotic patients with tracheal sleeve. Clin Dysmorphol 12:75, 2003.

6.7 Tracheoesophageal Fistula Definition

Tracheoesophageal fistula is an abnormal communication between the trachea and the esophagus. Tracheoesophageal fistula is almost always accompanied by esophageal atresia and discussed in detail in Chapter 24. Fistulous connection between the trachea and esophagus is also associated with tracheal agenesis, discussed in section 6.4. 6.8 Pulmonary Agenesis/Aplasia

Diagnosis

The diagnosis of tracheal cartilaginous sleeve is often not suspected. Affected individuals typically have additional malformations, most notably craniosynostosis syndromes, with associated symptomatic upper airway anomalies. The lesion does not usually lead to tracheal stenosis. Symptoms may include increased mucous production, cough, crouplike episodes, or increased respiratory infections. The diagnosis can be suspected at bronchoscopy with the finding of a smooth tracheal surface, or at the time of tracheostomy. The diagnosis has often been made at autopsy.1,2 Etiology and Distribution

Tracheal cartilaginous sleeve is a rare lesion, with 23 cases reported. Out of the 23 cases, 21 have craniosynostosis syndromes, with clinical diagnoses of Crouzon, Pfeiffer, and Apert syndromes.1–5 Two cases are reported with Goldenhar syndrome.1,3 No mutation in the FGFR2 gene (exons IIIa and IIIc) was found in three craniosynostosis patients studied by Okajima.6 Two had the clinical diagnosis of Crouzon syndrome and one had Pfeiffer syndrome; all had some atypical features. Although the pathogenesis is unknown, there is an obvious analogy between fusion of tracheal cartilage and fusion of cranial sutures and other joints in the craniosynostosis syndromes.2

Definition

Pulmonary agenesis refers to unilateral or bilateral absence of the bronchus, pulmonary parenchyma, and pulmonary vasculature. Pulmonary aplasia is considered in the same spectrum and differs only in the presence of a tracheal or bronchial stump. Pulmonary segmentation defects due to the absence of one or more lobes are included in this definition and are sometimes termed pulmonary hypoplasia. Excluded from this definition are primary pulmonary hypoplasia and pulmonary hypoplasia secondary to extrinsic factors including oligohydramnios, thoracic space-occupying lesions, etc. Diagnosis

Significant pulmonary aplasia or agenesis presents in the neonatal period with respiratory distress and cyanosis. Examination findings may be subtle, with decreased breath sounds and cardiac impulse shifted ipsilateral to the affected side. In unilateral agenesis, the affected hemithorax may be opacified or may show partial aeration due to shift of the normal lung and mediastinal contents. Further evaluation could include computerized tomography, echocardiography or angiography demonstrating absence of ipsilateral pulmonary artery, and bronchoscopy.

Fig. 6-3. Pulmonary agenesis. A. 31 week gestation female infant with Matthew Wood syndrome. Note bilateral microphthalmia and thoracic hypoplasia. B. Note extremely small thoracic cavity, elevated diaphragms, absent lungs, and large, globular heart with a single midline great artery (aorta). C. Note tracheal agenesis (long arrow) and empty pleural cavity (short arrow).

Table 6-5. Recognizable patterns associated with pulmonary agenesis and aplasia (including lobar aplasia) Causation Gene/Locus

Syndrome

Significant Features

Fryns

Large for gestational age, coarse facies, malformed ears, wide mouth, cleft lip/palate, microretrognathia, agenesis of corpus callosum, heart defect, renal defect, digital and nail hypoplasia

AR (229850)

Hydrolethalus

Growth retardation; cleft lip/palate; micrognathia; polydactyly; central nervous system, genitourinary, gastrointestinal, and diaphragmatic defects

AR (236680) 11q23-q25

Matthew Wood16

Microphthalmia, anophthalmia, pulmonary hypoplasia/agenesis

Uncertain (601186)

Microcephaly, congenital heart disease, unilateral renal agenesis, hyposegmented lungs17

Congenital microcephaly; growth retardation; cleft palate; ear, heart, genitourinary, and central nervous system defects

Uncertain (601355)

Pallister-Hall

Growth retardation; polydactyly; syndactyly; central nervous system defect including hypothalamic hamartoma; genitourinary, heart, and endocrine defects

Sporadic AD (146510) GLI3, 7p13

Pulmonary and diaphragmatic agenesis18

Unilateral or bilateral agenesis of the diaphragm, heart defect, skin tags (nose), hypoplastic uterus

Uncertain

Smith-Lemli-Opitz

Growth retardation; cleft palate; postaxial polydactyly; syndactyly; ambiguous genitalia; heart, urinary, and central nervous system defects

AR (268670) DHCR7, 11q12-q13

Tetra-amelia with pulmonary hypoplasia19

Amelia, micrognathia, cleft lip/palate, hydrocephalus

AR (273395)

VACTERL20

Vertebral, anal, cardiac, renal, and radial defects; tracheoesophageal fistula

Sporadic

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The Lower Respiratory Organs

Etiology and Distribution

The trachea develops as an outgrowth of the foregut during the 4th week of development. The respiratory diverticulum extends from the ventral wall of the foregut and becomes separated from the foregut. Right and left mainstem bronchi develop from the primitive trachea at 5 weeks gestation. The right side develops three secondary bronchi and the left side, two, which is the earliest evidence of asymmetric lung lobation. Growth of the lungs continues within the pleural cavities. Subsequent branching of the secondary bronchi continues throughout gestation, and even postnatally, and is regulated by epithelial-mesenchymal interactions between the endoderm of the lung buds and the surrounding splanchnic mesoderm. Fibroblast growth factors are important mediators of these epithelial-mesenchymal interactions; Fgf-10 knockout mice demonstrate complete pulmonary agenesis.1 Pulmonary agenesis and aplasia are uncommon defects; bilateral cases are especially rare. Mardini and Nyhan report a prevalence of 0.5 to 1 per 10,000 patients.2 Seventy percent of unilateral pulmonary agenesis involves the left side.3 Males and females are equally affected.4,5 Associated anomalies are common including the heart, diaphragm, vertebrae, ribs, thumbs, spleen, gastrointestinal and genitourinary tracts, and craniofacial defects (Fig. 6-3). Most cases in which chromosomes have been studied report normal karyotypes, although there are two reports of infants with chromosome anomalies including 2p21p246,7 and a rare association with trisomy 18.8 Several instances of sibling recurrence have been reported,9,10 including several consanguineous families,2 suggesting autosomal recessive inheritance in some cases. Monozygotic twins, both concordant and discordant for pulmonary agenesis/aplasia, have also been reported.11,12 Vitamin A deficiency in rats is associated with pulmonary agenesis and other anomalies.13 Recognizable patterns of malformation associated with pulmonary agenesis and aplasia are set forth in Table 6-5. Prognosis and Treatment

Bilateral pulmonary agenesis or significant aplasia is lethal. For unilateral or less severe cases, the mortality rate is 50% in the first year and may be associated with the presence of additional anomalies.14 Late presentations and deaths in adults from related and unrelated causes are reported.10,15 Management and treatment of the pulmonary complications, including pulmonary hypertension, is supportive.15 References (Pulmonary Agenesis/Aplasia) 1. Min H, Danilenko DM, Scully SA, et al.: Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 12:3156, 1998. 2. Mardini MK, Nyhan WL: Agenesis of the lung: report of four patients with unusual anomalies. Chest 87:522, 1985. 3. Gilbert EF, Opitz JM: The pathology of some malformations and hereditary diseases of the respiratory tract. Birth Defects Orig Artic Ser XII(6):239, 1976. 4. Oyamada A, Gasul BM, Holinger PH: Agenesis of the lung: report of a case, with a review of all previously reported cases. Am J Dis Child 85:182, 1953. 5. Maltz DL, Nadas AS: Agenesis of the lung: presentation of eight new cases and review of the literature. Pediatrics 42:175, 1968. 6. Say B, Carpenter NJ, Giacoai G, et al.: Agenesis of the lung associated with a chromosome abnormality (46,XX,2pþ). J Med Genet 17:477, 1980. 7. Schober PH, Mu¨ller WD, Behmel A, et al.: [Pulmonary agenesis in partial trisomy 2p and 21q]. Klin Padiatr 195:291–293, 1983.

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8. Voorhess ML, Vahard T, Gardner LI: Trisomy 16-18 syndrome. Lancet 2:992, 1962. 9. Podlech J, Richter J, Czygan P, et al.: Bilateral agenesis/aplasia of the lungs: report of a second case in the offspring of one woman. Pediatr Pathol Lab Med 15:781, 1995. 10. Fokstuen S, Schinzel A: Unilateral lobar pulmonary agenesis in sibs. J Med Genet 37:557, 2000. 11. Yount F: Agenesis of the right lung in each of identical twins. Arizona Med 5:48, 1948. 12. Booth JB, Berry CL: Unilateral pulmonary agenesis. Arch Dis Child 42:361, 1967. 13. Warkany J, Roth CB, Wilson JG: Multiple congenital malformations: a consideration of etiologic factors. Pediatrics 1:462, 1948. 14. Krummel TM: Congenital malformations of the lower respiratory tract. In: Kendig’s Disorders of the Respiratory Tract in Children, ed 6. Chernick V, Boat T, eds. WB Saunders Company, Philadelphia, 1998, p 307. 15. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 16. Seller MJ, Davis TB, Fear CN, et al.: Two sibs with anophthalmia and pulmonary hypoplasia (Matthew Wood syndrome). Am J Med Genet 62:227, 1996. 17. Ellis IH, Yale C, Thomas R, et al.: Three sibs with microcephaly, congenital heart disease, lung segmentation defects and unilateral absent kidney: a new recessive multiple congenital anomaly (MCA) syndrome? Clin Dysmorphol 5:129, 1996. 18. Toriello HV, Higgins JV, Jones AS, et al.: Pulmonary and diaphragmatic agenesis: report of affected sibs. Am J Med Genet 21:87, 1985. 19. Rosenak D, Ariel I, Arnon J, et al.: Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs. Am J Med Genet 38:25, 1991. 20. Knowles S, Thomas RM, Lindenbaum RH, et al.: Pulmonary agenesis as part of the VACTERL sequence. Arch Dis Child 63:723, 1988.

6.9 Congenital Cystic Adenomatoid Malformation Definition

Congenital cystic adenomatoid malformation is a pulmonary hamartomatous lesion composed of noncartilage-containing terminal respiratory structures resembling terminal bronchioles. There are three morphologic subtypes recognized: Type I, Macrocystic: One or more large cysts (2–10 cm) predominate. The cysts are lined by ciliated pseudostratified columnar epithelium, which occasionally produce mucin. Bronchiolar and alveolar elements are present between the cysts. Type II, Microcystic: Contains mostly small uniform cysts (0.5–2 cm) lined by cuboidal or columnar epithelium. Type III, Solid: An airless mass consisting almost entirely of bronchiolar and alveolar elements. Gross cysts are not obvious, but microscopic alveolar cysts are present.1,2 Diagnosis

The diagnosis of cystic adenomatoid malformation is often made by prenatal ultrasound. Other frequently associated findings include maternal polyhydramnios and hydrops fetalis.3 The differential diagnosis of fetal chest masses includes pulmonary sequestration, congenital diaphragmatic hernia, pulmonary lymphangiectasia, and congenital lobar emphysema. Fetal magnetic resonance imaging techniques can be utilized to aid in diagnosis and to guide pregnancy and neonatal management.4,5

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Cardiorespiratory Organs

Fig. 6-4. Congenital cystadenomatoid malformation. A. Radiograph of type 1 malformation shows the entire left lung to be involved with multiple cystic lesions, with the mediastinum shifted toward the right. B. A CT scan of a type 2 malformation shows a large cystic lesion in the right lung with crowding of adjacent parenchyma. At least one septum (arrow) is visible within the cyst.

Respiratory symptoms may be present at birth. Large lesions may cause mediastinal shift, and cyst rupture may cause pneumothorax.1 Chest radiograph will show a solid or cystic mass involving a portion of, or an entire, hemithorax. The radiographic findings may overlap with other pulmonary or extrapulmonary chest masses, including simple pulmonary cysts, congenital lobar emphysema, diaphragmatic hernia, and pulmonary sequestration. Computerized axial tomography or magnetic resonance imaging can be used to aid in diagnosis (Fig. 6-4). Etiology and Distribution

The incidence of cystic adenomatoid malformation has been estimated at 1 in 25,000 to 35,000 pregnancies,6 accounting for approximately 25% of congenital pulmonary parenchymal lesions.7 Type II lesions account for 73%, and types I and III account for approximately 13% each.8 Males and females are equally affected.2 The etiology and pathogenesis are unknown, although increased cell proliferation and decreased apoptosis of affected tissue has been demonstrated.9 Cystic adenomatoid malformations can be associated with other pulmonary lesions and nonrespiratory system defects. Large lesions may be complicated by the development of fetal hydrops. Congenital cystic renal disease or renal agenesis, congenital heart defects, and bony lesions were present in 25 of 142 cases reviewed by Stocker et al.7 Laberge reported a case of trisomy 18.6 Prognosis and Treatment

Type II lesions tend to be extensive and may have the greatest number of associated defects;7 thus, they carry a worse prognosis. In prenatally diagnosed cases, microcystic lesions, bilateral lesions, and fetal hydrops were each associated with poor prognosis, whereas polyhydramnios and mediastinal shift were not necessarily associated with poor outcome.10 Partial or apparently complete in utero regression of cystic adenomatoid lesions is well-documented,11,12 up to 56% in one series.6 Some infants are asymptomatic at birth, and chest radiograph may be normal or only demonstrate subtle abnormality.11–13 Normal chest radiograph does not indicate complete resolution of a cystic adenomatoid lesion, and computed tomography scan detects abnormalities not shown on chest radiograph.12,13 Timing of excision in an asymptomatic patient is controversial. Chronic or

recurrent pulmonary infection may result from unresected or unidentified lesions.14 References (Cystic Adenomatoid Malformation) 1. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 2. Mandell G: Congenital cystic adenomatoid malformation. www. emedicine.com/radio/topic186.htm. 3. Adzick HS, Harrison MR, Glick PL, et al.: Fetal cystic adenomatoid malformation: prenatal diagnosis and natural history. J Pediatr Surg 20:483, 1985. 4. Hubbard AM, Adzick NS, Crombleholme TM, et al.: Congenital chest lesions: diagnosis and characterization with prenatal MR imaging. Radiology 212:43, 1999. 5. Hubbard AM, States LJ: Fetal magnetic resonance imaging. Top Magn Reson Imaging 12:93, 2001. 6. Laberge JM, Flageole H, Pugash D, et al.: Outcome of the prenatally diagnosed congenital cystic adenomatoid lung malformation: a Canadian experience. Fetal Diagn Ther 16:178, 2001. 7. Stocker JT, Drake RM, Madewell JE: Cystic and congenital lung disease in the newborn. Perspect Pediatr Pathol 4:93, 1978. 8. Madewell JE, Stocker JT, Korsower JM: Cystic adenomatoid malformations of the lung: morphologic analysis. Am J Roentgenol Radium Ther Nucl Med 124:436, 1975. 9. Cass DL, Quinn TM, Yang EY, et al.: Increased cell proliferation and decreased apoptosis characterizes congenital cystic adenomatoid malformation of the lung. J Pediatr Surg 33:1043, 1998. 10. Bunduki V, Ruano R, Da Silva MM, et al.: Prognostic factors associated with congenital cystic adenomatoid malformation of the lung. Prenat Diagn 20:459, 2000. 11. Cacciari A, Ceccarelli PL, Pilu GL, et al.: A series of 17 cases of congenital cystic adenomatoid malformation of the lung: management and outcome. Eur J Pediatr Surg 7:84, 1997. 12. Van Leeuwen K, Teitelbaum DH, Hirschl RB, et al.: Prenatal diagnosis of congenital cystic adenomatoid malformation and its postnatal presentation, surgical indication and natural history. J Pediatr Surg 34:794, 1999. 13. Winters WD, Effmann EL, Nghiem HG, et al.: Disappearing fetal lung masses: importance of postnatal imaging studies. Pediatr Radiol 27:535, 1997. 14. Haller JA Jr, Golladay ES, Pickard LR, et al.: Surgical management of lung bud anomalies: lobar emphysema, bronchogenic cyst, cystic adenomatoid malformation, and intralobar sequestration. Ann Thorac Surg 28:33, 1978.

The Lower Respiratory Organs

6.10 Congenital Lobar Emphysema Definition

Congenital lobar emphysema is the postnatal hyperinflation of one or more lobes of the lung due to an intrinsic defect of the bronchopulmonary tree. Extrinsic compression causing segmental hyperinflation is excluded. Diagnosis

Most infants present in the newborn period with respiratory distress with or without cyanosis. Chest asymmetry, decreased breath sounds, hyperresonance on the affected side, and mediastinal shift may be apparent on physical examination. Chest radiograph performed shortly after birth may initially show an opaque, fluid-filled lobe, but follow-up radiograph will characteristically reveal overdistention and air trapping in the affected lobe, herniation across the mediastinum, and compression of surrounding normal lung tissue. Computerized tomography, ventilation/perfusion scan, and bronchoscopy can be used to aid in diagnosis.1 The diagnosis of congenital lobar emphysema can be made by fetal ultrasonography and fetal magnetic resonance imaging.2,3 The differential diagnosis includes other congenital chest masses (diaphragmatic hernia, cystic adenomatoid malformation, bronchopulmonary sequestration), and postnatal atelectasis with compensatory emphysema may also be considered. Other acquired lesions including bronchiolitis, asthma, and foreign body should be considered in cases that present beyond the neonatal period.1,4 Etiology and Distribution

Congenital lobar emphysema is the most common congenital lesion involving the lung parenchyma, accounting for approximately 50%.5 Typically, only one lobe is affected, with the left upper lobe being the most common, followed by the right middle and right upper lobes.1 In most cases, there is a deficiency or dysplasia of bronchial cartilage in the affected lobe5,6 leading to bronchial collapse and air trapping with expiration. Bronchial stenosis or atresia is also reported, as are a variety of other pathologic lesions.1,7 One series reported a male excess (1.8:1).5 Associated anomalies are uncommon. Congenital heart disease is reported in 10–15% of cases.4,8 Most cases are sporadic, although recurrence in twins,9 siblings,10,11 and mother-daughter12 and father-son13 pairs is reported. Prognosis and Treatment

Surgical treatment in the form of lobectomy or partial lobectomy is required for neonates with significant respiratory distress. Several cases diagnosed by fetal ultrasonography have appeared to regress in utero, but neonatal symptoms or radiographic progression led to surgical treatment.2,3 Nonoperative management is possible in mildly symptomatic or asymptomatic cases.8,14 References (Congenital Lobar Emphysema) 1. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 2. Olutoye OO, Coleman BG, Hubbard AM, et al.: Prenatal diagnosis and management of congenital lobar emphysema. J Pediatr Surg 35:792, 2000.

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3. Babu R, Kyle P, Spicer RD: Prenatal sonographic features of congenital lobar emphysema. Fetal Diagn Ther 16:200, 2001. 4. Krummel TM: Congenital malformations of the lower respiratory tract. In: Kendig’s Disorders of the Respiratory Tract in Children, ed 6. Chernick V, Boat T, eds. WB Saunders Company, Philadelphia, 1998, p 310. 5. Stocker JT, Drake RM, Madewell JE: Cystic and congenital lung disease in the newborn. Perspect Pediatr Pathol 4:93, 1978. 6. Dogan R, Demircin M, Sarigul A, et al.: Surgical management of congenital lobar emphysema. Turk J Pediatr 39:35, 1997. 7. Leape LL, Longino LA: Infantile lobar emphysema. Pediatric 34:246, 1964. 8. Karnak I, Senocak ME, Ciftci AO, et al.: Congenital lobar emphysema: diagnostic and therapeutic considerations. J Pediatr Surg 34:1347, 1999. 9. Thompson AJ, Reid AJ, Reid M: Congenital lobar emphysema occurring in twins. J Perinat Med 28:155, 2000. 10. Sloan H: Lobar obstructive emphysema in infancy treated by lobectomy. J Thorac Cardiovasc Surg 26:1, 1953. 11. Hendren WH, McKee DM: Lobar emphysema of infancy. J Pediatr Surg 1:24, 1966. 12. Wall MA, Eisenberg JD, Campbell JR: Congenital lobar emphysema in a mother and daughter. Pediatrics 70:131, 1982. 13. Roberts PA, Holland AJ, Halliday RJ, et al.: Congenital lobar emphysema: like father, like son. J Pediatr Surg 37:799, 2002. 14. Ozcelik U, Gocmen A, Kiper N, et al.: Congenital lobar emphysema: evaluation and long-term follow-up of thirty cases at a single center. Pediatr Pulmonol 35:384, 2003.

6.11 Primary Pulmonary Hypoplasia Definition

Primary pulmonary hypoplasia is the underdevelopment of the pulmonary parenchyma of one or both lungs. Excluded from this definition is pulmonary agenesis/aplasia in which there is unilateral or bilateral absence of the bronchus, pulmonary parenchyma, and vasculature. Also excluded is secondary pulmonary hypoplasia due to oligohydramnios, thoracic dysplasia, or thoracic space-occupying lesions. Diagnosis

Significant pulmonary hypoplasia presents in the immediate newborn period with respiratory distress and cyanosis. Physical examination is typically otherwise normal, without evidence of other malformations. Chest radiograph reveals small but clear lungs, normal heart size, elevated diaphragms, and bell-shaped thorax.1,2 Pneumothorax, either spontaneous or after mechanical ventilation, may complicate the picture. Severe pulmonary hypertension or persistent fetal circulation is also common, which makes accurate diagnosis of the primary pulmonary lesion difficult. Diagnosis can be suggested based on radiographic criteria2 but is often not made until autopsy. Lung weight to body weight ratio of less than 0.013 is diagnostic.3 The differential diagnosis includes pulmonary agenesis/aplasia and secondary pulmonary hypoplasia, the latter of which typically will have associated anomalies that lead to a specific diagnosis. Etiology and Distribution

Primary pulmonary hypoplasia is rare. In a series of 756 newborn autopsies, only 10 out of 77 cases of pulmonary hypoplasia were felt to be primary.4 A different series reported 3 cases in 1377 infants admitted to a newborn intensive care nursery over a 4-year period.1 Primary pulmonary hypoplasia is not associated with

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other congenital defects and is sporadic. The etiology and pathogenesis are unknown. The defect is hypothesized to occur after 16 weeks gestation with failure of development of terminal bronchioles and alveoli.5 Familial cases have been reported, including concordant identical twins and siblings of consanguineous parents,2,6,7 suggesting that there may be a genetic component. Prognosis and Treatment

The prognosis is dependent on the degree of pulmonary hypoplasia. Mortality is high with only 3 of 28 reported infants surviving to discharge.8 Mechanical ventilation with high inspired oxygen content and high ventilatory pressures is typical. A term infant was unsuccessfully treated with inhaled nitric oxide and high frequency oscillatory ventilation.8 Extracorporeal membrane oxygenation may only be helpful if there is sufficient pulmonary parenchymal tissue to sustain life.7

including bowel infarction, lead to diagnosis, which is made by lateral chest radiograph or bowel contrast study.6 Retroesophageal hernias also typically present after infancy with vomiting, gastroesophageal reflux, aspiration, or chronic respiratory symptoms. Diagnosis is confirmed by barium swallow.4 Eventration of the diaphragm may be asymptomatic or present with cardiorespiratory symptoms depending on the severity of the muscular hypoplasia. Respiratory symptoms tend to improve with age due to increased rigidity of the thoracic cage. Chest radiograph reveals elevation of the hemidiaphragm and fluoroscopy demonstrates limited or paradoxical movement of the diaphragm with respiration.4 The differential diagnosis of prenatally diagnosed diaphragmatic hernia includes other space-occupying lesions, including cystic adenomatoid malformations and bronchopulmonary sequestration. Etiology and Distribution

References (Primary Pulmonary Hypoplasia) 1. Swischuk LE, Richardson CJ, Nichols MM, et al.: Primary pulmonary hypoplasia in the neonate. J Pediatr 95:573, 1979. 2. Langer R, Kaufmann HJ: Primary (isolated) bilateral pulmonary hypoplasia: a comparative study of radiologic findings and autopsy results. Pediatr Radiol 16:175, 1986. 3. Askenazi SS, Perlman M: Pulmonary hypoplasia: lung weight and radial alveolar count as criteria of diagnosis. Arch Dis Child 54:614, 1979. 4. Page DV, Stocker JT: Anomalies associated with pulmonary hypoplasia. Am Rev Respir Dis 125:216, 1982. 5. Mendelsohn G, Hutchins GM: Primary pulmonary hypoplasia: report of a case with polyhydramnios. Am J Dis Child 131:1220, 1977. 6. Boylan P, Howe A, Gearty J, et al.: Familial pulmonary hypoplasia. Ir J Med Sci 146:179, 1977. 7. Cregg N, Casey W: Primary congenital pulmonary hypoplasia—genetic component to aetiology. Paediatr Anaesth 7:329, 1997. 8. Odd DE, Battin MR, Hallam L, et al.: Primary pulmonary hypoplasia: a case report and review of the literature. J Paediatr Child Health 39:467, 2003.

Formation of the body cavities begins during the 4th week of development after fertilization with transverse and ventral folding of the embryo. The mesoderm-derived septum transversum, which will form the central tendon of the diaphragm, originates cranial to the heart but is carried caudally with ventral folding of the head region. The septum transversum partially separates the pericardial and abdominal cavities, which are continuous dorsally through the pleuroperitoneal canals. Bilateral pleuroperitoneal membranes fuse with the dorsal mesentery, in which the openings for the aorta, inferior vena cava, and esophagus are located, and with the septum transversum to complete separation between the thoracic and

Fig. 6-5. Schematic showing location of diaphragmatic hernias.

6.12 Congenital Diaphragmatic Hernia Definition

Congenital diaphragmatic hernia is the absence or hypoplasia of the tendinous or muscular parts of the diaphragm, which allows herniation of abdominal viscera into the thoracic cavity. Posterolateral (Bochdalek), anterior (Morgagni), paraesophageal defects, defects of the central tendon, hemiagenesis, and eventration of the diaphragm are included. Diagnosis

Diagnosis of Bochdalek hernia is often made on fetal ultrasonogram. Associated sonographic features include polyhydramnios, deviation of the heart, absent or displaced stomach bubble, and dilated bowel loops within the thorax.1 Fetal magnetic resonance imaging is also used for diagnosis of fetal chest masses.2 Hydrops fetalis can also be a complicating feature.3 Postnatally, cardiorespiratory symptoms are frequent, including dyspnea, tachypnea, and cyanosis. Physical examination may reveal a scaphoid abdomen. Chest radiograph is usually diagnostic, showing mediastinal shift and abdominal viscera within the chest.4 Small defects may present later with cough, dyspnea, vomiting, or cyanosis.5 Morgagni hernias are typically small and do not commonly present in the neonatal period. Cardiorespiratory or gastrointestinal symptoms,

Table 6-6. Epidemiologic considerations of congenital diaphragmatic Hernia Characteristic

Summary Information

Prevalence

1–4 of 10,000 live births and stillbirths

Geographic variation

Low in Hungary (0.3 of 10,0000) and high in Japan (6.4 of 10,000)8

Gender difference

2 male to 1 female4

Temporal trends

Relatively stable

Twinning

Increased among conjoined twins9

Familial patterns

Isolated cases considered multifactorial, recurrence risk 2%10

The Lower Respiratory Organs

215

Table 6-7. Recognizable patterns associated with posterolateral diaphragmatic hernia Causation Gene/Locus

Syndrome

Significant Features

Trisomy 13

Holoprosencephaly, microcephaly, aplasia cutis congenita, microphthalmia, cleft lip/palate, malformed ears, heart defect polydactyly

Chromosomal

Trisomy 18

Growth retardation, microcephaly, cleft lip/plate, clenched hands or overlapping fingers, radial defect, short sternum, heart defect, vertebral defect, neural tube defect

Chromosomal

Wolf-Hirschhorn, del 4p16.3

Growth retardation, microcephaly, high forehead, prominent glabella, hypertelorism, ocular coloboma, cleft lip/palate, preauricular pits, heart defect, digital anomalies, mental retardation

Chromosomal

Pallister-Killian, Mosaic tetrasomy 12p

Coarse facies, frontotemporal sparse hair, tall forehead, hypertelorism, short anteverted nose, prominent philtrum, wide mouth, hypopigmented macules, mental retardation

Chromosomal

Trisomy 2227

Growth retardation, microcephaly, hypertelorism, epicanthal folds, ocular coloboma, cleft lip/palate, preauricular pits/tags, micrognathia, webbed neck, heart defect, distal phalangeal hypoplasia, anal atresia

Chromosomal

Other chromosomal: del 1q, 3q, 4p, 8p, 8q, 15q dup 1q, 2p, 4q, 22q28,29

Various defects depending on specific segmental aneuploidy

Chromosomal

Amniotic bands, limb-body wall complex30,31

Neural tube defect, facial cleft, limb defect, ventral wall defect, scoliosis, some with very short umbilical cord

Unknown

Cornelia de Lange

Growth retardation, microcephaly, brachycephaly, synophrys, long eyelashes, thin upper lip, downturned mouth, heart defect, asymmetric limb defect, hirsutism, mental retardation

Sporadic AD (122470) NIPBL, 5p13.1

Denys-Drash, Wilms tumor, pseudohermaphroditism32

Ambiguous genitalia, gonadal dysgenesis, renal disease, Wilms tumor, gonadoblastoma

Sporadic AD (194080) WT1, 11p13

Donnai-Barrow33

Hypertelorism, myopia, iris coloboma, deafness, agenesis of corpus callosum, omphalocele

AR (222448)

Fryns

Large for gestational age, coarse facies, malformed ears, wide mouth, cleft lip/palate, microretrognathia, agenesis of corpus callosum, heart defect, renal defect, digital and nail hypoplasia

AR (229850)

Goltz, focal dermal hypoplasia34,35

Focal areas of absent or hypoplastic skin with or without fat herniation, eye defects, dental defects, nail defects, heart defect, limb defects, laryngeal or esophageal papilloma

XLD (305600) Male lethal

Kabuki36

Growth retardation, microcephaly, long palpebral fissures with lateral lower lid eversion, trapezoidal philtrum, cleft palate, preauricular pit, heart defect, vertebral defect, renal defect, premature thelarche, hypotonia, mental retardation

Sporadic, AD

Lethal multiple pterygium37

Nuchal cystic hygroma, hydrops fetalis, hypertelorism, cleft palate, micrognathia, amyoplasia, pterygia, bony fusions, thin ribs, pulmonary hypoplasia

AR (253290) XL (312150)

Matthew Wood38

Microphthalmia, anophthalmia, pulmonary hypoplasia/agenesis

Uncertain (601186)

Meacham39

Male sex reversal, ambiguous genitalia, gonadal dysgenesis, double/septate vagina, lung defect, heart defect

Unknown

Microphthalmia with linear skin defects, MIDAS40

Asymmetric and linear erythematous skin, hypoplasia of head and neck, microphthalmia, corneal opacity, agenesis of corpus callosum, seizures, gonadal dysgenesis

XLD del Xp22.3

Pentalogy of Cantrell, thoracoabdominal

Midline supraumbilical ventral wall defect, omphalocele, sternal defect, ectopia cordis, heart defect

Unknown XLD (313850) Xq25-26.1

Simpson-Golabi-Behmel

Large for gestational age, tall stature, microcephaly, coarse facies, supernumerary nipples, postaxial polydactyly, hypotonia, mental retardation, embryonal tumor

(312870) GPC3, Xq26

abdominal cavities. Muscle cells originating from the lateral body wall form the crura and muscular portions of the diaphragm (Fig. 6-5). Bochdalek hernias result from defective development or failure of fusion of the pleuroperitoneal membranes, which occurs more commonly on the left side. Anterior herniation through the foramen of Morgagni, through which the epigastric vessels pass, is

rare. Herniation may also occur through the esophageal opening. Eventration of the diaphragm is abnormal elevation of the diaphragm due to deficient muscular development. Bochdalek hernias represent 90% of all congenital diaphragmatic hernias,4 with 85–90% being left-sided.7 Epidemiologic considerations of diaphragmatic hernia are shown in Table 6-6.

216

Cardiorespiratory Organs

Congenital diaphragmatic hernia may be an isolated defect or associated with multiple malformations. When congenital diaphragmatic hernia is diagnosed prenatally, associated abnormalities are detected in 26–72%.11–14 Associated defects include primarily cardiovascular, skeletal, genitourinary, and nervous systems. Associated anomalies are reported in 36–48% of liveborn infants.11,12 Cardiac defects are reported in 18–23% of infants with congenital diaphragmatic hernia.15,16 Identifiable syndromes, including chromosome anomalies, were diagnosed in 12–44% of cases with multiple malformations.11–13,16 Syndromes associated with Bochdalek type of congenital diaphragmatic hernia are shown in Table 6-7. Morgagni hernias account for 2–11% of all diaphragmatic hernias.17,18 One series of 15 cases showed a male excess of 4:1.18 Associated anomalies in that series included malrotation (27%) and congenital heart defects (27%). Several authors report an association with Down syndrome.17–19 Prognosis and Treatment

Congenital diaphragmatic hernia, especially when associated with multiple anomalies, is associated with dismal outcome.11–14 In isolated cases, mortality rates have improved over time due to advances in diagnosis, perinatal, neonatal, and surgical care, including extracorporeal membrane oxygenation.20 Survival rates for liveborn infants are reported as 56–86%.13,20–22 Survival rates are highest for infants with isolated and left-sided defects.22 Open fetal repair of fetal diaphragmatic hernia, once hoped to decrease complications such as pulmonary hypoplasia, is no longer utilized. However, fetoscopic tracheal occlusion to improve lung growth is being used, but randomized controlled trials have not yet been performed.23 Recently, ex utero intrapartum therapy (EXIT), maintaining uteroplacental blood flow and gas exchange during intrapartum fetal procedures, has been used to reduce tracheal occlusion and for prenatal treatment of congenital diaphragmatic hernia and other fetal airway malformations.24 Chronic pulmonary disease,25,26 gastroesophageal reflux, and developmental delay are common complications in surviving children.26 References (Congenital Diaphragmatic Hernia) 1. Benacerraf BR, Adzick NS: Fetal diaphragmatic hernia: ultrasound diagnosis and clinical outcome in 19 cases. Am J Obstet Gynecol 156: 573, 1987. 2. Hubbard AM, Adzick NS, Crombleholme TM, et al.: Congenital chest lesions: diagnosis and characterization with prenatal MR imaging. Radiology 212:43, 1999. 3. Sydorak RM, Goldstein R, Hirose S, et al.: Congenital diaphragmatic hernia and hydrops: a lethal association? J Pediatr Surg 37:1678, 2002. 4. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 5. Ozturk H, Karnak I, Sakarya MT, et al.: Late presentation of Bochdalek hernia: clinical and radiological aspects. Pediatr Pulmonol 31:306, 2001. 6. Salzberg AM, Krummel TM: Congenital malformations of the lower respiratory tract. In: Kendig’s Disorders of the Respiratory Tract in Children. Chernick V, Kendig E, eds. WB Saunders Company, Philadelphia, 1990, p 227. 7. McNamara JJ, Eraklis AJ, Gross RE: Congenital posterolateral diaphragmatic hernia in the newborn. J Thorac Cardiovasc Surg 55:55, 1968. 8. International Clearinghouse for Birth Defects Monitoring Systems 2002 Annual Report. www.icbd.org.publications.htm.

9. Edmonds L, Layde P: Conjoined twins in the United States, 1970– 1977. Teratology 25:301, 1982. 10. Norio R, Kaarianen H, Rapola J, et al.: Familial congenital diaphragmatic defects: aspects of etiology, prenatal diagnosis and treatment. Am J Med Genet 17:471, 1984. 11. Bollmann R, Kalache K, Mau H, et al.: Associated malformations and chromosomal defects in congenital diaphragmatic hernia. Fetal Diagn Ther 10:52, 1995. 12. Enns GM, Cox VA, Goldstein RB, et al.: Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: a retrospective study of 60 patients and literature review. Am J Med Genet 79:215, 1998. 13. Dillon E, Renwick M, Wright C: Congenital diaphragmatic herniation: antenatal detection and outcome. Br J Radiol 73:360, 2000. 14. Witters I, Legius E, Moerman P, et al.: Associated malformations and chromosomal anomalies in 42 cases of prenatally diagnosed diaphragmatic hernia. Am J Med Genet 103:278, 2001. 15. Greenwood RD, Rosenthal A, Nadas AS: Cardiovascular abnormalities associated with congenital diaphragmatic hernia. Pediatrics 57:92, 1976. 16. Cunniff C, Jones KL, Jones MC: Patterns of malformations in children with congenital diaphragmatic defects. J Pediatr 116:258, 1990. 17. Parmar RC, Tullu MS, Bavdekar SB, et al.: Morgagni hernia with Down syndrome: a rare association-case report and review of literature. J Postgrad Med 47:188, 2001. 18. Al-Salem AH, Nawaz Am, Matta H, et al.: Herniation through the foramen of Morgagni: early diagnosis and treatment. Pediatr Surg Int 18:93, 2002. 19. Honore LH, Torfs CP, Curry CJ: Possible association between the hernia of Morgagni and trisomy 21. Am J Med Genet 47:255, 1993. 20. Weber TR, Kountzman B, Dillon PA, et al.: Improved survival in congenital diaphragmatic hernia with evolving therapeutic strategies. Arch Surg 133:498, 1998. 21. Beresford MW, Shaw NJ: Outcome of congenital diaphragmatic hernia. Pediatr Pulmonol 30:249, 2000. 22. Geary MP, Chitty LS, Morrison JJ, et al.: Perinatal outcome and prognostic factors in prenatally diagnosed congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 12:107, 1998. 23. Sydorak RM, Harrison MR: Congenital diaphragmatic hernia: advances in prenatal therapy. Clin Perinatol 30:465, 2003. 24. Hedrick HL: Ex utero intrapartum therapy. Semin Pediatr Surg 12:190, 2003. 25. Muratore CS, Kharasch V, Lund DP, et al.: Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg 36:133, 2001. 26. Lally KP: Congenital diaphragmatic hernia. Curr Opin Pediatr 14:486, 2002. 27. Kim EH, Cohen RS, Ramachandran P, et al.: Trisomy 22 with congenital diaphragmatic hernia and absence of corpus callosum in a liveborn premature infant. Am J Med Genet 44:427, 1992. 28. Howe DT, Kilby MD, Sirry H, et al.: Structural chromosome anomalies in congenital diaphragmatic hernia. Prenat Diagn 16:1003, 1996. 29. Lurie IW: Where to look for the genes related to diaphragmatic hernia? Genet Couns 14:75, 2003. 30. VanAllen MI, Curry C, Gallagher L: Limb-body wall complex: I. Pathogenesis. Am J Med Genet 28:529, 1987. 31. Russo R, D’Armiento M, Pasquale A, et al.: Limb body wall complex: A critical review and a nosological proposal. Am J Med Genet 47:893, 1993. 32. Devriendt K, Deloof E, Moerman P, et al.: Diaphragmatic hernia in Denys-Drash syndrome. Am J Med Genet 57:97, 1995. 33. Donnai D, Barrow M: Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder? Am J Med Genet 47:679, 1993. 34. Patel JS, Maher ER, Charles AK: Focal dermal hypoplasia (Goltz syndrome) presenting as a severe fetal malformation syndrome. Clin Dysmorphol 6:267, 1997.

The Lower Respiratory Organs 35. Han XY, Wu SS, Conway DH, et al.: Truncus arteriosus and other lethal internal anomalies in Goltz syndrome. Am J Med Genet 90:45, 2000. 36. Donadio A, Garavelli L, Banchini G, et al.: Kabuki syndrome and diaphragmatic defects: a frequent association in non-Asian patients? Am J Med Genet 91:164, 2000. 37. Entezami M, Runkel S, Kunze J, et al.: Prenatal diagnosis of a lethal multiple pterygium syndrome type II. Case report. Fetal Diagn Ther 13:35, 1998.

217

38. Seller MJ, Davis TB, Fear CN, et al.: Two sibs with anophthalmia and pulmonary hypoplasia (Matthew Wood syndrome). Am J Med Genet 62:227, 1996. 39. Killeen OG, Kelehan P, Reardon W: Double vagina with sex reversal, congenital diaphragmatic hernia, pulmonary and cardiac malformationsanother case of Meacham syndrome. Clin Dysmorphol 11:25, 2002. 40. Allanson J, Richter S: Linear skin defects and congenital microphthalmia: a new syndrome at Xp22.2. J Med Genet 28:143, 1991.

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Part III Craniofacial Structures

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7 Skull John M. Graham, Jr.

N

eural crest cells in the head region differentiate into mesenchymal cells that form the bones of the face (viscerocranium), while the cranial base and other portions of the cranium are formed by the mesodermally derived occipital somites and somitomeres. The portion of the skull surrounding the brain is termed the neurocranium. The neurocranium is divided into the membranous part, which forms the flat bones of the cranial vault, and the chondrocranium, which forms the cartilaginous bones of the base of the skull. The chondrocranium develops by fusion of a number of cartilaginous structures, which ossify by endochondral ossification to form the base of the skull. Posteriorly, the base of the occipital bone is formed from parachordal cartilage and three occipital sclerotomes. Anteriorly, the sphenoid and ethmoid bones are formed from the hypophyseal cartilages and trabeculae cranii. On either side of the medial plate, the ala orbicularis and ala temporalis form the sphenoid bones, and the periotic capsule forms the temporal bones. The membranous neurocranium (dura mater) ossifies to form the cranial vault through bone spicules, which progressively radiate from primary ossification centers near the center of each bony plate toward the periphery, where the sutures develop. The membranous cranial bones are separated by connective tissue seams, which are termed sutures. Membranous bones enlarge during fetal and postnatal life by the apposition of new layers to the outer surface of the skull (ectocranial bone deposition), while endocranial osteoclastic bone resorption occurs on the inner surface. Growth of cranial bones is directly related to brain growth, and fusion of cranial sutures is related to the cessation of brain growth. There are six fibrous areas where two or more cranial bones meet (fontanels). The five major sutures are the metopic, sagittal, coronal, squamosal, and lambdoid sutures; the six fontanels are the anterior (1), sphenoidal (2), posterolateral (2), and posterior (1) (Fig. 7-1). The presence of the sutures and fontanels allow the bones of the skull to overlap each other (termed molding) during the birth process. At birth, the cranium is disproportionately large compared with the facial skeleton, and it continues to grow rapidly until the 5th to 7th years (Fig. 7-2). Different sutures become ossified at different times, with the metopic suture being the first to ossify at 4 to 7 months, while the remaining sutures do not become completely ossified until adulthood. Sutural synostosis involves secretion of various isoforms of transforming growth factor beta. Fibroblast growth factor

Fig. 7-1. Schematic showing location of cranial sutures and fontanels.

receptors (FGFR-1 and FGFR-2) are expressed in the precartilaginous craniofacial structures, while FGFR-3 is expressed in the growth plates of long bones. In general, FGFR-1 promotes osteogenic differentiation, FGFR-2 increases proliferation, and FGFR-3 increases long bone growth, with increased expression also noted in the occipital region. TWIST is a DNA-binding protein that regulates cell proliferation, and MSX2 and ALX4 regulate parietal cell growth. Mutations in these genes can affect the morphogenesis of the skull. Reference Sadler TW: Langman’s Medical Embryology, ed 9. Williams and Wilkins, Baltimore, 2004, p 173.

7.1 Craniosynostosis Definition

The term craniostenosis (literally ‘‘cranial narrowing’’) is used to describe an abnormal head shape that results from premature fusion of one or more sutures, while craniosynostosis is the process of premature sutural fusion that results in craniostenosis. In clinical usage, the term craniosynostosis is used more widely, 221

222

Craniofacial Structures

physical therapy and repositioning, or cranial orthotic therapy if those measures are unsuccessful.1–4 Diagnosis

Fig. 7-2. Skulls from a newborn (left), 7-year-old child (center), and adult (right) showing the proportional relationships between the neurocranium and viscerocranium, with the chondrocranial relationships displayed in the bottom frames. (Courtesy of Dr. Bernard Sarnat, Cedars-Sinai Medical Center, Los Angeles, CA.)

perhaps in an effort to distinguish deformational nonsynostotic head shapes from those caused by underlying sutural synostosis; however, the two terms are often used interchangeably. Plagiocephaly is a nonspecific term used to describe an asymmetric head shape, which can result from either craniosynostosis or cranial deformation, and differentiation between these two causes is critical to determining the proper mode of treatment (that is, surgery versus physical techniques). Synostotic plagiocephaly is usually treated with a neurosurgical procedure involving partial calvariectomy, while deformational plagiocephaly responds to early

In an otherwise normal fetus, prenatal relaxation of normal growth-stretch tensile forces in the underlying dura across a suture during late fetal life can result in craniosynostosis.5–10 This may also occur when the lack of growth stretch is caused by a deficit in brain growth, as in severe primary microcephaly. Experimental prolongation of gestation, resulting in fetal crowding after installation of a cervical clip in pregnant mice, has been shown to result in craniosynostosis.10 The degree of craniosynostosis was greatest among those fetuses located proximally in the uterine horns, where the crowding was most severe. The most common cause of craniostenosis in otherwise normal infants is constraint of the fetal head in utero.5–10 When external fetal head constraint limits growth stretch parallel to a cranial suture, it may lead to craniosynostosis of an intervening suture between the constraining points. Sagittal craniosynostosis (the most common type of craniosynostosis) usually occurs in an otherwise normal child. The constrained suture tends to develop a bony ridge, especially at the point of maximal constraint between the biparietal eminences. Such ridging can easily be palpated or visualized on skull radiographs, and threedimensional cranial computed tomography (3-D CT) allows the ridge to be seen even more clearly (Fig. 7-3). Craniosynostosis is usually recognized shortly after birth from the shape of the head. Early closure of a fontanel, head asymmetry, and/or palpable ridging along a closed suture can be presenting features. With synostosis, cranial radiographs may reveal sclerosis of the suture with no apparent intervening sutural ligament, but it may be difficult to distinguish an overlapping suture from synostosis. On cross-sectional images, dense ridging over the suture may be evident, particularly with sagittal and metopic synostosis. If there is uncertainty as to whether sutures are truly synostotic, 3-D CT can provide a more accurate appraisal (Fig. 7-3). In general, craniosynostosis begins at one point and then spreads along a suture.10,11 At the fused suture, there is complete sutural obliteration, with nonlamellar bone extending completely across the sutural space, while further away from the initial site of fusion, the sutural margins are closely approximated with ossifying connective tissue. As the age when the suture is surgically removed increases, there is a tendency for more of the suture to become synostotic, with synostosis usually beginning at only one location in most cases.10 Synostosis prevents future expansion at that site, and the rapidly growing brain then distorts the calvaria into an aberrant shape, depending on which sutures have become synostotic. The earlier the synostosis takes place, the greater the effect on skull shape. Craniosynostosis may be caused by many different mechanisms, such as mutant genes, chromosome disorders, storage disorders, hyperthyroidism, or failure of normal brain growth (Tables 7-1, 7-2, 7-3, 7-4). The entire topic of craniosynostosis has been comprehensively reviewed by Cohen and MacLean.11 Different terms have been used to describe the different head shape alterations caused by craniosynostosis, with the resultant head shape dependent on the suture involved. A long, keel-shaped skull with prominent forehead and occiput is termed dolichocephaly or scaphocephaly. This head shape is usually associated with premature sagittal suture closure and a palpable ridge toward the posterior end of the suture (Fig. 7-3). Syndromes featuring sagittal synostosis are listed in Table 7-1. Sagittal synostosis must be distinguished from lateral deformation of the infant cranium due to persistently sleeping on the side of the head (more common

Skull

223

Fig. 7-3. A. Schematic drawing showing sagittal synostosis with dolichocephaly. B, C. Radiographs showing dolichocephaly secondary to partial synostosis in a 6-month-old male. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.) D, E. 3-D CT scan in 6-week-old male showing sagittal synostosis.

in hypotonic, prone-sleeping, and prematurely born infants). Individuals with scaphocephaly have a decreased cephalic index (CI) of less than 76% (CI = head width/head length  100%). With the current emphasis on positioning infants for sleep in the supine position to reduce the incidence of sudden infant death syndrome

(SIDS), the average CI in infancy has increased from 76–81% to 86–88% in cultures with supine-sleeping infants.3 Premature fusion of both coronal sutures produces a high, wide forehead with a short skull, resulting in brachycephaly (Fig. 7-4), while fusion of one coronal suture produces an asymmetric

Table 7-1. Syndromes with craniosynostosis Syndrome

Major Features

Suture

Causation Gene/Locus

Acrocraniofacial dysostosis

Acrocephaly, short stature, ear anomalies, deafness, ptosis, choanal atresia, cleft palate, cardiac defects, polydactyly

Coronal

AR (201050)

Antley-Bixler

Brachycephaly, kleeblattschadel, choanal atresia, flat midface, cardiac defect, ambiguous genitalia, joint synostosis, multiple fractures

Coronal, lambdoid

AR (207410) POR, 7q11.2

Apert

Brachycephaly, acrocephaly, delayed closure of fontanel, kleeblattschadel, prominent eyes, flat facial profile, cleft or narrow palate, syndactyly

Coronal

AD (101200) FGFR2, 10q26

Armendares11

Retinitis pigmentosa, short fifth fingers with clinodactyly, growth deficiency

Coronal, sagittal

Unknown

Auralcephalosyndactyly

Brachycephaly, ridged or wide cranial sutures, ear anomalies, deafness, cardiac defect

Coronal

AD (109050)

Baller-Gerold

Turribrachycephaly, absent thumbs, radial aplasia, growth deficiency

Multiple

AR (218600)

Baraitser

Mental retardation, seizures, choroidal colobomas, beaked nose, cleft lip/palate, cystic dysplastic kidneys

Coronal

AR (218650)

Beare-Stevenson cutis gyrata

Brachycephaly, acrocephaly, kleeblattschadel, ear anomalies, midface hypoplasia, hepatomegaly

Multiple

AD (123790) FGFR2, 10q26

Berant11

Dolichocephaly, acrocephaly, radioulnar synostosis

Sagittal

AD

Boston type

Fronto-orbital recession, turribrachycephaly

Multiple

AD (604757) MSX2, 5q34-q35

Calabro11

Unilateral ulnar aplasia, micrognathia, oligodactyly, cryptorchidism, pulmonic stenosis, micropenis

Coronal, metopic

Unknown

Carpenter

Brachycephaly, acrocephaly, kleeblattschadel, ear anomalies, cardiac and genital defects, polydactyly, mental retardation

Multiple

AR (201000)

Chitayat hypophosphatemia

Dolichocephaly, renal hypophosphatemia, minor facial dysmorphism, intracerebral calcifications, nonrachitic bone changes

Sagittal

AR (241519)

COH11

Kleeblattschadel, polymicrogyria, absent olfactory tracts and bulbs, thumb duplication, bifid scrotum, agenesis of cervical thymic lobes, bilobed lungs

Multiple

Sporadic

Cole-Carpenter

Osteogenesis imperfecta, hydrocephalus, ocular proptosis, frontal bossing

Multiple

AD (112240)

Cranioectodermal dysplasia

Dolichocephaly, short stature, sparse hair, dental anomalies, brachydactyly, hypoplastic fibula

Sagittal

AR (218330)

Craniofacial dyssynostosis

Craniofacial dysostosis, mental retardation, short stature

Lambdoid, posterior sagittal

AR (218350)

Cranio-fronto-nasal dysplasia

Brachycephaly, widow’s peak, ear anomalies, cardiac and genital defects, polydactyly, mental retardation

Coronal (females only)

AD (304110) EFNB1, Xq28

Craniomicromelic dysplasia

Macroturricephaly, short palpebral fissures, pinched nose, micrognathia, microstomia, short limbs, hypoplastic lungs, absent/hypoplastic gallbladder, short intestine, hypoplastic uterus

Coronal

AR (602558)

Craniorhiny

Oxycephaly, recessed forehead, lack of frontonasal angle, nasal changes, absent nasolacrimal ducts

Coronal

AD (123050)

Craniosynostosis with ectopia lentis

Ectopia lentis, hirsutism on back, hyperlaxity of elbows and knees, hypoplastic toe nails

Sagittal, metopic

Unknown (603595)

Craniotelencephalic dysplasia

Protuberance of frontal bone, retarded neurologic development

Multiple

AR (218670) (continued)

224

Table 7-1. Syndromes with craniosynostosis (continued) Syndrome

Major Features

Suture

Causation Gene/Locus

Crouzon

Brachycephaly, kleeblattschadel, ridged sutures, deafness, convex beaked nose, tooth anomalies, malocclusion

Multiple

AD (123500) FGFR2, 10q26

Crouzon with acanthosis nigricans (Crouzonodermoskeletal)

Crouzon syndrome, choanal atresia, hydrocephalus, acanthosis nigricans

Multiple

AD (134934) FGFR3, 4p16.3

Curry-Jones11

Plagiocephaly, unilateral microphthalmia, iris coloboma, syndactyly, preaxial polydactyly, skin lesions, abnormal gut development

Unilateral Coronal

Unknown AR

Elejalde: acrocephalopolydactylous dysplasia

Acrocephaly, high birth weight, obesity, omphalocele, visceral anomalies, thick skin

Multiple

AR (200995)

Fontaine-Farriaux11

Phalangeal hypoplasia with anonychia, patches of lipodystrophy, aplasia of abdominal muscles, genital hypoplasia, hypospadias, cryptorchidism

Multiple

Unknown

Frydman trigonocephaly

Trigonocephaly, S-curved lower lids, preauricular tags, hypotelorism, omphalocele

Metopic

AD (190440)

Fryns type11

Asymmetric long face, high narrow forehead, short upper lip, highly arched palate, sensorineural hearing loss

Coronal, metopic

Unknown

Gomez-Lopez-Hernandez

Ataxia, trigeminal anesthesia, corneal opacity, ear deformities, pons-vermis fusion, parietal alopecia, midface hypoplasia

Multiple

Unknown AR (601853)

Gorlin-Chaudhry-Moss

Brachycephaly, hirsutism, deafness, microphthalmia, high/narrow palate, short stature, mental retardation

Coronal

AR (233500)

Hersh11

Sensorineural deafness, micrognathia, sparse curly hair

Coronal

AR

Holoprosencephaly with craniosynostosis

Semilobar holoprosencephaly, small vertebral bodies, coxa valga

Multiple

Unknown AR (601370)

Hunter-McAlpine

Microcephaly, mental retardation, short stature, minor acral anomalies

Coronal, lambdoid

AD (601379) Subtelomere rearrangement (5q, 13p)

Hypomandibular faciocranial dysostosis

Prominent eyes, deficient midface and zygomatic arches, short nose with anteverted nares, minute oral aperture, severe mandibular hypoplasia

Coronal

AR (241310)

Ives-Houston

Perinatal death, intrauterine growth retardation, marked microcephaly, severe malformations of limbs

Multiple

AR (251230)

Jackson-Weiss

Midface hypoplasia, feet abnormalities

Multiple

AD (123150) FGFR2, 10q26

Jones: craniosynostosisDandy-Walker malformation

Dolichocephaly, plagiocephaly, Dandy-Walker cyst

Sagittal

AD (123155)

Lin-Gettig

Dolichocephaly, trigonocephaly, agenesis of corpus callosum, facial anomalies, camptodactyly, hypogonadism

Sagittal, metopic

AR or XLR (218649)

Lowry

Fibular aplasia

Coronal, sagittal

AR (218550)

Lowry-MacLean

Mental retardation, cleft palate, proptosis, beaked nose, eventration of diaphragm, microcephaly, growth failure, mental deficiency

Multiple

Unknown AD (600252)

Michels

Anterior chamber eye abnormalities, craniofacial anomalies, skeletal defects

Lambdoid, coronal

AR (257920)

Muenke

Midface hypoplasia, downslanting palpebral fissures, highly arched palate, coned epiphyses

Coronal

AD (602849) FGFR3, 4p16.3

Opitz C trigonocephaly

Trigonocephaly, craniofacial dysmorphism, central nervous system abnormalities, mental deficiency, redundant skin

Metopic

AR (211750)

(continued)

225

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Craniofacial Structures

Table 7-1. Syndromes with craniosynostosis (continued) Syndrome

Major Features

Suture

Causation Gene/Locus

Osteoglophonic dysplasia

Acrocephaly, kleeblattschadel, hypertelorism, prominent eyes, rhizomelia, osteoporosis

Multiple

AD (166250)

Pfeiffer

Brachycephaly, kleeblattschadel, hypertelorism, cutaneous syndactyly, broad thumbs/hallux

Coronal; sagittal variable

AD (101600) FGFR1, 8p11.2-p11.1 FGFR2, 10q26

Pfeiffer cardiocranial

Dolichocephaly, anomalous ears, cleft palate, cardiac defect, genital defect, joint contractures, mental retardation

Sagittal

AR (218450)

Philadelphia type

Dolichocephaly, cutaneous syndactyly

Sagittal

AD (601222)

Richieri-Costa overgrowth11

Dolichocephaly, mental retardation, overgrowth, distal arthrogryposis, sacral dimple, joint laxity

Sagittal

AR

Saethre-Chotzen

Brachycephaly, ear anomalies, prominent eyes with ptosis, asymmetric face, cleft/high palate

Coronal; lambdoid/ metopic variable

AD (101400) TWIST, 7p21

Sakati

Acrocephalopolysyndactyly, short limbs, congenital heart defect, ear anomalies, skin defects

Multiple

AD (101120)

San Francisco type11

Midface hypoplasia, ptosis of eyelids, bulbous nose, small ears

Multiple

AD

Say-Barber

Microcephaly, short stature, flexion contractures, chemotactic defect, increased infections, hypogonadism

Multiple

AR (251240)

Trigonocephaly, short stature, developmental delay

Metopic

XLR (314320)

Say-Poznanski

Kleeblatschadel, polydactyly, abnormal metacarpals and metatarsals, angular ulnas, short and wide clavicles, unusually shaped ribs

Multiple

Unknown

SCARF

Skeletal abnormalities, cutis laxa, ambiguous genitalia, psychomotor retardation, facial abnormalities

Multiple

XLR (312830)

Seckel

Microcephaly, growth deficiency, beaked nose, micrognathia, mental deficiency

Multiple

AR (210600) ATR, 3q22-q24

Shprintzen-Goldberg

Dolichocephaly, hypertelorism, proptosis, maxillary hypoplasia, micrognathia, arachnodactyly

Sagittal

Sporadic (182212) FBN1, 15q21.1 (some cases)

Spondyloepiphyseal dysplasia with craniosynostosis

Spondyloepiphyseal dysplasia, cataracts, micrognathia, cleft palate, mental deficiency

Coronal

AR (602611)

Thanatophoric dysplasia

Kleeblattschadel, short stature, platybasia, macrocephaly, short limbs, narrow thorax

Multiple

AD (187600) FGFR3, 4p16.3

Tricho-dento-osseous type I

Dolichocephaly, kinky or curly hair, enamel hypoplasia, radiodense bones, normal calvarial thickness

Sagittal

AD (190320) DLX3, 17q21.3-q22

Ventruto

Symphalangism, carpal and tarsal fusion, brachydactyly, strabismus, hip osteochondritis

Coronal

AD (113100) GDF5, 20q11.2

Say-Meyer 11

head shape termed plagiocephaly (Fig. 7-5). When coronal craniosynostosis occurs, it is important to examine the patient carefully for associated anomalies that might suggest a recognizable syndrome. Evaluation of the limbs, ears, and cardiovascular system are quite helpful in diagnosing syndromes associated with coronal craniosynostosis (Table 7-1). Limb defects, such as syndactyly, brachydactyly, carpal coalition, or broad, deviated thumbs and/or halluces, can suggest an associated syndrome and indicate what types of molecular analysis to pursue. It is also important to examine both parents for similar anomalies, carpal coalition, and/or facial asymmetry, since these findings may represent variable expression of an altered gene in a parent.

Premature fusion of both the coronal and sagittal sutures generally leads to a tall, towerlike skull (turricephaly), with more severe synostosis of multiple sutures producing a tall, pointed skull (acrocephaly or oxycephaly). In this condition, the limitations of calvarial expansion are so extreme that there may be limited room for brain growth (Fig. 7-6). Synostosis of multiple cranial sutures is more likely to result in elevated intracranial pressure and to require shunting for hydrocephalus. In extreme cases, a cloverleaf head shape can result from multiple suture synostosis, usually with signs of increased intracranial pressure and a ‘‘beaten copper’’ radiographic appearance of the inner table of the skull (Fig. 7-6A). There may also be optic atrophy, proptosis, and

Skull

227

Table 7-2. Chromosomal anomalies associated with craniosynostosis

Table 7-3. Conditions with secondary craniosynostosis

del(1)(q24-q31)

Metabolic disorders

del(2)(q14-q21)

Hyperthyroidism

del(2)(q24.3-q32.1) dup(3)(pter-p21) del(3)(q27-qter) dup(3)(q21qter)

Rickets Hypophosphatemia Hypercalcemia, idiopathic Mucopolysaccharidoses and related disorders

del(4)(q21.1-q22.1)

Mucopolysaccharidosis I-H (Hurler)

dup(5)(pter-p11)

Mucopolysaccharidosis IV (Morquio)

dup(6)(pter-p21)

Mucopolysaccharidosis VI (Maroteaux-Lamy)

del(6)(q22.2-q23.1) dup(6)(q25-qter) del(7)(pter-p15) del(8)(q21-q22)

Beta glucuronidase deficiency Mucolipodosis III (psuedo-Hurler) Alpha-D-mannosidase deficiency Hematologic disorders

dup(8)(q22-qter)

Sickle cell

del(9)(pter-p22)

Thalassemia

del(11)(p12-p15.3)

Polycythemia vera

del(11)(q23-qter)

Congenital hemolytic icterus

del(12)(pter-p13.1)

Teratogens

del(13)(q32-qter)

Hydantoin

dup(13)(q14-qter)

Retinoids

dup(13)(q14.1-14.3)/tetrasomy(13) (q14.3-q22)

Valproate

Tetrasomy 14q

Methotrexate

dup(15)(q22-qter)

Fluconazole

Trisomy 16 mosaicism

Trimethadione

del(17)(p11.2) del(18p)/dup(20p)

Aminopterin

Cyclophosphamide Malformations

del(22)(q11)

Microcephaly

45,X

Holoprosencephaly

45,X/46,X,þ frag

Encephalocele

46, fragX(q27.3)Y

Iatrogenic disorders

47,XX,þcen frag/46,XX Partial trisomy X

Hydrocephalus with shunt Adapted from Cohen and MacLean11

Triploidy Induced chromosomal aberrations Y chromosome aberrations in vivo with mitotic instability in vitro Adapted from Cohen and MacLean11

loss of vision. Combinations of sutural synostosis, such as sagittal plus coronal, are also referred to as compound craniosynostosis, and multiple suture synostosis usually has a genetic basis (Table 7-1). A triangle-shaped skull (trigonocephaly) is caused by premature fusion of the metopic suture (Fig. 7-7). The similarity in epidemiologic features between sagittal and metopic craniosynostosis suggests that prenatal lateral constraint of the frontal part of the head may be a frequent cause of metopic craniosynostosis. Examples of constraint-induced metopic synostosis have included a monozygotic triplet whose forehead was wedged between the buttocks of her two co-triplets, and an infant whose head was compressed within one horn of his mother’s bicornuate uterus.8 Syndromic metopic synostosis can also occur, and trigonocephaly

is seen in a variety of syndromes (Table 7-4), some of which are associated with mental retardation or chromosome anomalies. Unilateral lambdoid synostosis results in trapezoidal plagiocephaly (Fig. 7-8), which differs from deformational posterior plagiocephaly due to supine positioning and torticollis (Fig. 7-9), and from synostotic anterior plagiocephaly due to unicoronal synostosis (Fig. 7-5). Unlike coronal synostosis, facial structures and orbits are usually less affected by lambdoid synostosis. Radiographic signs include trapezoidal cranial asymmetry, small posterior fossa, and sutural sclerosis with ridging; however, sole reliance on skull radiographs and clinical signs can lead to misdiagnosis, so it is best to confirm the diagnosis of suspected lambdoid synostosis with a 3-D CT scan, which clearly images the involved suture(s) and permits secure diagnosis (Fig. 7-8). Among 102 patients with deformational posterior plagiocephaly and 130 patients with craniosynostosis requiring surgery, only four patients (3.1%) manifested clinical, imaging, and operative features of true unilambdoidal craniosynostosis.15 These features included a thick bony ridge over the fused suture, with contralateral parietal and

228

Craniofacial Structures

Table 7-4. Syndromes with trigonocephaly Syndrome

Major Features

Causation Gene/Locus

Atelencephaly11

Brain anomalies, cutis gyrata of scalp, hypertelorism, cleft palate, genital anomalies, seizures, mental retardation

Unknown

Blepharophimosis with facial and genital anomalies

Ptosis, midface hypoplasia, low-set ears, dental anomalies, sensorineural hearing loss, mental retardation

AR (604314)

Craniosynostosis, early and asymmetric closures of fontanels, cranial asymmetry

Del 7pter-p15

-9p monosomy

Synophrys, short broad neck, long philtrum, mental retardation

AD (158170) Del 9pter-p22

-11q monosomy (Jacobsen)

Intrauterine growth restriction, failure to thrive, ventricular septal defect, pyloric stenosis, micro-macrocephaly

Isolated (147791) Del 11q23-qter

C-trigonocephaly (Opitz)

Dysplastic and low-set ears, small nose with anteverted nares, cardiac defect, polydactyly, syndactyly

AR (211750)

Fronto-ocular

Proptosis, ptosis, elevated nasal bridge, developmental disabilities, congenital heart defects

AD, XLD (605321)

Frydman-trigonocephaly

Auricular tags, synophrys, hemivertebrae, omphalocele

AD (190440)

Goldblatt: hypospadius, mental retardation

Ear anomalies, synophrys, beaked nose, joint laxity, mental retardation

AR (241760)

Holoprosencephaly

Arhinencephaly-cebocephaly-cyclopia, primary defect in prechordal mesoderm

AR (236100) Multiple loci

Lin-Gettig

Agenesis of corpus callosum, dolichocephaly, facial anomalies, camptodactyly, hypogonadism

AR (218649)

Say-Meyer

Short stature, early closure of fontanels, highly arched palate, mental retardation

XLR (314320)

Chromosomal abnormalities -7p deletion

Trigonocephaly

Agenesis of olfactory bulbs

AR (275600)

Valproic acid embryopathy

Low nasal bridge, midface hypoplasia, long philtrum, meningomyelocele, cleft lip

Prenatal exposure

frontal bulging, and an ipsilateral occipitomastoid bulge, leading to tilting of the ipsilateral skull base and a downward/posterior displacement of the ear on the synostotic side. In contrast, infants with deformational, nonsynostotic posterior plagiocephaly had a parallelogram-shaped head, with forward displacement of the ear and frontal bossing on the side ipsilateral to the occipitoparietal flattening, accompanied by contralateral occipital bossing (Fig. 7-9).2 Of the 102 patients with deformational posterior head deformation, only three had severe, progressive deformation requiring surgery; the other cases of deformational plagiocephaly were successfully managed with changes in sleeping position or helmet therapy.15 When craniosynostosis occurs secondary to decreased brain growth associated with severe microcephaly, the head shape tends to be normal, but quite small. Brachycephaly, turricephaly, and acrocephaly associated with exophthalmos, shallow orbits; low-set ears; broad nasal bridge; a narrow, highly arched palate; and malocclusion may suggest a syndromic form of craniosynostosis, especially when there are associated distal limb anomalies (broad deviated halluces or thumbs, syndactyly of the third and fourth fingers, and/or clinodactyly). Syndromic craniosynostosis can be associated with mental retardation, hydrocephalus, and/or optic atrophy secondary to increased intracranial pressure. Craniosynostosis has also occurred with numerous chromosomal abnormalities, and may arise secondarily when there is reduced brain growth or metabolic/hematologic alterations of cranial bones (Tables 7-1 to 7-4). Plagiocephaly, which literally translates from the Greek term plagio kephale, or ‘‘oblique head,’’ is a term used to describe

asymmetry of the head shape when viewed from the top.1,2 It is a nonspecific term that has been used to describe head asymmetry caused by either premature sutural fusion or postnatal head deformation resulting from a positional preference; hence, modifying terms such as ‘‘nonsynostotic,’’ ‘‘deformational,’’ or ‘‘positional’’ have been used to distinguish plagiocephaly without synostosis. The term deformational plagiocephaly should suffice to distinguish this type of defect and its proper type of management. The side of the plagiocephaly is usually indicated by the bone that has been most flattened by the deforming forces (usually the occiput for infants who sleep on their backs). Late during fetal life, the head may become compressed unevenly in utero, but most plagiocephalic head deformation occurs postnatally due to a positional preference.2 Such inequality of positional gravitational forces results in asymmetric molding of the head and/or face. Torticollis is a condition in which the sternocleidomastoid muscle is shorter or tighter on one side of the neck, usually causing the head to tilt toward the affected muscle and the head to turn away. This is the most frequent cause of deformational plagiocephaly, which results in progressive occipital flattening when an infant with torticollis is placed in a supine sleeping position and preferentially turns his or her head to one side.2 Since the torticollis is usually on the side opposite the head turn, the forehead on the side of the torticollis may appear normal or recessed, while the forehead and ear ipsilateral to the flattened occiput appears to have become displaced anteriorly (Fig. 7-9).2 If the infant sleeps on his or her stomach with a preferential head turn, then the frontal region on the side of the torticollis becomes flattened as the infant turns his or her head away from the short or tight sternocleidomastoid

Skull

Fig. 7-4. A. Schematic showing bilateral premature coronal synostosis. B and C. Front and top views of bilateral coronal synostosis by 3-D CT in a 3-month-old female. Fig. 7-5. 3-D CT of unilateral nonsyndromal right-sided coronal synostosis in a 3-month-old female.

229

230

Craniofacial Structures

Fig. 7-6. A. Radiograph showing acrocephaly or oxycephaly in a 14-year-old female with Apert syndrome; note the complete absence of normal sutures and presence of a ‘‘beaten copper’’ radiographic appearance of the inner table of the skull. (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.) B and C. 3-D CT of compound synostosis (left frontal and lateral views) involving both coronal sutures and the sagittal suture with associated hydrocephalus in a 6-week-old male, showing irregular cranial configuration with multiple areas of skull thinning (lu¨ckenscha¨del).

muscle. Deformational plagiocephaly is usually not associated with premature closure of a cranial suture; however, since craniosynostosis can also be caused by fetal head constraint when both deformational plagiocephaly and craniosynostosis occur together, the diagnosis can be difficult, requiring complex management (Fig. 7-10).

Late fetal compression may affect the sternocleidomastoid muscle, resulting in ischemic changes within the muscle, with or without consequent fibrosis and persistent torticollis. Such compression is most likely to occur in first-born babies and in large babies, and deformational plagiocephaly is also much more frequent among multiple gestation infants.1,2 In the

Skull

Fig. 7-7. Metopic synostosis. A. Photographs show trigonocephaly in a 1-year-old male secondary to metopic synostosis with associated microcephaly (occipitofrontal circumference less than third centile) but normal development. His brother, father, and paternal grandfather were similarly affected. (Reprinted with permission from Hennekam RCM and van den Boogaard MJ. Clin Genet 38:374, 1990.) B. Radiographs show trigonocephaly associated with metopic synostosis. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.) C. 3-D CT scans of metopic synostosis in an otherwise normal 2-month-old male.

231

232

Craniofacial Structures

Fig. 7-8. 3-D CT scan in a 2-month-old female with left lambdoid craniosynostosis. A. Rear view shows a thick bony ridge over the fused lambdoid suture on the left, with contralateral parietal and frontal bulging, and an ipsilateral occipitomastoid bulge, leading to tilting of the ipsilateral skull base and a downward/posterior displacement of the left ear on the synostotic side. B. Top view shows a trapezoidal skull shape.

infants with limited mobility due to hypotonia, hydrocephalus, macrocephaly, or limb anomalies are also more likely to develop deformational plagiocephaly, so this anomaly can complicate syndromes with these features. Predisposing factors resulting in excessive or asymmetric head deformation include restrictive intrauterine environments, poor muscle tone, torticollis, clavicular fracture, cervical-vertebral abnormalities, sleeping position, multiple gestation, and incomplete bone mineralization. It is essential to place infants on their backs for sleep, except in cases of prematurity, gastroesophageal reflux, or obstructive sleep apnea. Infants should be placed on their stomachs whenever they are awake and under direct adult supervision to develop their motor skills and encourage full range of neck motion.3 The development of excessive positional brachycephaly, with or without plagiocephaly, can be an early indication that parents are not providing their infants with adequate ‘‘tummy time.’’ It is important to distinguish deformational plagiocephaly from that which results from craniosynostosis, because therapy and management differ. Fig. 7-9. Right occipital deformational posterior plagiocephaly in a supine-sleeping 6-month-old female infant with left-sided congenital muscular torticollis. Note that all sutures remain open, with a parallelogram-shaped head when viewed from the top.

torticollis-plagiocephaly deformation sequence, the infant characteristically has a head tilt toward the side of shortened sternocleidomastoid muscle. By definition, this anomaly involves deformation or reshaping of normal structures, and thus the growth and development of the brain is usually normal. However,

Etiology and Distribution

The frequency of craniosynostosis is 3.4 per 10,000 births, and it is usually an isolated, sporadic anomaly in an otherwise normal child. About 8% of all craniosynostosis cases are familial. Familial types of craniosynostosis are most frequent in coronal synostosis, accounting for 14.4% of coronal synostosis, 6% of sagittal synostosis, and 5.6% of metopic synostosis,12–14 while lambdoidal synostosis is almost never familial. The frequency of associated twinning is increased, and most twin pairs are discordant, especially with sagittal and metopic

Skull

233

Fig. 7-10. This 3-D CT scan depicts an otherwise normal 9-year-old female, who has untreated left lambdoid craniosynostosis with persistent left torticollis resulting in striking craniofacial asymmetry and facial scoliosis.

synostosis. This would tend to support fetal crowding as a cause of these types of synostosis, while concordance for coronal synostosis is much higher for monozygotic twins than dizygotic twins, suggesting that many cases of coronal synostosis have a genetic basis.13 Sagittal synostosis is the most common type of craniosynostosis, accounting for 50–60% of cases and occurring in 1.9 per 10,000 births, with a 3.5:1 male to female ratio.12 Only 6% of cases are familial, with 72% of cases sporadic and no paternal or maternal age effects noted. Twinning occurred in 4.8% of 366 cases, with only one monozygotic twin pair being concordant, and intrauterine constraint is the cause for most cases.12 Coronal craniosynostosis is the second most frequent type of craniosynostosis (accounting for 20–30% of cases). Unilateral coronal craniosynostosis can be either genetic or due to fetal head constraint from an aberrant fetal lie, multiple gestation, or small uterine cavity.6,7 Approximately 71% of unilateral coronal craniosynostosis is right-sided, and 67% of vertex presentations are in the left occiput transverse position, possibly explaining the prevalence of right-sided, unilateral, coronal craniostenosis.6 Nonsyndromic coronal craniosynostosis occurs in 0.94 per 10,000 births, with 61% of cases sporadic, and 14.4% of 180 pedigrees familial. Bilateral cases occur much more frequently than unilateral cases, and coronal synostosis is more frequent in females (with a male to female ratio of 1:2). The paternal age is significantly older than average (32.7 years), and these data have been interpreted as being consistent with autosomal dominant inheritance with 60% penetrance, when the synostosis has a genetic basis.13 Metopic synostosis occurs in about 0.67 per 10,000 births, making it the third most frequent type of craniosynostosis (accounting for 10–20% of patients). Like sagittal synostosis, metopic synostosis is more frequent in males (3.3:1 male to female ratio) and seldom familial (5.6% of cases).14 There is no maternal or paternal age effect, and the frequency of associated twinning was 7.8% of 179 pedigrees studied, with only two twin monozygotic pairs concordant.14

Familial craniosynostosis is usually transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. A wide variety of chromosomal anomalies have also been associated with craniosynostosis (Table 7-2). This emphasizes the importance of chromosomal analysis for patients with syndromic craniosynostosis in whom a recognizable monogenic syndrome is not apparent, particularly when there is associated developmental delay and growth deficiency. As comparative genomic hybridization becomes more clinically available, this will be even more useful than standard cytogenetics for many such cases. In addition, craniosynostosis can occur as a component of numerous syndromes, many of which manifest phenotypic overlap and genetic heterogeneity (Table 7-1).11 Craniosynostosis syndromes with a demonstrated mutational basis include Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Saethre-Chotzen syndrome, Jackson-Weiss syndrome, Boston craniosynostosis, Beare-Stevenson cutis gyrata syndrome, and Muenke syndrome. However, the efficiency of actually detecting a mutation for a given syndrome varies from about 60% for Crouzon syndrome to 98% for Apert syndrome.11 Secondary craniosynostosis (Table 7-3) can occur with certain primary metabolic disorders (hyperthyroidism, rickets), storage disorders (mucopolysaccharidosis), hematologic disorders (thalassemia, sickle cell anemia, polycythemia vera, congenital hemolytic icterus), brain malformations (holoprosencephaly, microcephaly, encephalocele, or overshunted hydrocephalus), and selected teratogenic exposures (diphenylhydantoin, retinoic acid, valproic acid, aminopterin, fluconazole, cyclophosphamide).11 Inability to demonstrate a mutation does not rule out a genetic basis for the craniosynostosis, and not every person with a pathogenic mutation manifests craniosynostosis. Bilateral coronal synostosis often lacks sutural ridging and usually has a genetic pathogenesis, suggesting that all such patients should be screened for mutations. Among 57 patients with bilateral coronal synostosis, mutations in fibroblast growth factor receptor (FRGR) genes were found for all 38 patients with a syndromic form of craniosynostosis. Among 19 patients with nonsyndromic bilateral craniosynostosis, mutations were found in or near exon 9 of FGFR2 in four

234

Craniofacial Structures

patients, as well as finding the common Pro250Arg mutation in exon 7 of FGFR3 in 10 patients (Muenke syndrome); only five patients (9%) lacked a detectable mutation in FGFR1, -2, or 3.16 This study suggests that mutation analysis should be considered in most patients with bilateral coronal synostosis. Prognosis, Prevention, and Treatment

Mild degrees of craniostenosis may not always require surgery; however, in moderately severe cases, early surgery is usually warranted. The usual indication for surgery is to restore normal craniofacial shape and growth. When both the coronal and sagittal sutures are synostotic, impairing brain growth early in infancy, surgery is indicated to help prevent neurologic and ophthalmologic complications associated with increased intracranial pressure and inadequate orbital volume. A variety of neurosurgical techniques have been developed for the treatment of craniosynostosis.11 Most of these techniques involve removing the aberrant portion of the bony calvaria from its underlying dura, including the area surrounding the synostotic suture(s). If this is done within the first few months after birth, a new bony calvaria will usually develop within the remaining dura mater under the same principles that guide normal prenatal calvarial morphogenesis. As long as there is continued growth stretch from the expanding brain, the sites over the dural reflections remain unossified, thereby maintaining the sutures in a fibrous, open state. Thus the calvaria and its sutures usually re-form normally after a partial calvarectomy for craniosynostosis. The new bony calvaria begins to develop within 2 to 3 weeks after surgery and is usually firm by 5 to 8 weeks after surgery. If the procedure is done after 3 to 4 months of age, the approach is similar with the exception that pieces of the calvaria are usually replaced in a mosaic pattern over the dura mater to act as nidi for the mineralization of new calvaria. Newer endoscopic repair techniques have been developed, followed by postoperative orthotic molding. Such procedures are most effective if done relatively early in infancy. These techniques are most effective in normal infants without a syndromic type of craniosynostosis. Following early surgery for isolated craniosynostosis (primary fronto-orbital advancement and/or calvarial vault remodeling at a mean age of 8 months), only 13% of 104 patients (10 bilateral coronal, 57 unilateral coronal, 29 metopic, and eight sagittal) required a second cranial vault operation for residual defects at a mean age of 23 months. Perioperative complications were minimal (5%), with 87.5% of patients considered to have satisfactory craniofacial form and low rates of hydrocephalus (3.8%), shunt placement (1%), and seizures (2.9%). Among such cases of isolated craniosynostosis, unilateral coronal synostosis was the most problematic type due to vertical orbital dystopia, nasal tip deviation, and altered craniofacial growth problems with residual craniofacial asymmetry.17 In a second study of 167 children with both nonsyndromal (isolated) and syndromal craniosynostosis (12 bilateral coronal, 18 unilateral coronal, 39 metopic, and 46 sagittal), repeat operations were necessary in only 7%. Repeat operations were more common in syndromic cases (27.3%) than in nonsyndromic craniosynostosis (5.6%).18 Even though intracranial pressure can be elevated in patients with nonsyndromic craniosynostosis, they may not have decreased cranial volumes either before or after surgical repair and as a group show slightly larger intracranial volumes when compared with normal controls. This could reflect the impact of fetal head constraint on fetuses with larger heads, or it might relate to the known association of macrocephaly with nonsyndromic coronal craniosynostosis due to the common Pro250Arg mutation in FGFR3

(which was not analyzed in these studies).19 Hydrocephalus occurs in 4 –10% of patients with craniosynostosis and is more frequent with syndromic and multiple sutural craniosynostosis. In nonsyndromic patients, the rate of cerebral ventricular dilation is the same as that observed in the general population, and it appears to be related to venous hypertension induced by jugular foramen stenosis. Such dilation usually stabilizes spontaneously and rarely requires shunting. Some cases of progressive hydrocephalus in syndromic craniosynostosis cases were related to multiple sutural involvement, thereby constricting cranial volume, constricting the skull base, crowding the posterior fossa, and causing jugular foraminal stenosis.20 These findings were most frequent among patients with Crouzon, Pfeiffer, and Apert syndromes, especially in association with cloverleaf skull abnormalities. A diffuse beaten copper pattern on skull radiographs, along with obliteration of anterior sulci or narrowing of basal cisterns in children under the age of 18 months, is predictive of increased intracranial pressure in over 95% of cases.21 References (Craniosynostosis) 1. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005. 2. Graham JM Jr, Gomez M, Halberg A, et al.: Management of deformational plagiocephaly: repositioning versus orthotic therapy. J Pediatr 146:258, 2005. 3. Graham JM Jr, Kreutzman J, Earl D, et al.: Deformational brachycephaly in supine-sleeping infants. J Pediatr 146:253, 2005. 4. Graham JM Jr: Craniofacial deformation. Ballieres Clin Pediatr 6:293, 1998. 5. Graham JM Jr, deSaxe M, Smith DW: Sagittal craniostenosis: fetal head constraint as one possible cause. J Pediatr 95:747, 1979. 6. Graham JM Jr, Badura R, Smith DW: Coronal craniostenosis: fetal head constraint as one possible cause. Pediatrics 65:995, 1980. 7. Higgenbottom MC, Jones KL, James HE: Intrauterine constraint and craniosynostosis. Neurosurgery 6:39, 1980. 8. Graham JM Jr, Smith DW: Metopic craniostenosis and fetal head constraint: two interesting experiments of nature. Pediatrics 65:1000, 1980. 9. Koskinen-Moffet LK, Moffet BC, Graham JM Jr: Cranial synostosis and intra-uterine compression: a developmental study of human sutures. In: Factors and Mechanisms Influencing Bone Growth. AD Dixon, BG Sarnat, eds. Alan R. Liss Inc., New York, 1982, p 365. 10. Koskinen-Moffett L, Moffet BC: Sutures and intrauterine deformation. In: Scientific Foundations and Surgical Treatment of Craniosynostosis. JA Pershing, MT Edgerton, JA Jane, eds. Williams and Wilkins, Baltimore, 1989, p 96. 11. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management, ed 2. Oxford University Press, New York, 2000. 12. Lajeunie E, Le Merrer M, Bonati-Pellie C, et al.: Genetic study of scaphocephaly. Am J Med Genet 62:282, 1996. 13. Lajeunie E, Le Merrer M, Bonati-Pellie C, et al.: Genetic study of nonsyndromic coronal craniosynostosis. Am J Med Genet 55:500, 1995. 14. Lajeunie E, Arnaud E, Le Merrer M, et al.: Syndromal and nonsyndromal primary trigonocephaly: analysis of a series of 237 patients. Am J Med Genet 55:500, 1998. 15. Huang MHS, Gruss JS, Clarren SK, et al.: The differential diagnosis of posterior plagiocephaly: true lambdoid synostosis versus positional molding. Plast Reconstr Surg 98:765, 1996. 16. Mulliken JB, Steinberger D, Kunze S, et al.: Molecular diagnosis of bilateral coronal synostosis. Plast Reconstr Surg 104:1603, 1999. 17. McCarthy JG, Glasberg SB, Cutting CB, et al.: Twenty-year experience with early surgery for craniosynostosis: I. Isolated craniofacial synostosis— results and unsolved problems. Plast Reconstr Surg 96:273, 1995. 18. Williams JK, Cohen SR, Burstein FD, et al.: A longitudinal, statistical study of reoperation rates in craniosynostosis. Plast Reconstr Surg 100:305, 1997. 19. Polley JW, Charbel FT, Kim D, et al.: Nonsyndromal craniosynostosis: longitudinal outcome following cranio-orbital reconstruction in infancy. Plast Reconstr Surg 102:619, 1998.

Skull 20. Cinalli G, Sainte-Rose C, Kollar EM, et al.: Hydrocephalus and craniosynostosis. J Neurosurg 88:209, 1998. 21. Tuite GF, Evanston J, Chong WK, et al.: The beaten copper cranium: a correlation between intracranial pressure, cranial radiographs, and computed tomographic scans in children with craniosynostosis. Neurosurgery 39:691, 1996.

7.2 Kleeblattscha¨del Kleeblattsch€ adel is a term used to describe a cloverleaf skull configuration consisting of protrusion of each of the cranial bones, with broadening of the temporal region and face. These cranial protrusions are separated into focal bulges by furrows along the suture lines (Fig. 7-11). The eyes often protrude, leading to corneal ulceration, scarring, and subsequent blindness if the corneal surface remains unprotected.1 Occipital encephaloceles can occur, and associated hydrocephalus is common. The palate is usually highly arched, but clefting is rare. The presence of kleeblattscha¨del indicates that multiple sutural fusions occurred during early prenatal life. Often the sagittal, coronal, and lambdoid sutures are involved, although other combinations are also possible, including coronal, lambdoid, and metopic closure, or sagittal and squamosal closure. In addition, increased thickening of the base of the occipital bone prevents lengthening of the skull, thus yielding the typical shape.2 One child has also been described who had a cloverleaf skull without craniosynostosis (in which the primary defect was thought

235

to be a cranial bone dysplasia that allowed for eventration of the brain and resultant cloverleaf configuration).3 Multiple sutural synostosis is much more likely to result from genetic mutations in fibroblast growth factor receptor genes, TWIST, or MSX2, all of which result in syndromes that can present with cloverleaf skull or kleeblattscha¨del (Table 7-5).4 This skull anomaly can result from synostosis involving the coronal, lambdoid, and metopic sutures with bulging of the cerebrum through the open sagittal suture or through open squamosal sutures. There can also be synostosis of the sagittal and squamosal sutures with eventration through a widely patent anterior fontanel. The most common syndrome associated with cloverleaf skull is thanatophoric dysplasia type 2, which is due to mutations in FGFR3. Type 2 Pfeiffer syndrome due to mutations in FGFR2 can result in cloverleaf skull, as can Crouzon syndrome and Apert syndrome, which are also due to mutations in FGFR2. Other syndromes, such as FGFR3-associated coronal synostosis, rarely result in cloverleaf skull, but some rare syndromes like Boston craniosynostosis and Crouzon syndrome with acanthosis nigricans can sometimes manifest cloverleaf skull. In Boston craniosynostosis, the mutant MSX2 product has enhanced affinity for binding to its DNA target sequence, resulting in activated osteoblastic activity and aggressive cranial ossification.5–7 In Crouzon syndrome with acanthosis nigricans, a specific FGFR3 mutation (Ala391Glu) leads to early onset of acanthosis nigricans during childhood, often with associated choanal atresia and hydrocephalus.8 The association of choanal atresia with hydrocephalus in an individual with Crouzon facial features should suggest molecular analysis for this mutation, and

Fig. 7-11. A. Radiographic view of kleeblattscha¨del or cloverleaf skull configuration in a newborn infant. B. This child with cloverleaf skull configuration due to Crouzon syndrome with acanthosis nigricans caused by an Ala391Glu mutation in FGFR3 had associated hydrocephalus and choanal atresia and underwent early posterior skull release at 9 weeks with subsequent craniofacial reconstruction at 2 years, along with early shunting for hydrocephalus and postoperative orthotic therapy. At age 5 years his facial features and cognitive skills were relatively normal.

236

Craniofacial Structures

Table 7-5. Syndromes with cloverleaf skull (kleeblattschadel) Syndrome

Major Features

Causation Gene/Locus

Amniotic bands

Unusual facial clefts, cephalocele, congenital amputation

Unknown (217100)

Antley-Bixler

Brachycephaly, choanal atresia, flat midface, cardiac defect, ambiguous genitalia, joint synostosis

AD (207410) POR, 7q11.2

Apert

Brachycephaly, acrocephaly, delayed closure of fontanels, prominent eyes, flat midface, cleft or high palate, syndactyly

AD (1901200) FGFR2, 10q26

Campomelia: Cumming type

Cervical lymphocele, multicystic dysplastic kidneys, polysplenia, lung hypoplasia

AR (211890)

Campomelic dysplasia

Flat facial profile, tracheal/laryngeal anomalies, bowed long legs, deficient adipose tissue

AD (114290) SOX9, 17q24.3-q25.1

Carpenter

Brachycephaly, acrocephaly, ear anomalies, cardiac and genital defects, polydactyly

AD (201000)

Crouzon

Brachycephaly, ridged sutures, deafness, convex/beaked nose, tooth anomalies, malocclusion

AD (123500) FGFR2, 10q26

Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal)

Crouzon syndrome, multiple synostosis, choanal atresia, hydrocephalus, acanthosis nigricans

AD (134934) FGFR3, 4p16.3

Cutis gyrata-acanthosis nigricans (Beare-Stevenson)

Brachycephaly, acrocephaly, ear anomalies, midface hypoplasia, hepatomegaly

AD (123790) FGFR2, 10q26

Kleetblattschadel

Craniosynostosis, hydrocephalus, exophthalmos, corneal ulcerations

AR (148800) Heterogeneous

Micromelic bone dysplasia with cloverleaf skull

Micromelia less severe than thanatophoric dysplasia, similar radiologic picture

AD or AR (156830)

Multiple congenital anomalies with cloverleaf skull

Short limbs and hands, frontal bossing, cataract, narrow chest, ambiguous genitalia, agenesis of corpus callosum, ventricular septal defect

AR (607161)

Osteoglophonic dysplasia

Acrocephaly, hypertelorism, prominent eyes, rhizomelia, osteoporosis

AD (166250)

Pfeiffer

Brachycephaly, hypertelorism, skin syndactyly, broad thumbs/hallux

AR (101600) FGFR1, 8p11.2-p11.1 FGFR2, 10q26

Say-Poznanski

Polydactyly of hands and feet, short clavicles, winged scapulas, unusually shaped ribs

Unknown (217100)

Thanatophoric dysplasia

Short stature, platybasia, macrocephaly, wide sutures, short limbs, narrow thorax

AD (187600) FGFR3, 4p16.3

Thanatophoric-cloverleaf skull

Short stature, platybasia, craniosynostosis, narrow thorax, short limbs

AD (187601) FGFR3, 4p16.3

Craniosynostosis (Boston type)

Forehead retrusion, frontal bossing, turribrachycephaly, visual problems

Unknown (604757, 216340) MSX2, 5q34-q35

the combination of hydrocephalus with craniosynostosis may predispose toward a cloverleaf skull.8 Eighty-five percent of children with kleeblattscha¨del will have other anomalies, and the pattern is often consistent with a syndrome diagnosis (Table 7-5). No ethnic or sex predilection has been noted. The prognosis is usually syndrome-dependent and can be quite poor, with early death due to respiratory difficulties or progressive brain damage from hydrocephalus, which is common.9 However, subtotal craniectomy within the first 3 weeks of life in individuals with mild kleeblattscha¨del may result in normal or near-normal development.9–11 Early extensive calvarectomy is merited to preserve brain function and development as well as to allow reformation of the craniofacial skeletal features. Many craniofacial surgeons prefer to begin with a posterior skull release in the early months of life (mean age 4 months), followed by fronto-orbital advancement around the end of the 1st year (mean age 14 months), with insertion of a ventriculoperitoneal shunt at the time of the first procedure if there is associated hydrocephalus.12 The use of postoperative orthotic molding can help to channel brain growth into a more normal form,

leading to improved postoperative results over those obtained via surgery alone.8 When lambdoid synostosis occurs as part of a syndrome with multiple suture involvement, there is often bilateral involvement, and early posterior release may alleviate some associated increased intracranial pressure. Patients with kleeblattscha¨del need to be followed carefully for hydrocephalus, which may be part of the syndrome rather than due to the multiple suture synostosis. Restricted growth of the posterior fossa is particularly common in severe craniofacial dysostosis syndromes. The purpose of surgery should be to decompress the brain, expand the bony orbits to accommodate the globes, and open airway passages.11 Prenatal diagnosis may be possible by ultrasonography.1

References (Kleeblattscha¨del) 1. Stevenson RE, Saul RA: The significance of the kleeblattscha¨del malformation. Proc Greenwood Genet Center 5:76, 1986. 2. Dambrain R, Freund M, Verellen G, et al.: Considerations about the cloverleaf skull. J Craniofac Genet Dev Biol 7:387, 1987.

Skull 3. Witt DR: Rare kleeblattscha¨del anomaly without craniosynostosis. Proc Greenwood Genet Center 7:161, 1988. 4. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management, ed 2. Oxford University Press, New York, 2000. 5. Warman ML, Mulliken JB, Hayward PG, et al.: Newly recognized autosomal dominant disorder with craniosynostosis. Am J Med Genet 46:444, 1993. 6. Jabs EW, Muller U, Li X, et al.: A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 75:443, 1993. 7. Ma L, Golden S, Maxson R: The molecular basis of Boston-type craniosynostosis: the pro148-to-his mutation in the N-terminal arm of the MSX2 homeodomain stabilized DNA binding without altering nucleotide sequence preferences. Hum Mol Genet 5:1915, 1996. 8. Schweitzer DN, Graham JM Jr, Lachman RS, et al.: Jabs Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3. Am J Med Genet 98:75, 2001. 9. Frank LM, Mason MA, Magee WP Jr, et al.: The kleeblattscha¨del deformity: neurologic outcome with early treatment. Pediatr Neurol 1:379, 1985. 10. Turner PT, Reynolds AF: Generous craniectomy for kleeblattscha¨del anomaly. Neurosurgery 6:555, 1980. 11. Kroczek RA, Muhlbauer W, Zimmermann I: Cloverleaf skull associated with Pfeiffer syndrome: pathology and management. Eur J Pediatr 145:442, 1986.

237 12. Sgouros S, Goldin JH, Hockley AD, et al.: Posterior skull surgery in craniosynostosis. Child Nerv Syst 12:727, 1996.

7.3 Wide Cranial Sutures Cranial sutures are considered to be widened when they are separated by more than two standard deviations above the mean suture width for age. Diagnosis is confirmed radiographically, although it may also be appreciated on palpation of the skull. Criteria for determining suture width in infants up to 45 days old have been published by Erasmie and Ringertz.1 Wide cranial sutures themselves cause no impairment, but they may be an indication of increased intracranial pressure or caused by craniosynostosis in another part of the skull. Wide cranial sutures are a feature of numerous syndromes (Table 7-6). There are several possible causes of wide cranial sutures, including increased intracranial pressure, delayed maturation of bone, or resorption of bone. The younger the child, the earlier sutural diastasis will appear after acutely increased intracranial pressure. The prognosis depends on the underlying cause.

Table 7-6. Syndromes with wide cranial sutures Syndrome

Major Features

Causation Gene/Locus

Acromelic frontonasal dysostosis

Frontonasal dysplasia, central nervous system malformations, limb defects

AR (603671)

Cleidocranial dysostosis

Brachycephaly, wormian bones, delayed fontanel closure, joint contractures, acro-osteolysis

AD (119600) CBFA1, 6p21

Craniolenticulosutural dysplasia

Large fontanels, frontal bossing, hyperpigmentation, forehead hemangioma, hypertelorism, broad prominent nose

AR (607812) 14q13-q21

Cree mental retardation

Brachycephaly, triangular facies, hypertelorism, ocular colobomas, bifid scrotum, psychomotor retardation, webbed neck and fingers

AR (606851)

Cutis laxa, recessive, type II

Delayed fontanel closure, low birth weight, hydrocephalus, kyphoscoliosis, joint laxity, mental retardation

AR (219200)

Fibrochondrogenesis

Brachycephaly, wide sutures, ear anomalies, flat and round face, rhizomelia

AR (228520)

Hajdu-Cheney

Platybasia, wormian bones, delayed fontanel closure, short stature, oligodontia, vertebral anomalies

AD (102500)

Hypothyroidism

Slow growth, coarse facies, umbilical hernia, delayed development

Variable

Mandibuloacral dysplasia

Wormian bones, large fontanel, beaked nose, micrognathia, dental anomalies, skin atrophy

AR (248370) LMNA, 1q21.2

Oto-palato-digital II

Sclerosis, wormian bones, hypertelorism, micrognathia, skeletal anomalies, syndactyly, polydactyly

XLR (304120) FLNA, Xq28

Prader: psuedodeficiency rickets

Delayed fontanel closure, short stature, enamel anomalies, aminoaciduria, hypotonia, seizures, multiple fractures

AR (264700) CYP27B1, 12q14

Pycnodysostosis

Delayed fontanel closure, wormian bones, beaked nose, micrognathia, hepatosplenomegaly, multiple fractures

AR (265800) Cathepsin K, 1q21

Restrictive dermopathy

Thick, cracked, or peeling skin; ectropion of eyelids; joint contractures; open mouth

AR (275210)

Rickets

Short stature, widened metaphyses

Variable

Schinzel-Gideon: hypertrichosis-midface retraction

Sclerosis of skull, wormian bones, midface retraction, hypertrichosis, hydronephrosis, mental retardation

AR (269150)

Wiedemann-Rautenstrauch

Delayed fontanel closure, neonatal teeth, large penis, deficient adipose, short stature

AR (264090)

Yunis-Varon

Delayed fontanel closure, dysplastic ears, sparse hair, facial anomalies, absent or hypoplastic clavicles and thumbs

AR (216340)

Zellweger

High forehead, ocular anomalies, hepatosplenomegaly, hypotonia, seizures; peroxisomal disorder that displays genetic heterogeneity

AR (214100) PEX 1, 2, 3, 5, 6, 12 Multiple loci

238

Craniofacial Structures

Reference (Wide Cranial Sutures) 1. Erasmie V, Ringertz H: Normal width of cranial sutures in neonates and infants. Acta Radiol 17:572, 1976.

7.4 Anomalies of Fontanels Definitions Size

A fontanel whose size is either 2 standard deviations (SD) below or 2 SD above the mean for age is termed small or large, respectively. Time of Closure

Closure of the anterior fontanel before 6 months is considered early, whereas closure after 18 months is late. The other fontanels are normally closed at birth. Extra Fontanels

Extra fontanels are inconsistently occurring bony defects situated along the suture lines or at the junction of major bone plates of the skull. One such extra fontanel occurs along the sagittal suture about 2 cm anterior to the posterior fontanel. This fontanel is called the obeliac, interparietal, or sagittal fontanel, as well as the fontanel of Gerdy. Being midline, it is distinct from the parietal foramina, but parietal foramina may evolve in the lateral extremes of a large sagittal fontanel. Glabellar, metopic, or cerebellar fontanels also exist (Fig. 7-12).1 Diagnosis

The anterior fontanel is the largest of the fontanels and is diamondshaped (Figs. 7-1, 7-12). It normally closes by 18 months. The posterior fontanel is triangular in shape and is usually closed at birth. Fontanel size may be measured in several different ways (Fig. 7-13). Measurement of the anterior fontanel may be expressed as width (measurement along the coronal suture), length (measurement along the sagittal suture), area (width  length), or diagonal diameter. Standard curves are available for measurements taken by each method.2 The posterior fontanel is usually measured only in length

Fig. 7-12. Schematic showing glabella, metopic, sagittal, and cerebellar fontanels (stippled) in relation to constant fontanels (solid). See also the newborn skull pictured in Fig. 7-2.

(measurement along the sagittal suture) but may also be measured along the lambdoid suture (width) and the area calculated (length  width). Depending on the cause, a small or absent anterior fontanel may be noted at birth by palpation and confirmed by measurement and comparison with normal values for length and width.2 A small or absent anterior fontanel usually indicates some type of underlying pathology, with the most common etiologies including any cause of congenital microcephaly, craniosynostosis (particularly involving the metopic suture), or accelerated bone maturation such as occurs in hyperthyroidism.3 Large fontanels may be noted at birth by palpation and confirmed by measurement (Fig. 7-13). Causes of both large fontanels and delayed closure include increased intracranial pressure or delayed ossification of the cranium.3 Several syndromes in which a large or late-closing fontanel is part of the phenotype are listed in Table 7-7. Cleidocranial dysplasia is a common genetic syndrome that results in delayed closure of the anterior fontanel (Fig. 7-14).

Fig. 7-13. Left: mean anterior fontanel measurement (length plus width divided by two) during the 1st year. The posterior fontanel was fingertip size or smaller in 95% of neonates, based on 201 full-term Caucasian infants from Seattle, WA, and adapted from Popovitch and Smith.3 Right: percentiles for anterior fontanel size from term to age 24 months for both sexes by measurement of oblique diameter, based on data from Duc and Largo.7

Table 7-7. Syndromes with delayed closure or large fontanel Syndrome

Major Features

Causation Gene/Locus

Aase

Short stature, cleft lip/palate, cardiac defects, triphalangeal thumb, anemia, hepatosplenomegaly

AR (205600)

Acrocallosal

Macrocephaly, malformed ears, mental/growth retardation, hypertelorism, cleft lip/palate, cardiac septal defects

AR (200990) 12p13.3-p11.2

Acrogeria

Wormian bones, short stature, alopecia, premature aging, deficient adipose, prominent vessels, distal limb skin atrophy

AR (201200)

Al-Gazali: Hirschsprung-hypoplastic nails

Facial anomalies, hydronephrosis, anal atresia, cutis laxa, mental retardation

AR (601356)

Antley-Bixler

Brachycephaly, choanal atresia, flat midface, cardiac defect, ambiguous genitalia, joint synostosis

AD (207410) POR, 7q11.2

Apert

Acrocephaly, brachycephaly, cloverleaf skull, prominent eyes, flat facial profile, cleft or narrow palate, syndactyly

AD (101200) FGFR2, 10q26

Beckwith-Wiedeman

Macroglossia, omphalocele, macrosomia, ear creases

AD (130650) UPD 11p15.5

‘‘Baby Rattle’’ pelvis dysplasia

Bifid distal ends of long bones, absent vertebral body ossification, midface hypoplasia, protuberant abdomen

Unknown (605838)

Bartsocas-Papas (popliteal pterygium, lethal)

Digital hypoplasia, facial cleft, absent eyebrows/eyelashes, absent nails

AR (263650)

Chondrodysplasia punctata

Short stature, flat facial profile, limb asymmetry, sparse hair

XLD (302960) EBP, Xp11.23-p11.22

Chromosomal anomalies

Prominent feature in numerous chromosomal aberrations del(1p), del(11p), del(16q), dup(1q), dup(7p), dup(7q), dup(9p), dup(10p)

Chromosomal

Cleidocranial dysostosis

Brachycephaly, wormian bones, wide sutures, flat midface, hypoplastic clavicles, short ribs

AD (119600) CBFA1, 6p21

Coffin-Lowry

Short stature, prominent ears, coarse facial features, kyphosis/scoliosis, large hands, joint laxity

XL (303600) RSK2, Xp22.2-p22.1

Crane-Heise

Cleft lip/palate, agenesis of clavicles and cervical vertebrae, talipes equinovarus

AR (218090)

Craniometadiaphyseal dysplasia

Sclerosis of skull, deafness, prominent eyes, facial weakness, osteosclerosis

AD (123000) ANKH, 5p15.2-p14.1

Cutis laxa, type II, autosomal recessive

Wide cranial sutures, low birth weight, hydrocephalus, kyphoscoliosis, joint laxity, mental retardation

AR (219200)

De Barsy

Cutis laxa, corneal clouding, mental retardation, dwarfism

AR (219150)

Dysosteosclerosis

Short stature, fractures, cranial nerve compression, cranial hyperostosis

AR (224300)

Ehlers Danlos type VII

Short stature, blue sclerae, pneumothorax, hernias, joint laxity, delayed motor milestones

AR (225410) ADAMTS2, 5q23

ACE inhibitors

Oligohydramnios, pulmonary hypoplasia, renal tubular dysgenesis

Prenatal exposure

Aminopterin/methotrexate

Microcephaly, cranial dysplasia, cleft palate, mesomelia, hypodactyly

Prenatal exposure

Fluconozole

Brachycephaly, depressed nasal bridge, midfacial hypoplasia, proptosis, craniosynostosis

Prenatal exposure

Hydantoin

Metopic ridging, hypertelorism, short nose, cleft lip/palate, hypoplasia of distal phalanges, short neck, widely spaced nipples

Prenatal exposure

Primidone

Microcephaly, hirsutism, cardiac defects, metopic ridging, anteverted nares, micrognathia

Prenatal exposure

Rubella

Microcephaly, deafness, cataracts, glaucoma, congenital heart defects, hepatosplenomegaly

Prenatal exposure

Fibrochondrogenesis

Brachycephaly, wide cranial sutures, ear anomalies, rhizomelia

AR (228520)

GAPO

Growth retardation, alopecia, pseudoanodontia, optic atrophy, macrocephaly, cerebral atrophy, facial anomalies, hepatomegaly, mental retardation

AR (230740)

Glutaric aciduria II

Undermineralization of skull, dolichocephaly, brain abnormalities, organic aciduria

XLR (231680) Multiple loci: ETFA, 19q13.3 ETFB, 15q23-q25 ETFDH, 4q32-qter

Exposures

(continued)

239

Table 7-7. Syndromes with delayed closure or large fontanel (continued) Syndrome

Major Features

Causation Gene/Locus

Hallerman-Streiff (progerioid syndrome)

Sparse hair, corneal clouding, thin nose, dental anomalies

AR (234100)

Hypophosphatasia

Undermineralization of skull, dental anomalies, bowed long bones, fractures

AR (241510) ALPL, 1p36.1-p34

Hypothyroidism

Coarse facies, slow growth, umbilical hernia, slow development

Variable

Infantile multisystem inflammatory disease

Chronic meningitis, migratory skin rash, joint inflammation, progressive visual defect, perceptive deafness

Unknown (607115)

Kenny-Caffey

Thick calvaria, wide cranial sutures, macular abnormalities, sparse eyebrows/lashes, hypercalcemia or hypocalcemia

AD (127000) TBCE, 1q42-q43

Lenz-Majewski

Thick or thin calvaria, sclerosis of skull, choanal atresia, joint laxity and/or contractures, cutis laxa

AD (151050)

Melnick-Needles

Sclerosis of skull, proptosis, full cheeks, cleft or high palate, vertebral anomalies, skeletal defects

XLD (309350) FLNA, Xq28

Mevalonic aciduria

Dolichocephaly, microcephaly, ear anomalies, cataract, hepatosplenomegaly, hypotonia, mental retardation

AR (251170) MVK, 12q24

Opsismodysplasia

Small nose; rib, vertebral, and skeletal defects; rhizomelia; hypotonia

AR (258480)

Opitz BBBG

Hypertelorism, esophageal abnormalities, hypospadias, mental retardation

AD (145410) 22q11.2 XL (300000) MID1, Xp22

Osteogenesis imperfecta

Blue sclerae, numerous fractures, deafness

AD (166200, 259400) Multiple loci: COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Osteosclerotic chrondrodysplasia, lethal

Midface hypoplasia; micrognathia; increased density of base of skull, clavicles, vertebrae, ribs

Unknown (603393)

Oto-palato-digital

Hypertelorism, cleft palate, abnormal ears, deafness, broad thumbs, curved toes

XLD (311300) FLNA, Xq28

Parietal foramina (cranium bifidum)

Seizures, cleft lip/palate, spina bifida occulta, defects in parietal bone and medial frontal bone

AD (168500) MSX2, 11p11.2 ALX4, 5q34-q35

Progeria

Low birth weight, premature aging, short stature, alopecia

AD (176670) LMNA, 1q21.2

Pycnodysostosis

Wormian bones, wide cranial sutures, beaked nose, micrognathia, hepatosplenomegaly

AR (265800) Cathepsin K, 1q21

Ritscher-Schinzel (3C syndrome)

Macrocephaly, undermineralization of skull, parietal foramen, hydrocephalus, facial anomalies, hypotonia, mental retardation

AR (220210)

Robinow

Macrocephaly, hypertelorism, small nose, hemivertebrae, genital defect, short limbs

AR (268310) ROR2, 9q22

Rubinstein-Taybi

Microcephaly, downward-slanting palpebral fissures, ptosis, beaked nose, broad thumbs and great toes

AD (180849) CREBBP, 16p13.3

Russell-Silver

Short stature, triangular face, asymmetry, clinodactyly, hypoglycemia

Isolated (180860) UPD 7p11.2

Schinzel-Giedion

Sclerosis of skull, wide sutures, limb anomalies, mental retardation

AR (269150)

Urbach: skeletal dysplasia (rhizomelic syndrome)

Short stature, sparse hair, large tongue, pulmonary stenosis

AR(268250)

Wiedemann-Rautenstrauch

Wide cranial sutures, neonatal teeth, large penis, deficient adipose, short stature

AR (264090)

Winchester

Short stature, severe joint contractures, corneal opacities, coarse facies, osteoporosis

AR (247950)

Yunis-Varon

Wide cranial sutures, dysplastic ears, sparse hair, facial anomalies, absent or hypoplastic clavicles and thumbs

AR (216340)

Zellweger

High forehead, ocular anomalies, hepatosplenomegaly, hypotonia, seizures

AR (214100) Heterogeneous

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Skull

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Fig. 7-14. Cleidocranial dysplasia in an 8-year-old male. Skull radiograph shows a large anterior fontanel and chest radiograph shows absent clavicles. (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute and Children’s Hospital, Wilmington, DE.)

Occasionally, the anterior fontanel will ossify into a bony plate, which may be slightly elevated in relation to the rest of the cranium. This may relate to decreased growth-stretch tensile forces across the anterior fontanel and is sometimes seen with multiple sutural synostosis; however, it can also occur in otherwise normal infants, in which case it is considered a normal variant.4 Instead of the usual flat, uncalcified, diamond-shaped anterior fontanel, there is a slightly raised diamond-shaped plate of bone in its place. Etiology and Distribution

A small or absent anterior fontanel may be secondary to microcephaly (because of decreased brain growth), craniosynostosis af-

fecting the metopic, sagittal, and/or coronal suture, or accelerated osseous maturation. There have also been reports of normal infants with absent anterior fontanels at birth. The shape of the anterior fontanel bone often remains visible on skull radiographs throughout childhood and into adulthood, with a characteristic appearance on Towne projection. The appearance of the fusing anterior fontanel bone can be confused with a depressed skull fracture in the lateral projection.5 Occasionally, children thought to have a small or absent anterior fontanel will have an anterior intrafontanel bone, which is of no significance. Causes of large or late-closing fontanels include increased intracranial pressure or delayed ossification of the skull (Table 7-7).3

242

Craniofacial Structures 5. Girdany, BR, Blank E: Anterior fontanel bones. AJR Am J Roentgenol 95:148, 1965. 6. Chemke J, Robinson A: The third fontanelle. J Pediatr 75:617, 1968. 7. Duc G, Larago RH: Anterior fontanelle: size and closure in term and preterm infants. Pediatrics 78:904, 1986.

7.5 Cranial Dermal Sinus

Fig. 7-15. Age at closure of anterior fontanel (cumulative percentage). Based on data from Zurich, Switzerland (111 term neonates and 131 preterm neonates collected from 1974 to 1978).7

The sagittal fontanel is caused by a lack of union at the medial edge of junction of the two parietal ossification centers. This union normally occurs by the 7th month of gestation but may occur 2 to 3 months after birth.6 Anterior fontanel closure occurs in 1% of normal infants by age 3 months, in 38% by 12 months, in 70% by 18 months, and in 97% by 24 months (Fig. 7-15).7 Therefore, early or late closure is reasonably common, but care must be taken to rule out underlying pathology. In normal infants there is no sex difference in the size and age of closure of the anterior fontanel, nor is there any correlation with gestational age at delivery, head circumference, or bone age. The size of the fontanel at birth does not predict time of closure.7 A sagittal fontanel is found in 6.3% of all newborns. In one study of those with a diameter of greater than 13 mm, 5% had major anomalies and 35% had minor anomalies. In those with a diameter less than 13 mm, two of 45 infants studied had Down syndrome, and one had a major anomaly. The latter group accounted for two-thirds of all children with this third fontanel.4 Although it is unknown whether there is ethnic variability in the prevalence of sagittal fontanels, the majority of individuals with this feature are male.6 Individuals with Down syndrome commonly have large fontanels that close late, along with a sagittal fontanel and persistence of the metopic suture.6 Diagnosis of an extra fontanel is made by palpation or radiography. It is often an isolated malformation but may be sometimes be associated with rare syndromes. Prognosis

In all cases, prognosis is dependent on the underlying cause. If the anomaly is isolated, there is no ill effect. References (Anomalies of Fontanels) 1. Currarino G: Normal variants and congenital anomalies in the region of the obelion. AJR Am J RoentgenoI 127:487, 1976. 2. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, New York, 1989, p 121. 3. Popich GA, Smith DW: Fontanelles: range of normal size. J Pediatr 80:749, 1972. 4. Keats TE: Atlas of Normal Roentgen Variants That May Simulate Disease. Mosby Year Book, St Louis, 1992, p 13.

A cranial dermal sinus is a midline depression or tract lined by stratified squamous epithelium that extends from the skin toward the central nervous system or its coverings. Cranial dermal sinuses are associated with bony defects in 80% of cases.1 Diagnosis is best achieved radiographically via computed tomography (CT) scan, which reveals a low-density lesion that may be surrounded by an enhancing ring.2 Cranial dermal sinuses are most common in the occipital region but can be found anywhere. Size can vary from a very small defect to a large, expanding mass. Clinical presentation is often as a cutaneous localized swelling that presents as infection or cystic expansion of the sinus tract beneath the skin surface, occasionally with drainage. There is often an abnormal distribution of hair along the defect. Occasionally cystic expansion occurs within the cranial cavity, which obstructs cerebrospinal fluid flow, compresses the adjacent neural structures, and/or ruptures to cause sterile meningitis, which can be recurrent.1,2 Cranial dermal sinuses are thought to be the result of faulty separation of neurectoderm from cutaneous ectoderm during early gestation.1 The recommended treatment is surgery; prognosis is good if treatment is done prior to the development of complications. In the facial region, the most frequent congenital midline mass is a nasal dermoid sinus cyst, which can have intracranial extension and be associated with other anomalies.3,4 Nasal dermoid sinus cysts constitute 11–12% of dermoids found in the head and neck4 and usually arise sporadically, although reports of familial occurrence have been documented.3,4 At 50 to 60 days, the nasal and frontal bones develop through intramembranous ossification, remaining separated by a space termed the fonticulus nasofrontalis. During growth, the nasal process of the frontal bone separates the skin from the dura. The dura connects to the frontal aspect of the skull via a projection that ends at an opening in the frontal bones termed the foramen cecum. The foramen cecum eventually fuses with the fonticulus nasofrontalis in the area of the future cribriform plate, thereby obliterating the previous neuroectodermal connection. If this process remains incomplete, dermal connections (termed nasal dermoid sinus cysts) may occur anywhere from the nasal tip to the intracranial space through the foramen cecum.3 Such dermoid sinus cysts contain both ectodermal and mesodermal derivatives, and they are composed of a stratified squamous epithelial lining and specialized adnexal structures such as hair follicles, pilosebaceous glands, and smooth muscle.3 Nasal pits are present in 50% of patients with nasal dermoids,5 often with hairs protruding from the pit, and they can appear anywhere along the nose, with intracranial extension noted in 36–45% of cases.3,4 Associated anomalies were present in 41% of one series examined by a multidisciplinary team, and they were associated with syndromes such as hemifacial microsomia, orofaciodigital syndrome (Type1), frontonasal dysplasia, chromosome problems, VATER association, and/or central nervous system malformations.4 Complications can result from enlargement of the cyst, skeletal distortion, and recurrent infection, so surgical excision

Skull

243

is recommended after CT scanning to identify intracranial extension and to plan the surgical approach. References (Cranial Dermal Sinus) 1. Shackelford GD, Shackelford PG, Sehwetschenau PR, et al.: Congenital occipital dermal sinus. Radiology 111:161, 1974. 2. Starinsky R, Wald U, Michowitz SD, et al.: Dermoids of the posterior fossa: case reports and review. Clin Pediatr 27:579, 1988. 3. Posnick JC, Bortoluzzi P, Armstrong DC, et al.: Intracranial nasal dermoid sinus cysts: computed tomographic scan findings and surgical results. Plast Reconstr Surg 93:745, 1994. 4. Wardinsky TD, Pagon RA, Kropp RJ, et al.: Nasal dermoid sinus cysts: association with intracranial extension and multiple malformations. Cleft Palate Craniofac J 28:87, 1991. 5. McCaffey TV, McDonald TJ, Gorenstein A: Dermoid cyst of the nose: review of 21 cases. Otolaryngol Head Neck Surg 95:303, 1979.

7.6 Parietal Foramina (Includes Cranium Bifidum) Parietal foramina are small defects in the superoposterior angles of the parietal bones through which emissary veins may pass through the calvaria. Usually, parietal foramina present as symmetrical oval defects situated on each side of the sagittal suture, which are separated from each other by a narrow bridge of bone, and their size diminishes with age. They are covered with scalp tissue and hair and are detected through palpation and radiography. Occasionally, brain covered by dura and intact scalp can bulge through extensive lesions, suggesting the possibility of an encephalocele, but the location of these lesions off the midline differentiates them from neural tube closure defects. Sometimes the entire sagittal suture remains widely patent from the frontal to the parietal bones, and this is termed cranium bifidum, with this defect subsequently ossifying to resemble parietal foramina during mid-childhood or adulthood. (Fig. 7-16).1 Parietal foramina usually are small, with 60% less than 1 mm; such small defects can only be detected radiographically. However, 10% are 5 mm or more and can be as large as 50 mm in diameter. Reported individuals have had defects as large as 57 mm in diameter, with seizures apparently secondary to venous obstruction and meningocerebral adhesions at the margins of the defect.2 Although parietal foramina themselves cause no impairment, they can occur as part of the phenotype in a few syndromes (Table 7-8). The diagnosis of large parietal foramina may be suspected by palpation but is best confirmed radiographically.3

Fig. 7-16. Parietal foramina (arrows) in an adult woman. Two of her four children also had large parietal foramina.

Parietal foramina represent defects of calvarial ossification, and they usually manifest autosomal dominant inheritance with variable expression. As ossification of the parietal bones normally progresses, sagittal fontanels form within the posterior parietal bones. These fontanels normally close by the 7th fetal month; however, closure may be delayed and not occur until later in life. Parietal foramina may result if midsagittal bridging occurs, and ossification lateral to the bony bridging remains incomplete. Thus, parietal foramina evolve from the sagittal fontanel but are distinct lesions in that the sagittal fontanel is a single midline defect, whereas parietal foramina are usually paired defects just off the midline.4 Small parietal foramina are found in 60–70% of all adults, whereas large parietal foramina are present in less than 1% of adults.1,3,6 Small unilateral defects are more common than bilateral defects. When the defect is unilateral, it more often involves the right side, and males are more commonly affected than females, with a ratio of 5:3.6 Goldsmith initially called this condition Catlin marks after observing the condition in 16 members of a five-generation family named Catlin.5 This genetic condition can present as cranium bifidum in early life, developing into parietal foramina by later childhood. Cranium bifidum means literally ‘‘cleft skull,’’ and it presents as a wide opening between the frontal and parietal bones, which normally begin their process of intramembranous ossification in the center of each bone and then spread towards the

Table 7-8. Syndromes with parietal foramina Syndrome

Major Features

Causation Gene/Locus

Parietal foramina with cleidocranial dysplasia

Dolichocephaly, macrocephaly, dysplastic ears

AD (168550)

Potocki-Shaffer

Mental retardation, brachy-/turricephaly, craniofacial dysostosis

Unknown (601224) Del 11p11.2

Ritscher-Schinzel: Dandy-Walker anomaly-atrioventricular septal defect

Delayed closure of fontanels, macrocephaly, undermineralization of skull, hydrocephalus, facial anomalies, hypotonia, mental retardation

AR (220210)

Rubinstein-Taybi

Broad thumbs and toes, downslanted palpebral fissures, hypoplastic maxilla, large anterior fontanel

AD (180849) CBP, 16p13.3

Saethre-Chotzen

Short stature, maxillary hypoplasia, deafness, hypertelorism, cleft palate, congenital heart defects

AD (101400) TWIST, 7p21 FGFR2, 10q26

244

Craniofacial Structures

sutures. During mid-childhood, these areas ossify, leaving only symmetric openings in the frontal and parietal bones. One reported family included individuals with both cranium bifidum and parietal foramina, confirming that cranium bifidum in infancy and early childhood can evolve into large parietal foramina in later childhood and adulthood.3 Wilkie et al. described heterozygous MSX2 mutations in three unrelated families with enlarged parietal foramina, suggesting that loss of MSX2 activity results in calvarial defects.7 A second gene has been implicated in those families who do not link to 5q34-q35, where MSX2 is located, and mutations or deletions of ALX4 on 11p11.2 can also result in parietal foramina.8 Parietal foramina can occur as an isolated trait due to mutations in or haploinsufficiency of MSX2 or ALX4, or as a component of a multiple congenital anomaly syndrome, such as Saethre-Chotzen syndrome, Cleidocranial dysplasia, or Rubinstein-Taybi syndrome. The combination of parietal foramina with multiple exostoses is now known to be a contiguous gene deletion of ALX4 and EXT2 on chromosome 11p11-p12 (also termed DEFECT11 syndrome). Surgery is usually unnecessary, since the lesions tend to ossify on their own, but occasionally a protective helmet is used for extensive defects. Care must be exercised during delivery to avoid trauma to the brain underlying such extensive parietal foraminal defects. Location and intact scalp tissue help to differentiate parietal foramina from encephaloceles. This lesion must also be differentiated from scalp vertex aplasia (Section 7.8), which is also inherited in an autosomal dominant fashion, when it is an isolated trait. There is usually denuded scalp over such lesions, which can include both scalp and calvaria, but their location in the midline near the hair whorl sets these lesions apart from parietal foramina. They usually heal with some degree of scarring and absence of scalp

hair, so these bald spots should be searched for on the scalps of both parents. Occasionally, areas of scalp vertex aplasia can be part of a syndrome such as trisomy 13, or they can result from in utero vascular disruption. When scalp vertex aplasia occurs with absence of digits, the possibility of Adams-Oliver syndrome needs to be considered. Finally, vertex craniotabes can present as an extensive area of incomplete calvarial ossification over the vertex in the midline, but the edges are not sharp and demarcated like parietal foramina, and vertex craniotabes ossifies quite rapidly within the first few months after birth.

References (Parietal Foramina) 1. Currarino G: Normal variants and congenital anomalies in the region of the obelion. AJR Am J RoentgenoI 127:487, 1976. 2. Epstein JA, Epstein BS: Deformities of the skull surface in infancy and childhood. J Pediatr 70:636, 1967. 3. Little BB, Knoll KA, Klein VR, et al.: Hereditary cranium bifidum and symmetric parietal foramina are the same entity. Am J Med Genet 35:353, 1990. 4. Murphy J, Gooding CA: Evolution of persistently enlarged foramina. Radiology 97:391, 1970. 5. Goldsmith WM: The ‘‘Catlin mark’’: the inheritance of an unusual opening in the parietal bones. J Hered 13:69, 1922. 6. O’Rahilly R, Twohy MJ: Foramina parietalia permagna. Am J Roentgenol Radiol Ther 67:551, 1952. 7. Wilkie AOM, Tang Z, Elanko N, et al.: Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nat Genet 24:387, 2000. 8. Wu YQ, Badano JL, McCaskill C, et al.: Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous genedeletion syndrome. Am J Hum Genet 67:1327, 2000.

Fig. 7-17. Wormian bones. Deficient cranial ossification with multiple bone islands (wormian bones) in a 6-year-old male with cleidocranial dysplasia. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.)

Skull

7.7 Wormian Bones Wormian bones are accessory bones that occur within cranial suture lines or fontanels.1,2 Wormian bones are named for Dr. Worm, not because they are ‘‘wormlike.’’ They can occur singly, or in large numbers, and are diagnosed radiographically. Although they can occur within any suture, they are rare in coronal or sagittal sutures (Fig. 7-17). They do not cause any impairment themselves, but their significance is variable. In one study, the majority of children with an ‘‘excessive’’ number of wormian bones had some abnormality of the central nervous system.1 These abnormalities ranged from gross malformations to minimal brain dysfunction, though this study may have been biased as coming from a hospital-based population. Thus, some individuals with many Wormian bones may have other anomalies and/or central nervous system dysfunction (Table 7-9). More than 10 Wormian bones is unusual. The pathogenesis of wormian bones is thought to be related to intracranial strain along with open sutures causing ossification

245

defects. Such sutural bones persist and are not incorporated into the adjacent bone during mineralization and maturation.2 Although the prevalence of wormian bones in the general population is 17%, the prevalence varies with age. Males are more often affected than females, and differences between ethnic groups have been noted. Blacks have more wormian bones than whites or Native Americans, and 80% of Chinese individuals have wormian bones, which represents the highest incidence. A positive correlation has been noted between the frequency of wormian bones and the degree of deformation in Kakiutl Indians, who practiced head binding, but it is unclear how this anomaly might be related to unusual postnatal deformational practices.3 Wormian bones are commonly seen in osteogenesis imperfecta and other disorders that result in defective cranial bone mineralization. Such infants also become quite brachycephalic as a consequence of postnatal supine positioning with soft cranial bones.4 The increased frequency of wormian bones in Chinese infants might relate to traditional supine sleep position practices in this population and their resultant brachycephalization. If so, an increased frequency of wormian bones may soon be noted in other cultures that

Table 7-9. Syndromes with Wormian bones Syndrome

Major features

Causation Gene/Locus

Acrogeria

Delayed fontanel closure, short stature, alopecia, premature aging, deficient adipose tissue, prominent vessels, acro-osteolysis

AR (201200)

Aminopterin, prenatal

Microcephaly, cranial dysplasia, cleft palate, mesomelia, hypodactyly

Prenatal drug exposure

Cleidocranial dysostosis

Brachycephaly, late fontanel closure, wide sutures, flat midface, hypoplastic clavicles, short ribs

AD (119600) CBFA1, 6p21

Grant

Brachycephaly, delayed fontanel closure, micrognathia, blue sclerae, joint laxity

AD (138930)

Hajdu-Cheney

Platybasia, delayed fontanel closure, wide sutures, short stature, oligodontia, vertebral anomalies

AD (102500)

Hallermann-Streiff (progeroid syndrome)

Microphthalmia, small pinched noses, hypotrichosis

AR (264090)

Hypophosphatasia

Poorly mineralized cranium, short ribs, hypoplastic fragile bones

AR (241500) ALPL, 1p36.1-34

Hypothyroidism

Coarse facies, slow growth, umbilical hernia, slow development

Variable

Infantile multisystem inflammatory disease (CINCA)

Chronic meningitis, migratory skin rash, joint inflammation, progressive visual defect, perceptive deafness

(607115) CIAS1, 1q44

Mandibular dysplasia

Large fontanel, wide cranial sutures, beaked nose, micrognathia, dental anomalies, skin atrophy

AR (248370) LMNA, 1q21.2

Menkes

Brain malformation, brittle and kinky hair, dry skin, seizures, mental retardation

XLR (309400) ATP7A, Xq12-q13

Oto-palato-digital II

Sclerosis of skull, wide sutures, hypertelorism, micrognathia, skeletal anomalies, syndactyly, polydactyly

XLR (304120) FLNA, Xq28

Osteogenesis imperfecta

Blue sclerae, numerous fractures, deafness

AD (166200, 259400) Heterogeneous COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Progeria

Alopecia, atrophy of subcutaneous fat, skeletal hypoplasia and dysplasia, premature aging

AD (176670) LMNA, 1q21.2

Pycnodysostosis

Large fontanel, wide sutures, beaked nose, micrognathia, hepatosplenomegaly, multiple fractures

AR (265800) Cathepsin K, 1q21

Roberts-SC phocomelia

Hypomelia, midfacial defect, severe growth deficiency

AR (269000)

Schnizel-Giedon hypertrichosis-midface retraction

Sclerosis of skull, wide sutures, limb anomalies, mental retardation

AR (269150)

Stratton-Parker

Growth hormone deficiency, dextrocardia, brachycamptodactyly

Unknown (185120)

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Craniofacial Structures

have recommended supine sleep positioning to prevent sudden infant death syndrome. References (Wormian Bones) 1. Pryles C, Khan AJ: Wormian bones. Am J Dis Child 133:380,1979. 2. Gooding CA: Cranial sutures and fontanelles. In: Radiology of the Skull and Brain. TH Newton, DO Potts, eds. Medibooks, Great Neck, NY, 1971. 3. Bennett KA: The etiology and genetics of wormian bones. Am J Phys Anthropol 23:255, 1965. 4. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Co, Philadelphia, 2005.

7.8 Scalp Vertex Aplasia Scalp vertex aplasia, or aplasia cutis congenita (ACC), is a relatively common congenital defect resulting in localized absence of skin, usually occurring on the scalp as an isolated finding not associated with other abnormalities. Scalp vertex aplasia begins as multiple or solitary sharply marginated raw areas with absence of skin that mature into atrophic scars devoid of adnexal structures, usually in the scalp vertex area or midline superior occipital region (Fig. 7-18).1 The cause of these lesions is heterogeneous and includes vascular disruption, trauma, teratogens, and genetic factors.2 Because vas-

cular disruption and placental infarcts are seen in antiphospholipid antibody syndrome, some cases of extensive scalp vertex aplasia may be related to the effects of this maternal disease state or some other type of thrombophilia during pregnancy.2,3 The frequency is one per 3000 live births, and a classification system of subtypes for ACC has been suggested by Frieden.4 Lesions may be ulcerated, bullous, cicatricial, or covered with a tough, translucent membrane, and they occasionally extend to the bone or dura.1 They may be circular, elongated, stellate, or triangular in shape and of variable depth,5 with 86% of the solitary lesions occurring on the scalp, most often near the parietal hair whorl.6,7 Type 1 ACC manifests scalp involvement without other abnormalities, and when familial, it manifests autosomal dominant inheritance.8,9 Less frequently, other parts of the body may be involved, with or without associated defects. When the lesions are midline and overlying the spine or midcranium, they can be associated with occult spinal dysraphism or tiny encephaloceles (ACC type 4). When there are multiple areas of ACC involving primarily the lower extremities, particularly the flank, thighs, and knees, a careful examination of the placenta may reveal a fetus papyraceus, which occurs in one in 12,000 live births and affects one in 200 twin pregnancies.10–12 Larger defects can be complicated by hemorrhage, venous thrombosis, and rarely meningitis. With extensive ACC and other vasculodisruptive defects, survival during the neonatal period can be severely compromised.13 ACC can be associated with teratogenic or genetic disorders, and it is important to search for

Fig. 7-18. Examples of scalp vertex cutis aplasia in an otherwise normal infant (A) and in an infant with trisomy 13 (B).

Skull

associated malformations in order to counsel parents concerning prognosis and recurrence risks in relation to the underlying disorder. ACC associated with epidermal nevus or nevus sebaceous syndrome (or ACC type 3) is the association of a sebaceous nevus (a linear yellow verrucous nevus) on the head and neck with variable ocular, cerebral, neurologic, skeletal, cardiac, and other abnormalities, usually on a sporadic basis.14,15 Epidermolysis bullosa (EB) is a term applied to a group of hereditary skin disorders that result in the formation of blisters after minor skin trauma. There are three subtypes, based on the histopathologic location of the

247

bullae: dystrophic EB with subepidermal bullae below the periodic acid-schiff (PAS) staining basement membrane, junctional EB with subepidermal bullae above the PAS-staining membrane, and simplex EB with intraepidermal bullae in the suprabasal area.16,17 Dystrophic and simplex EB can be either autosomal recessive or dominant, but junctional EB is always autosomal recessive. EB can be associated with pyloric atresia and/or ACC and manifest autosomal recessive inheritance, and histopathology is usually of the junctional type.16 These findings suggest that when ACC occurs with EB, it is most likely to be autosomal recessive, and some cases

Fig. 7-19. Thin cranial bones in infants with kleeblattscha¨del due to multiple suture synostosis (A and B) and early amnion rupture (C and D). Cranial bones in B. are uniformly thin, while the cranium in D. has irregular areas of localized thinning.

248

Craniofacial Structures

of junctional EB with pyloric atresia have demonstrated mutations in integrin beta 4.16 Finally, ACC has been associated with numerous cytogenetic and genetic malformation syndromes as ACC type 9.2,9,18,19 Wound treatment in cases of superficial ulceration is conservative with antibacterial dressings, but extensive or deep lesions may require reconstruction of the scalp. Small hairless areas can be excised and covered with a neighboring flap from the scalp.20 This approach works for the most common scalp ACC lesions, which are frequently round, punched-out lesions in the vertex region or less frequently triangular lesions in the temporal region (termed temporal triangular alopecia).20,21 With extensive scalp lesions (over 6 cm in diameter), it is especially important to avoid eschar formation immediately after birth by covering exposed dura with split thickness skin grafts from adjacent healthy scalp and moist dressings. Prompt closure is important because of the high risk of fatal hemorrhage from the sagittal sinus when the eschar becomes dry and separated, causing the underlying dura to become damaged and tear.21 Once the superficial defect is completely healed, the subsequent scar alopecia may be treated by tissue-expanded local flaps, pericranial flaps, or free vascularized flaps when the child is older. With prompt closure and a healthy underlying dura, cranial bone growth will occur after prompt early wound closure, and the risk of fatal hemorrhage or meningitis is greatly lessened.22 References (Scalp Vertex Aplasia) 1. Tann HH, Tay YK: Familial aplasia cutis congenita of the scalp: a case report and review. Ann Acad Med Singapore 26:500, 1997. 2. Evers MEJW, Steijlen PM, Hamel BCJ: Aplasia cutis congenita and associated disorders: an update. Clin Genet 47:295, 1995. 3. Roll C, Hanssler L, Voit T, et al.: Aplasia cutis congenita—etiological relationship to antiphospholipid syndrome? Clin Dysmorphol 8:215, 1999. 4. Frieden IJ: Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14:646, 1986. 5. Rudolph RJ, Schwartz W, Leyden JJ: Bitemporal aplasia cutis congenita. Arch Dermatol 110:615, 1974. 6. Demmel U: Clinical aspects of congenital skin defects: I. Congenital skin defects of the head of the newborn; II. Congenital defects of the trunk and extremities of the newborn; III. Causal and formal genesis of congenital skin defects of the newborn. Eur J Pediatr 121:21, 1975. 7. Stephan MJ, Smith DW, Ponzi JW: Origin of scalp vertex aplasia cutis. J Pediatr 101:850, 1982. 8. Itin P, Pletscher M: Familial aplasia cutis congenita of the scalp without other defects in 6 members of three successive generations. Dermatologica 177:123, 1988. 9. Fimiani M, Seri M, Rubegni P, et al.: Autosomal dominant aplasia cutis congenita: report of a large Italian family and no hint for candidate chromosomal regions. Arch Dermatol Res 291:637, 1999. 10. Mannino FL, Jones KL, Benirschke K: Congenital skin defects and fetus papyraceus. J. Pediatr 91:559, 1977. 11. Daw E: Fetus papyraceus—11 cases. Postgrad Med J 59:598, 1983. 12. Leaute-Labreze C, Depaire-Duclos F, Sarlangue J, et al.: Congenital cutaneous defects as complications in surviving co-twins: aplasia cutis congenita and neonatal Volkmann ischemic contracture of the forearm. Arch Dermatol 143:1121, 1998. 13. Lane W, Zanol K: Duodenal atresia, biliary atresia, and intestinal infarct in truncal aplasia cutis congenita. Ped Dermatol 17:290, 2000. 14. Hogler W, Sidoroff A, Weber F, et al.: Aplasia cutis congenita, uvula bifida and bilateral retinal dystrophy in a girl with naevus sebaceous syndrome. Brit J Dermatol 140:542, 1999. 15. Shields JA, Shields CL, Eagle RC, et al.: Ocular manifestation of the organoid nevus syndrome. Ophthalmology 104:549, 1997. 16. Maman E, Maor E, Kachko L, et al.: Epidermolysis bullosa, pyloric atresia, aplasia cutis congenita: histopathological definition of an autosomal recessive disease. Am J Med Genet 78:127, 1998.

17. Gilbert-Barness E, Barness LA: Disorders of collagen metabolism. In: Metabolic Diseases: Foundations of Clinical Management, Genetics and Pathology. Eaton Publishing, Natick, MA, 2000. 18. Zvulunov A, Kachko L, Manor E, et al.: Reticulolinear aplasia cutis congenita of the face and neck: a distinctive cutaneous manifestation in several syndromes linked to Xp22. Br J Dermatol 138:1046, 1998. 19. Edwards MJ, McDonald D, Moore P, et al.: Scalp-ear-nipple syndrome: additional manifestations. Am J Med Genet 50:247, 1994. 20. Kruk-Jeromin J, Janik J, Rykala J: Aplasia cutis congenita of the scalp: report of 16 cases. Dermatol Surg 24:549, 1998. 21. Trakimas C, Sperling LC, Skelton HG, et al.: Clinical and histologic findings in temporal triangular alopecia. J Am Acad Dermatol 31:205, 1994. 22. Yang JY, Yang WG: Large scalp and skull defect in aplasia cutis congenita. Br J Plast Surg 53:619, 2000.

7.9 Thin Cranial Bones Thin cranial bones are those that appear thinner than average and have little or no diploe. The diagnosis of thin cranial bones is made radiographically and is usually subjective.1 Radiolucency is often noted (Fig. 7-19). Thin calvarial bones can be secondary to craniosynostosis (particularly adjacent to the ridging in sagittal synostosis) and hydrocephalus, or it can occur as part of several syndromes in which undermineralization is a feature (Table 7-10).2 Areas of radiolucency are called craniolacunae (luckensch€ € adel) and are often secondary to spinal dysraphism (Fig. 7-20). These generally disappear by age 1 year.3 Regionally thinned areas can also occur in association with porencephaly, subdural hygroma, arachnoid cyst, and some tumors.2 Generalized thinning of cranial bones also results from increased dural distension, when expansion of the brain outpaces the growth of the skull. In other instances, undermineralization is the cause. As with thickened cranial bones, it is unknown whether thin cranial bones can occur as an isolated trait. Craniolacunae probably represent defective membranous bone formation, particularly along the inner periosteum of the vault.3 Craniolacunae probably do not occur as isolated traits. Prognosis is dependent on the underlying cause of this condition, and lacunar skull defects themselves have no direct effects on the infant. References (Thin Cranial Bones) 1. Ethier R: Thickness and texture. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 154. 2. Hodges FJ III: Pathology of the skull. In: Neuroradiology of the Head and Neck, vol 3. JM Taveras, ed. JB Lippincott Co, Philadelphia, 1989. 3. McRae DL: Lacunar skull, lu¨ckenscha¨del. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 648.

7.10 Undermineralization of the Skull Undermineralization of the skull results in increased radiolucency of the cranial bones and is attributable to decreased calcium deposition. Although this is distinct from thin cranial bones, the two traits are often found together, and for this reason, both entities are covered in Table 7-10. Congenital undermineralization occurs in a number of syndromes, particularly osteogenesis imperfecta and hypophosphatasia (Fig. 7-21). Hypophosphatasia occurs in at least three forms, including infantile, childhood, and adult forms. Undermineralization is most pronounced in the infantile form and least evident in the adult form. The infantile form can usually be diagnosed

Skull

249

Table 7-10. Syndromes with thin cranial bones and/or defective ossification Syndrome

Major Features

Causation Gene/Locus

Achondrogenesis

Macrocephaly, severe micromelia, early death

AR (200600, 200710) COL2A1, 12q13.11-q13.2

Aminopterin, prenatal

Microcephaly, cranial dysplasia, cleft palate, mesomelia, hypodactyly

Drug exposure

Anderson (familial osteodysplasia)

Large earlobes, midface hypoplasia, kyphosis, scoliosis

AR (607689) FARA2, 5q31.1

Cleidocranial dysplasia

Brachycephaly, late fontanel closure, wide sutures, flat midface, hypoplastic clavicles, short ribs

AD (119600) CBFA1, 6p21

Crane-Heise

Cleft lip/palate, agenesis of clavicles and cervical vertebrae, talipes equinovarus

AR (218090)

Ehlers-Danlos

Short stature, blue sclerae, ectopia lentis, mitral valve prolapse, joint hypermobility/dislocation

AD (130000, 225400) Heterogeneous COL5A1, 9q34.2-q34.3 COL5A2, 2q31 COL1A1, 17q21.31-q22

Hallermann-Streiff

Sparse hair, corneal clouding, thin nose, dental anomalies

AR (264090)

Hypophosphatasia

Premature shedding of teeth, rachitic skeletal changes, bowed long bones, fractures, low serum phosphatase

AR (241510) ALPL, 1p36.1-p34

Hydrops-ectopic calcification moth-eaten skull dysplasia

Macrocephaly, micrognathia, narrow thorax, rhizomelia, polydactyly, laryngeal/tracheal calcifications

AR (215140) LBR, 1q42.1

Lethal (osteosclerotic) skeletal dysplasia (Ashey-Kendall)

Short trunk, micromelia, small chest, abnormal lung lobation, situs inversus, polyhydramnios

AR (259775)

Metaphyseal chondrodysplasia-Jansen type

Thick cranium, deafness, micrognathia, limb anomalies, multiple fractures, short stature

AD (156400) PTHR, 3p22-p21.1

Osteogenesis imperfecta

Blue sclerae, fractures, osteopenia, wormian bones, dentinogenesis imperfecta, deafness

AD (166200, 259400) COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Oto-palato-digital type II

Microcephaly, small mouth, cleft palate, syndactyly

XLR (304120) FLNA, Xq28

Restrictive dermopathy

Hypertelorism, micrognathia, severe intrauterine growth restriction, polyhydramnios, cleft palate

AR (275210)

Ritscher-Schinzel

Macrocephaly, large fontanel, parietal foramina, hydrocephalus, facial anomalies, hypotonia, mental retardation

AR (220210)

Stanescu dysostosis

Brachycephaly, midface hypoplasia, tooth anomalies

AD (122900)

Fig. 7-20. Lu¨ckenscha¨del in an infant with congenital hydrocephalus treated with ventriculoperitoneal shunting due to a meningomyelocele. Note lacunar skull patterning due to rapid brain expansion. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.) See also Fig. 7-6.

by fetal ultrasound, whereas the other forms are often diagnosed after birth by radiographs and measurement of serum alkaline phosphatase levels.1–3 The other conditions listed in Table 7-10 are less frequent, and also diagnosed through radiographic and clinical features. Fluorosis and vitamin D-dependent rickets can also produce postnatal undermineralization of the skull, but areas of sclerosis are also present in fluorosis.4 The incidence of undermineralization is low, and prognosis is dependent on cause, varying widely from stillbirth or death during infancy, to little effect. References (Undermineralization of the Skull) 1. Goodman RM, Gorlin RJ: The Malformed Infant and Child. Oxford University Press, New York, 1983. 2. Wynne-Davies R, Hale CM, Apley AG: Atlas of Skeletal Dysplasias. Churchill Livingstone, New York, 1987. 3. Edeiken J: Roentgen Diagnosis of Diseases of Bone, vol 2, ed 3. Williams & Wilkins, Baltimore, 1981, p 858. 4. Christie DP: The spectrum of radiographic bone changes in children with fluorosis. Radiology 36:85, 1980.

7.11 Craniotabes Prolonged forceful pressure on the fetal vertex may result in diminished cranial mineralization, affecting the superior portions of the parietal bones. Such craniotabes is more likely to occur in

250

Craniofacial Structures

Fig. 7-21. A and B. Undermineralization of calvarium in newborn infant with lethal osteogenesis imperfecta (Type II). C. Extensive brachycephalization in an infant with severe osteogenesis (Type III) due to severe undermineralization.

first-born infants, especially with early fetal head descent into a vertex presentation for a prolonged period of time. Mild degrees of craniotabes occur in about 2% of newborn babies, and more extensive degrees of craniotabes are less common.1,2 Craniotabes was first described in congenital syphilis, and it can also be seen with subclinical rickets due to vitamin D deficiency.3–8 Rickets should be considered in any infant with a nonvertex presentation, whose mother might be at risk for nutritional deficiency, and such infants usually manifest generalized craniotabes with osteomalacia. With compression-related craniotabes, the superior parietooccipital region tends to be soft to palpation and often indents upon finger compression. In extreme cases, the entire top of the head can be involved (Fig. 7-22). The presence of a normally firm bony calvaria along the sides of the calvaria and in the mastoid regions readily differentiates this benign form of craniotabes from more generalized problems of decreased mineralization, such as hypophosphatasia, osteogenesis imperfecta, or infantile rickets. Within the affected region of the calvaria, the sutures and fontanels may also feel wider than usual. Accentuated vertex molding can be an associated feature in a fetus with prolonged vertex engagement. Benign vertex craniotabes has not been reported in babies in breech presentation, and radiolucency of the parietal bones in the vertex of the skull is considered to be a normal anatomic variant on neonatal head computed tomography scans.9

With compression-related craniotabes, the prognosis is excellent, and the calvaria usually mineralizes in a normal fashion within 1 to 2 months after birth.10 If the mother has vitamin D-deficient rickets and there is more generalized craniotabes and osteomalacia, this condition usually manifests a prompt response to vitamin D therapy over the next few months. Vitamin D-deficient rickets generally is accompanied by metaphyseal changes at the wrist and low 25-hydroxyvitamin D concentrations (less than 12 ng/mL), with a variably elevated alkaline phosphatase level. As in other defects of skeletal mineralization, such as osteogenesis imperfecta and hypophosphatasia, initial care must be taken to avoid fractures. Infants with osteogenesis imperfecta or hypophosphatasia usually show generalized osteomalacia, brittle bones, and wormian bones. References (Craniotabes) 1. Graham JM, Smith DW: Parietal craniotabes in the neonate: its origin and relevance. J Pediatr 95:114, 1979. 2. Fox GN, Maier MK: Neonatal craniotabes. Am Fam Physician 30:149, 1984. 3. Pettifor JM, Isdale JM, Sahakian J, et al.: Diagnosis of subclinical rickets. Arch Dis Child 55:155, 1980. 4. Pettifor JM, Pentopoulos M, Moodley GP, et al.: Is craniotabes a pathognomonic sign of rickets in 3-month-old infants? S Afr Med J 65:549, 1984.

Skull

251

Fig. 7-23. Mild thickening of the calvarium in a 3-year-old male with Sanfilippo syndrome (mucopolysaccharidosis III).

Fig. 7-22. Newborn infant with early head descent and engagement, resulting in extensive vertex molding with craniotabes over the conical deformation.

5. Kokkonen J, Koivisto M, Lautala, et al.: Serum calcium and 25-OH-D in mothers of newborns with craniotabes. J Perinat Med 11:127, 1983. 6. Congdon P, Horsman A, Kirby PA, et al.: Mineral content of the forearms of babies born to Asian and white mothers. Br Med J [Clin Res] 286:1233, 1983. 7. Park W, Paust H, Kaufmann HJ, et al.: Osteomalacia of the mother— rickets of the newborn. Eur J Pediatr 146:292, 1987. 8. Reif S, Katzir Y, Eisenberg Z, et al.: Serum 25-hydroxyvitamin D levels in congenital craniotabes. Acta Paediatr Scand 77:167, 1988. 9. Pastakia B, Herdt JR: Radiolucent ‘‘zones’’ in parietal bones seen on computed tomography: a normal variant. J Comput Assist Tomogr 8:108, 1984. 10. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005.

7.12 Thick Cranial Bones Increased thickness of cranial bones is detected on radiographic examination, and there may be normal or increased cranial density. The calvaria has three tables: the inner and outer tables are composed of compact bone, while the middle table (diploe) consists of cancellous bone. In general, the thickness of the normal skull is proportionate to the width of the middle table. The diagnosis of a thickened cranium is made radiographically, although no formal criteria have been established for determining whether cranial bones are thick (Fig. 7-23). Although there is wide variability among different individuals, in general the thickest part of a normal cranium is no greater than 1 cm. The density of the skull may be increased, normal, or decreased.1 Thickening of the middle table is usually a manifestation of overproliferation of bone marrow in hemolytic disease or bone

Fig. 7-24. Thickening of the calvarium with ‘‘hair on end’’ pattern in a 4-year-old male with thalassemia. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.)

diseases (Fig. 7-24). In hemolytic diseases, such as thalassemia, vertical striations (‘‘hair on end’’ appearance) occur, whereas in bone diseases, such as osteopetrosis, sclerosis occurs.1–4 Overgrowth of the middle table can also occur in microcephaly. In situations in which a shunt has been placed to relieve hydrocephalus, thickening of both inner and middle tables can occur. Thickening of only the outer table is extremely rare.1 Numerous syndromes with thick calvarial bones have been described (Table 7-11). There are both ethnic and sex-related variations in skull thickness. Women have thicker skulls than men, and blacks have thicker skulls than whites. It is unknown whether thick cranial bones can occur as an isolated trait, and the prognosis depends on the underlying condition. References (Thick Cranial Bones) 1. Ethier R: Thickness and texture. In: Radiology of the Skull and Brain. TH Newton, DO Potts, eds. Medibooks, Great Neck, NY, 1971, p 154. 2. Becker MH, Genieser NB, Piomelli S, et al.: Roentgenographic manifestations of pyruvate kinase deficiency hemolytic anemia. AJR Am J Roentgenol 113:491, 1971.

Table 7-11. Syndromes with thick cranial bones Syndrome

Prominent Features

Causation Gene/Locus

Acrodysostosis

Brachycephaly, hearing loss, minor facial anomalies, mesomelia of upper limbs, mental retardation

AD (101800)

Acromegaly

Functional pituitary adenoma, acanthosis nigricans, galactorrhea

AD (102200) GNAS1, 11q13

Aspartylglycosaminuria

Brachycephaly, cataract, coarse facial features, hepatosplenomegaly, telangiectasia

AR (208400) AGA, 4q32-q33

Camurati-Engelmann (diaphyseal dysplasia)

Diaphyseal dysplasia, weakness, leg pain

AD (131300) TGFB-1, 19q13.1

Clouston (ectodermal dysplasia)

Nail dystrophy, dyskeratotic palms and soles, hair hypoplasia

AD (129500) GJB6, 13q12

Cockayne

Asthenia, short stature, cataracts, prominent nose, premature aging, joint contractures, mental retardation

AR (216400) ERCC8, Chr. 5

Coffin-Lowry

Short stature, prominent ears, coarse facial features, kyphosis/scoliosis, large hands, joint laxity

XLR (303600, 102500) RSK2, Xp22/2-p22.1

Craniodiaphyseal dysplasia

Facial distortion

AD (218300)

Craniometaphyseal dysplasia

Sclerosis of skull, deafness, prominent eyes, facial weakness, osteosclerosis

AD (123000) ANKH, 5p15.2-p14.1

Dyke-Davidoff-Masson

Sclerosis of skull, cerebral atrophy, hemiplegia, seizures

Dysosteosclerosis

Sclerosis of skull, short stature, dental anomalies, mental retardation, multiple fractures

AR (224300)

Van Buchem

Optic atrophy, deafness, diffuse osteosclerosis

AR (239100) 17q11.2

Worth

Sclerosis of skull, prominent mandible, dental cysts, osteosclerosis

AD (144750) LRPS, 11q13.4

Fanconi anemia

Small stature, radial aplasia, thumb deformity, pancytopenia, microcephaly, congenital heart defect, kidney malformations, mental retardation

AR (227650) FANCA-G, 16q24.3 Multiple loci

Fluorosis

Joint deformity, spine rigidity, myelopathy, dental mottling

Toxicity

Fountain

Sclerosis of skull, coarse facial features, small broad hands, cutis laxa, skin granuloma, mental retardation

AR (229120)

Fucosidosis

Short stature, coarse facial features, cardiomegaly, hepatosplenomegaly

AR (230000) FUCA, 1p34

Homocystinuria

Subluxation of lens, malar flush, osteoporosis

AR (236200) CBS, 21q22.3

Hyperphosphatasia

Plagiocephaly, macrocephaly, deafness, retinal anomalies, kyphosis/ scoliosis, heart defects, bowed long bones, patchy pigmentation

AR (239300)

Endosteal hyperostosis

Hypoparathyroidism

Cataracts, seizures, chronic tetany, hypocalcemia, hyperphosphatemia

Variable

Hypothyroidism

Coarse facies, slow growth, umbilical hernia, slow development

Variable

Infantile multisystem inflammatory disease

Chronic meningitis, migratory skin rash, joint inflammation, progressive visual defect, perceptive deafness

(607115) CIAS1, 1q44

Jansen-metaphyseal dysplasia

Sclerosis of skull, deafness, micrognathia, limb anomalies, multiple fractures, short stature

AD (156400) PTHR, 3p11-p21.1

Kenny-Caffey

Delayed fontanel closure, wide cranial sutures, macular abnormalities, sparse eyebrows/lashes, hypercalcemia or hypocalcemia

AD (127000) TBCE, 1q42-q43

Lenz-Majewski

Delayed fontanel closure, sclerosis of skull, choanal atresia, joint laxity, and/or contractures, cutis laxa

AD (151500)

Lipodystrophy-cystic angiomatosis

Hirsutism, hepatosplenomegaly, muscle hypertrophy, acanthosis nigricans

AR (272500)

Mannosidosis (alpha)

Large ears, coarse facial features, vertebral anomalies, mental retardation

AR (248500) MAN2B1, 19cen-q12

Marfan

Arachnodactyly with hyperextensibility, lens subluxation, aortic dilation

AD (154700) FBN1, 15q21.1

Marshall

Short stature, cataracts, sensorineural deafness, short depressed nose, large eyes

AD (154780) COL11A1, 1p21

Morgagni-Stewart-Morel

Hyperostosis frontalis interna, obesity, hypertrichosis, hyperprolactinemia, diabetes

AD (144800) (continued)

252

Table 7-11. Syndromes with thick cranial bones (continued) Syndrome

Prominent Features

Causation Gene/Locus

II

Early alveolar ridge hypertrophy, joint limitation, tight thick skin in early infancy

AR (252500) GNPTA, 4q21-q23

IIIA

Coarse facies, stiff joints by 2–4 years, no mucopolysacchariduria

AR (252600) GNPTA, 4q21-q23

I-H (Hurler)

Coarse facies, stiff joints, mental deficiency, cloudy corneas by 1–2 years

AR (252800) IDUA, 4p16.3

II (Hunter)

Coarse facies, growth deficiency, stiff joints by 2–4 years, clear corneas

XLR (309900) IDS, Xq28

IIIA (Sanfilippo)

Mild coarse facies, mild joint stiffness, mental deficiency

AR (252900) SGSH, 17q25.3

IV (Morquio)

Onset at 1–3 years of age, mild coarse facies, severe kyphosis and knock-knees, cloudy corneas

AR (253000) GALNS, 16q24.3

Myhre: growth deficiencyclefting-mental retardation

Minor facial anomalies, vertebral defects, genital anomalies

AD (139210)

Myotonic dystrophy

Myotonia with muscle atrophy, cataract, hypogonadism

AD (160900) DMPK, 19q13.2-q13.3

Neu-Laxova

Microcephaly/lissencephaly, canine facies with exophthalmos, syndactyly with subcutaneous edema

AR (256520)

Osteogenesis imperfecta

Blue sclerae, numerous fractures, deafness

AD (166200, 259400) Multiple loci COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Osteopathia striata

Hearing loss, scoliosis, cleft palate

AD (166500)

Osteopetrosis

Dense, thick, fragile bone; secondary pancytopenia; cranial nerve compression

AR (259700) Multiple loci: CLCN7, 16p13 LRP5, 11q13.4-q13.5 GL, 6q21 TCIRG1, 11q13.4-q13.5

Osteosclerosis-distal

Cortical hyperostosis

AD (126250)

Oto-palato-digital

Short stature, hypertelorism, facial anomalies, abnormal toes, mental retardation

XLD (311300) FLNA, Xq28

Mucolipidosis

Mucopolysaccharidosis

Pagoni: calvarial hyperostosis

Sclerosis of skull, wide forehead, flat nasal bridge

XLR (302030)

Proteus

Segmental overgrowth, hemihypertrophy, nevi

Unknown (176920)

Polyostotic fibrous dysplasia (McCune-Albright)

Deafness, blindness, irregular skin pigmentation, sexual precocity, hyperthyroidism, hyperparathyroidism, Cushing syndrome, acromegaly

Mosaic (174800) GNAS1, 20q13.2

Pycnodysostosis

Osteosclerosis, short distal phalanges, delayed closure of fontanels

AR (265800) Cathepsin K, 1q21

Pyle metaphyseal dysplasia

Prominent supraorbital ridges, broad clavicles, thick ribs, muscle weakness, osteoporosis

AR (265900)

Pyruvate kinase deficiency

Severe hemolytic anemia

AR (266200) Cathepsin K, 1q21

Salla (Sialuria)

Growth retardation, mental retardation, ataxia, athetosis, impaired speech

AR (604369) SLCI7A5, 6q14-q15

Sclerosteosis

Syndactyly, square-jawed appearance

AR (269500) SOST, 17q12-q21

Sickle cell anemia

Anemia, joint pain, aplastic crises, splenic sequestration, priapism, dactylitis

AR (603903)

Spherocytosis

Splenomegaly, gallstones, jaundice

AD (182900) ANK1, 8p11.2

Thalassemia

Anemia, splenomegaly

AR (141900) HBB, 11p15.5

Tricho-dento-osseous syndrome II

Sparse curly hair, dental hypoplasia, premature dental eruption

AD (190320) DLX3, 17q21.3-q22

Vitamin D intoxication

Hypotonia, anorexia, irritability, constipation, polydipsia, polyuria, pallor, aortic valve stenosis, vomiting, hypertension, retinopathy, cloudy cornea

Excess ingestion

Weill-Marchesani

Brachydactyly, small spherical lens, short stature

AR (277600) ADAMTS10, 19p13.3-13.2 253

254

Craniofacial Structures

3. Leeds N, Seaman WB: Fibrous dysplasia of the skull and its differential diagnosis. Radiology 78:570, 1962. 4. Hodges FJ III: Pathology of the skull. In: Radiology: Diagnosis, Imaging, Intervention, vol 3, chapt 3. JM Taveras, ed. JB Lippincott, Philadelphia, 1989, p 1.

7.13 Sclerosis and Hyperostosis of the Skull Increased density or overmineralization of the cranial bones can be generalized or localized, and this is termed sclerosis or hyperostosis of the skull. Sclerosis generally refers to an increase in bone density without an alteration in width, while hyperostosis is caused by bone overgrowth that leads to an increase in density and width; however, not all cases fit cleanly into one category or the other.1 Hyperostosis is distinct from thick cranial bones, although hyperostosis and occasionally sclerosis can also cause thick cranial bones.2 Most of the sclerosing bone dysplasias manifest generalized changes that are classified on the basis of the distribution and configuration of these abnormalities. One subclassification divides these disorders into osteosclerosis, craniotubular dysplasias, and craniotubular hyperostoses. In such conditions, basal sclerosis may be present without significant calvarial involvement, but the converse rarely occurs.1 The presence of sclerosis or hyperostosis can be diagnosed radiographically or by computed tomography, and scintigraphy may provide information on disease progression (Fig. 7-25).3 Radiologic changes are age-related, and definitive diagnosis may be difficult in early childhood.1 All conditions that cause generalized osteosclerosis affect the skull.1 Localized sclerosis of the base of the skull can occur in fibrous dysplasia, Jansen-type metaphyseal dysplasia, severe anemia, hypercalcuria, and Paget disease. It may also be seen with a meningioma or inflammation.1 Symptoms include narrowing of cranial nerve foramina, which in turn can cause nerve palsy, deafness, or vision defects.4 Increased intracranial pressure is not uncommon, and papilledema can occur as a

complication. Craniosynostosis also occurs in some cases, perhaps related to overstimulation of bone growth along suture edges. Several syndromes have sclerosis as a feature (Table 7-12). Two primary pathologic processes can lead to sclerosis: overproduction of bone and/or failure of osteoclastic absorption of bone.2 The prognosis depends on the underlying cause and varies from individuals being asymptomatic to sudden death from medullary compression. In addition, facial palsy as well as hearing and vision loss may occur due to cranial nerve compression within stenotic formena.3,4 This may require decompression. Craniotomy to relieve increased intracranial pressure may also be indicated. References (Sclerosis and Hyperostosis of the Skull) 1. Kozlowski K, Beighton P: Gamut Index of Skeletal Dysplasias, ed 2. Springer, New York, 1995, p 33. 2. Ethier R: Thickness and texture. In: Radiology of the Skull and Brain. TH Newton, DG0 Potts, eds. Medibooks, Great Neck, NY, 1971. 3. Kumar B, Murphy WA, Whyte MP: Progressive diaphyseal dysplasia (Engelmann disease): scintigraphic-radiographic correlations. Radiology 140:87, 1981. 4. Beighton P, Durr L, Hamersma H: The clinical features of sclerosteosis: a review of the manifestations in twenty five affected individuals. Ann Intern Med 84:393, 1976.

7.14 Vertex Birth Molding Vertex birth molding refers to the mechanical changes in fetal head shape that result from cranial compression and bony adjustments within the cranial vault as the neonate in vertex presentation passes through the birth canal.1 Additional soft tissue swelling can significantly alter the shape of the neonatal head, and prolonged pressure against the fetal cranium can delay normal ossification in the vertex region (benign vertex craniotabes). The birth canal is a long, curved tube through which a mature fetal

Fig. 7-25. Progressive cranial hyperostosis at 4 months (left), 15 months (center), and 5 years (right) in a patient with craniodiaphysial dysplasia. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.)

Skull

255

Table 7-12. Syndromes with hyperostosis/sclerosis of skull Syndrome

Major Features

Causation Gene/Locus

Camurati-Engelmann

Diaphyseal dysplasia, muscle weakness, deafness

AD (131300) TGFB-1, 19q13.1

Craniodiaphyseal dysplasia

Facial distortion, mental retardation

AR (218300)

Craniometaphyseal dysplasia

Thick cranium, deafness, prominent eyes, facial weakness, osteosclerosis

AD (123000) ANKH, 5p15.2-p14.1

Dysosteosclerosis

Short stature, dental anomalies, mental retardation, multiple fractures

AR (224300)

Van Buchem type

Optic atrophy, deafness, diffuse osteosclerosis

AR (239100) 17q11.2

Worth type

Thick cranium, prominent mandible, dental cysts, osteosclerosis

AD (144750) LRP5, 11q13.4

Familial hyperostosis cranialis interna (Manni)

Recurrent facial palsy; variable impaired smell, taste, vision, and cochleovestibular function

AD (144755)

Fluorosis

Joint deformity, spine rigidity, myelopathy, dental mottling

Toxicity: none

Frontometaphyseal dysplasia

Coarse facial features, flexion contractures, arachnodactyly, deafness

XLR (305620) FLNA, Xq28

Jansen-metaphyseal dysplasia

Thick cranium, deafness, micrognathia, limb anomalies, multiple fractures, short stature

AD (156400) PTHR, 3p22-p21.1

Lenz-Majewski

Delayed closure fontanel, thick cranium, choanal atresia, joint laxity and/or contractures, cutis laxa

AD (151050)

McCune-Albright

Proptosis, diabetes, hypercalcemia, bowed long bones, genital anomalies, skin hyperpigmentation

Somatic mosaicism (174800) GNAS1, 20q13.2

Melnick-Needles

Large fontanel, proptosis, full cheeks, cleft or high palate, vertebral anomalies, skeletal defects

XLD (309350) FLNA, Xq28

Morgagni Stewart Morel

Hyperostosis frontalis interna, obesity, hypertrichosis, hyperprolactinemia, diabetes

AD (144800)

Oculodentodigital dysplasia

Microcephaly, hearing loss, cleft lip and palate, mental retardation

AD (164200) GJA1, 6q21-23.2

Osteopathia striata

Hearing loss, scoliosis, cleft palate

AD (166500)

Osteosclerosis, distal

Cortical hyperostosis

AD (126250)

Oto-palato-digital

Conductive deafness, cleft palate, facial anomalies, widely spaced toes

XLD (311300) FLNA, Xq28

Oto-palato-digital II

Microcephaly, small mouth, cleft palate, syndactyly

XLR (304120) FLNA, Xq28

Paget

Short stature, wide forehead, flat nasal bridge

AR (239000) TMFRSF11B, 8q24

Pagon-calvarial hyperostosis

Thick cranium, wide forehead, flat nasal bridge

XLR (302030)

Endosteal hyperostosis

Proteus

Hemihypertrophy, macrodactyly, subcutaneous tumors

Unknown (176920)

Pychodysostosis

Osteosclerosis, short distal phalanges, delayed closure of fontanels

AR (265800) Cathepsin K, 1q21

Sclerosteosis

Syndactyly, thickening and overgrowth of bone

AR (269500) SOST, 17q12-q21

head can only pass by rotating as it descends. There are a number of factors that influence the fetal cranial response to the normal forces of labor around the time of delivery, such as fetal head position and size, gestational age, maternal pelvic shape and dimensions, and the quality of uterine contractions.2,3 During normal vertex molding, moderate anteroposterior compression causes the frontal and occipital bones to slide under the parietal bones along the entire length of the coronal and lambdoid sutures. This elongates the occipitofrontal diameter to its greatest

possible extent to diminish the vertical diameter of the fetal head to its smallest dimensions. The cranial base is capable of bending slightly to allow elevation of the occipital plates, with biparietal pressure decreasing the transverse diameter enough to prevent the frontal and occipital bones from overriding the parietal bones when longitudinal pressure is applied.4 Vertex molding is characterized by an elevation of the vertex, an increase in the biparietal diameter, and an inward displacement of the occipital and frontal

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Craniofacial Structures

bones, which cause a reduction in the occipitofrontal diameter. The amount of molding is directly related to the length of labor, and normal vertex molding results from pressures from the maternal soft tissues, not the bony pelvis.5,6 A contracted pelvis is associated with more fetal head molding than that seen in normal deliveries, and excessive muscular contraction in the lower uterine segment results in more vertex molding, with an increased elevation of the fetal vertex. In a photographic and anthropometric study of vertex molding in 319 term infants delivered vaginally, several factors influenced the degree of molding.7 Infants born to primiparous women showed significantly more molding, as did those born after oxytocin-stimulated labors and via vacuum extraction. The duration of the first stage of labor did not influence the degree of molding, but a prolonged second stage in primiparous mothers was associated with more extensive molding. Fetuses born in occiput posterior and breech presentations showed significantly less molding than those born in occiput anterior presentation. Some degree of molding does occur within the uterus prior to labor, and repetitive Braxton-Hicks contractions throughout pregnancy were also a factor influencing the head shape of infants before the onset of labor.7 Extreme fetal head elongation due to vertex molding, from fetal cephalic fixation with persistent uterine contractions, has been noted via prenatal ultrasonography as early as 30 weeks gestation.8 During initial cervical dilation, pressure is greatest on the upper portion of the parietal bones, leading to a decrease in biparietal diameter, with a slight increase in the height and curvature of the vertex. At complete dilation, the biparietal diameter decreases to its smallest dimension, with continued elevation and curvature of the vertex and inward bending of both the frontal and occipital bones. As the fetus descends, pressure shifts to the lower portions of the parietal bones, causing them to rotate inward and move upward, thereby increasing the biparietal diameter, along with progressively widening the temporosquamosal and sagittal sutures. Recovery from this molded state takes place in two phases: first, an acute elastic recovery before the head is actually delivered, and second, a slower viscoelastic recovery during the postpartum period, which is usually completed within 3 to 7 days after delivery.9 With any normal fetus presenting in the vertex position, there may be appreciable molding of the head at birth. This is especially likely if the infant is the first born with the fetal head located deep in the uterine outlet for a prolonged time or if the mother has a prolonged second stage of labor and/or an incompletely dilated rigid cervix. The typical vertex molded newborn head is elongated and cylindrical and resumes a rounded shape within the 1st week of life (Fig. 7-26).1 The forehead tends to slope and the parieto-occipital region is prominently elevated into a conical shape. Head circumference measurements may be spuriously low because of the degree of molding. Persistent vertex molding usually reflects prolongation of the initial stages of normal fetal molding due to entrapment of the fetal head. The prognosis for spontaneous resolution of normal vertex birth molding, as well as the traumatic components that may accompany it, is generally excellent. With extensive vertex molding, management of the infant’s resting position will usually facilitate a complete return to normal form.1 If the baby is allowed to rest exclusively on the sides of the head, this conical deformation may become stabilized, and an elongated head shape will persist. Thus, it is important to bring pressure against the vertex to help collapse the conical head shape that may persist with extensive vertex molding.1 Along the leading part of the parieto-occipital region there may be edema of the skin and subcutaneous tissues, the so-called caput

Fig. 7-26. Vertex birth molding in a term newborn male whose head shape, with postnatal supine positioning and a blanket roll under the shoulders so as to put pressure against the top of the elongated fetal vertex cone, returned to normal appearance.

succedaneum. Associated craniotabes may also be extensive in the vertex region (Fig. 7-22C). Hemorrhages may occasionally be evident in the sclera and in the retina, and occasionally there may be a traumatic subperiosteal hemorrhage, most commonly in the outer table of the parietal bone. This will give rise to a soft, fluctuant mass. With time, its borders will become elevated and craterlike as the raised periosteum begins to deposit bone at its borders. The subperiosteal hemorrhage with a subsequent crater-rim of bone at its outer borders may give the impression of a skull fracture, sometimes raising the question of a depressed skull fracture, but such subperiosteal hemorrhage usually is a benign lesion. Rarely, posterior fossa hemorrhage in the term neonate can lead to severe molding with elongation of the head. These infants are readily distinguished from benign vertex molding by their neurologic deficits. References (Vertex Birth Molding) 1. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005. 2. Passingham RE: Changes in the size and organization of the brain in man and his ancestors. Brain, Behavior and Evolution 11:73, 1975. 3. Compton AA: Soft tissue and pelvic dystocia. Clin Obstet Gynecol 30:69, 1987. 4. Moloy HC: Studies of head molding during labor. Am J Obstet Gynecol 44:762, 1942. 5. Borell U, Fernstrom I: X-ray diagnosis of muscular spasm in the lower part of the uterus from the degree of molding of the fetal head. Acta Obstet Gynecol Scand 38:188, 1959. 6. Borell U, Fernstrom I: The mechanisms of labor in face and brow presentation. Acta Obstet Gynecol Scand 39:626, 1960. 7. Sorbe B, Dahlgren SS: Some important factors in the molding of the fetal head during vaginal delivery—a photographic study. Int J Gynaecol Obstet 21:205, 1983. 8. Carla SJ, Wyble L, Lense J, et al.: Fetal head molding: diagnosis by ultrasound and a review of the literature. J Perinatol 11:105, 1991. 9. McPherson GK, Kriewall TJ: The elastic modulus of fetal cranial bone: a first step towards an understanding of the biomechanics of fetal head molding. J Biomech 13:9, 1980.

Skull

7.15 Breech Head (Bathrocephaly) The frequency of singleton breech presentation at term is 3.1%, rising to 6.2% if multiple births are included.1–4 Among a large series of infants with deformations, 32% were in breech presentation, and 23% of malformed infants were also in breech presentation.3 Among 142 infants with spina bifida, 38% were in breech presentation and 68% had lower extremity weakness or paralysis, but among those with paralyzed legs, 93% manifested breech presentation.4 Thus, there are numerous fetal and maternal factors that can lead to breech presentation and thereby increase the risk for adverse outcomes. Though there is controversy concerning the best mode of delivery for infants in breech presentation, most studies suggest that the risk for neonatal morbidity and mortality is increased when term, singleton infants in breech presentation are delivered vaginally, as opposed to by cesarean section.3,5–8 Traumatic injuries following vaginal delivery of breech infants can include fractures and dislocations, brachial plexus injuries, facial nerve injuries, cerebral hemorrhages, bruising with hyperbilirubinemia, cervical cord injuries, cord prolapse, birth asphyxia, and testicular trauma.2–5 Breech presentation is more common in the primigravida, especially the older primigravida, presumably because of the shape of the uterus and the reduced space for fetal and uterine growth. The spatial restrictions associated with twinning also increase the likelihood of breech presentation, especially for the second in birth order. The prematurely born baby is also less likely to have shifted into the vertex birth position, and prematurity is more common with multiple births. Unless there is oligohydramnios or twinning, the premature fetus in breech presentation generally does not have deformations. This is because there has not been sufficient constraint to cause fetal deformation. Furthermore, breech presentation can be considered normal with prematurity, since at 32 weeks of gestation, 25% of all fetuses are in breech presentation, and after this time, the majority of fetuses shift into vertex presentation.3 Any situation that causes oligohydramnios, whether it be chronic leakage of amniotic fluid or lack of urine flow into the amniotic space, will restrict movement and greatly increase the chance of the fetus being in breech presentation. Alterations in the size and shape of the uterine cavity may also increase the frequency of breech presentation. This may be secondary to uterine structural anomalies or to myomas. The implantation and placement of the placenta may also be a factor, since 66% of placentas in breech deliveries implant in the cornualfundal region (versus 4% of vertex presentations), while 76% of vertex presentations implant on the midwall of the uterus (versus 4% of breech presentations).3 About 70% of fetuses in breech presentation have their legs extended in front of the abdomen.4 Breech presentation with the hips flexed and knees extended is termed frank breech. With the hips and knees flexed, it is called complete breech, and with the hips and knees extended, it is called footling breech. Prolonged breech position in late fetal life will give rise to increased uterine fundal pressure and molding of the fetal head, which may become retroflexed. This type of constraint results in anterior-posterior elongation of the head (dolichocephaly) with a prominent occipital shelf (bathrocephaly), and it is commonly termed breech head (Fig. 7-27).9,10 The shoulders are often thrust under the auricle, and there may also be distortion of the mandible. The legs may be caught in front of the fetus, tending to dislocate the hips and occasionally causing genu recurvatum of the knee and often cal-

257

caneovalgus position of the feet. In the complete breech position, with the legs flexed across the abdomen, the feet are liable to be compressed into an equinovarus position. The head is elongated into a dolichocephalic form, often with a prominent occipital shelf, termed bathrocephaly. There may be redundant folds of skin in the posterior neck as a result of compression due to retroflexion of the head. The lambdoid sutures may appear to be overlapping and/or ridged because of the fetal head constraint. The lower auricle may be forced upward into the location where the shoulder has been, and there may be a ‘‘hollow’’ appearance at the manubrial region of the mandible. The shoulder compression is often asymmetric, and hence there may be asymmetry of the mandible with an ‘‘upward tilt’’ on the more compressed side. Torticollis may occur secondary to asymmetric stretching or frank tearing of the sternocleidomastoid muscle or due to clavicular fracture during a traumatic breech vaginal delivery; 20% of torticollis occurs in babies who were in breech presentation.2,3 Of gravest concern is the vaginal delivery of a breech fetus with a hyperextended head (measured angle of less than 908 by ultrasound between the cervical vertebrae and the tangent plane of the occipital bone), which occurs in 11–15% of breech fetuses and is associated with cervical cord damage when delivered vaginally. In management of breech presentation, three factors must be considered.10 First is prevention of the deformities and complications of vaginal delivery by moving the fetus into the vertex position before the time of delivery by external cephalic version. Second is avoidance of the complications that relate to vaginal delivery of the breech fetus by utilizing cesarean section delivery, particularly when the fetal head is hyperextended. Third is the Fig. 7-27. Newborn male in prolonged breech presentation with bathrocephaly and equinovarus foot deformation. Breech positioning results in prominent occipital shelf with shoulders thrust up and head slightly retroflexed, resulting in bathrocephaly.

258

Craniofacial Structures

management of any deformations and complications after delivery of the breech fetus. After birth, the head shape and the mandibular retrusion tend to gradually return to normal, with no specific management being indicated.10 The most important question is whether an otherwise normal infant became caught in the breech position. If so, the prognosis, without birth complications, is usually excellent. If the infant was in the breech presentation because of a fetal problem, the prognosis relates predominantly to the basic diagnosis.10 An elongated, scaphocephalic head may also result from sagittal craniosynostosis. Usually palpation of the normally mobile sagittal suture is all that is required to clarify this diagnosis. Any doubt that might exist can usually be resolved by radiographs and follow-up examination, which shows progressive improvement toward normal form for the molded breech head.

Management of a transverse lie at term consists of expectant management, external cephalic version, or elective cesarean section.2,3 With expectant management, the spontaneous conversion rate to a longitudinal lie before labor is as high as 83%.2 This must be weighed against the increased risks of cord prolapse and birth trauma/asphyxia with persistent transverse lie versus the risks of cesarean section. The proven value of external cephalic version in term breech deliveries and in multiparous women with a transverse lie should not be extended to primiparous women with a transverse lie (who may have some kind of underlying pathology inhibiting the normal process of version). The compressive effects of a prolonged transverse lie or prolonged face and brow presentation can cause extensive facial compression (Fig. 7-28).4

References (Breech Head, Bathrocephaly)

In face and brow presentations, the face is the compressed presenting part, usually with extension of the head. Face presentation occurs in 1 to 2 per 1250 deliveries,5–7 and brow presentation occurs in one per 1444 deliveries.7 Face presentation is more common in multiparas (81%) and is variably associated with large infants weighing over 4000 grams (42%), small infants weighing less than 2300 grams (16%), and cephalopelvic disproportion.5–7 High parity, low birth weight, and cephalopelvic disproportion have also been proposed as etiologic factors in brow presentation, with relative cephalopelvic disproportion attributed to the presenting diameters of the fetal head being greater in brow presentation than in face or vertex presentations.7 In face presentation, the fetal head is hyperextended so that the occiput touches the back, and the presenting part is the fetal face between the orbital ridges and the chin.7 The growth of the fetal mandible and nose may be restrained. The position of comfort for the baby after birth is often with the neck retroflexed. As a consequence of compression of the chin and neck region with retroflexion, there tends to be redundant folds of skin in the

1. Lee KS, Khoshnood B, Sriram S, et al.: Relationship of cesarean delivery to lower birth-weight-specific neonatal mortality in singleton breech infants in the United States. Obstet Gynecol 92:769, 1998. 2. Dunn PM: Congenital postural deformities. Br Med Bull 32:71, 1976. 3. Dunn PM: Breech delivery: perinatal morbidity and mortality. 5th European Congress of Perinatal Medicine, Uppsala Sweden, 1976, p 57. 4. Dunn PM: Breech delivery: maternal and fetal aetiological factors. 5th European Congress of Perinatal Medicine, Uppsala Sweden, 1976, p 76. 5. Cheng M, Hannah M: Breech delivery at term: a critical review of the literature. Obstet Gynecol 82:605, 1993. 6. Thorpe-Beeston JG, Banfeld PJ, Saunders NJ: Outcome of breech delivery at term. Br Med J 305:746, 1992. 7. Roman J, Bakos O, Cnattingius S: Pregnancy outcomes by mode of delivery among term breech births: Swedish experience 1987–1993. Obstet Gynecol 92:945, 1998. 8. Albrechtsen S, Rasmussen S, Dalaker K, et al.: Perinatal mortality in breech presentation sibships. Obstet Gynecol 92:775, 1998 9. Haberkern C, Smith DW, Jones KL: The ‘‘breech head’’ and its relevance. Am J Dis Child 133:154, 1979. 10. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005.

7.16 Other Cranial Deformations Due to Abnormal Fetal Presentation Transverse Lie

Transverse lie occurs in 2.5 per 1000 deliveries and is associated with multiparity (90%), prematurity (13%), placenta previa (11%), polyhydramnios (8%), uterine anomalies (8%), and uterine myomas (3%), especially when the myomas are located in the lower uterine segment. Predisposing factors, such as uterine structural anomalies, prematurity, and placenta previa, are found in 66% of primiparas, but in only 33% of multiparas.1 In association with multiparity, women delivering transverse-lying infants tend to be older than those delivering vertex-presenting infants, with the other factors such as low-lying placenta, uterine anomalies, myomas, or prematurity occurring more frequently in primigravidas. Laxity of abdominal musculature in multiparous women is believed to be the predominant factor accounting for the liability toward transverse lie in these women. The occurrence of polyhydramnios may relate to being unable to swallow amniotic fluid because the wall of the uterus obstructs the mouth. Full frontal constraint may flatten the face, limit mandibular growth, and result in a retroflexed head with a prominent occipital shelf. There may be associated torticollis and/or scoliosis, as well as other deformations.

Face and Brow Presentation

Fig. 7-28. Face presentation with severe limitation of mandibular growth, which recovered after birth.

Skull

anterior upper neck, with retrognathia and an extremely prominent occipital shelf (Fig. 7-28). In some instances, the prolonged facial compression may lead to feeding difficulties, with difficulty swallowing. There may also be jaw subluxation and a palpable/ audible click as the jaw moves in and out of the socket (similar to that detected with a subluxable hip). Prolonged compression of the neck against the pubic ramus during delivery can cause trauma to the trachea or the larynx.8 In brow presentation, the fetal head is midway between flexion and hyperextension, and the presenting part is the brow between the orbital ridges and the anterior fontanelle.7 Most cases of brow presentation are diagnosed during labor and delivery, with cephalopelvic disproportion being the suspected cause for many persistent brow presentations, resulting in prolonged dysfunctional labors. The brow is unusually prominent, whereas the midface is less prominent than usual. There may be increased molding with persistent brow presentations in the frontoposterior position, making conversion more difficult and leading to excessively prolonged labors in 40–50% of cases.7,9 Face and brow presentation carry an increased risk of difficult labor. Cesarean section merits consideration, especially if the fetus is large, the mother has a relatively small pelvis, or there is a persistent mentum posterior presentation with arrested descent. If progress is being made in dilation and descent, the optimal management of face and brow presentations is expectant, but if progress ceases, delivery should be by cesarean section.7 Only anterior face positions can be delivered vaginally because of the inability of the fetal neck to further extend in the posterior position. After delivery of the fetus in face or brow presentation, there tends to be catch-up of the restrained facial growth toward normal.4 Though there is hyperextension of the fetal head in vaginal face presentation, vaginal delivery does not appear to pose the same risks for spinal and cerebellar injuries, as is seen with

259

breech presentation. The head gradually resumes a more normal posture, and the redundant skin that may be present on the anterior neck with face presentation usually resolves with postnatal growth. Usually no treatment other than gentle massage is indicated for congenital jaw subluxation.4 References (Other Cranial Deformations Due to Abnormal Fetal Presentation) 1. Gemer O, Segal S: Incidence and contribution of predisposing factors to transverse lie presentation. Int J Gynecol Obstet 44:219, 1994. 2. Phelan JP, Boucher M, Mueller E, et al.: The nonlaboring transverse lie: a management dilemma. J Reprod Med 31:184, 1986. 3. Lau WC, Fung HYM, Lau TK, et al.: A benign polypoid adenomyoma: an unusual cause of persistent fetal transverse lie. Eur J Obstet Gynecol Reprod Biol 74:23, 1997. 4. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005. 5. Fougerousse CE: Management of face presentation. J Ark Med Soc 63:462, 1967. 6. Benedetti TJ, Lowensohn RI, Turscott AM: Face presentation at term. Obstet Gynecol 55:199, 1980. 7. Cruikshank DP, Cruikshank JE: Face and brow presentation: a review. Clin Obstet Gynecol 24:333, 1981. 8. Lansford A, Arias D, Smith BE: Respiratory obstruction associated with face presentation. Am J Dis Child 116:318, 1968. 9. Jennings PN: Brow presentation and vaginal delivery. Aust N Z J Obstet Gynecol 8:219, 1968.

7.17 Anomalies of the Sella Turcica Anomalies include abnormal size and/or shape of the sella turcica, which is the central depression within the sphenoid bone that

Fig. 7-29. A. Enlarged and J-shaped sella turcica in a 13-year-old male with mucopolysaccharidosis I–H. B. Enlarged, rounded sella turcica in a 10-year-old male with mucopolysaccharidosis I–H/I–S.

260

Craniofacial Structures

contains the pituitary gland. Assessment of the sella turcica can best be done radiographically or by computed tomography.1 Measurements of normal sella turcica size have been published, with considerable overlap between normal and abnormal ranges.2,3 Small sellas have been described in patients with hypopituitarism and myotonic dystrophy, whereas large sellas occur in patients with storage disorders, pituitary tumors, empty sella syndrome, craniopharyngioma, intrasellar aneurysm, untreated hypogonadism, and hypothyroidism (Fig. 7-29). A J-shaped sella describes the lateral profile of the sella turcica in which the sella resembles a ‘‘J’’ lying on its side. A J-shaped sella can occur as a normal variant but may also occur in individuals with calvarial enlargement or optic nerve gliomas.4 Bridged sella is caused by bony bridging between anterior and posterior clinoids and can be a normal variant. It can also be seen in nevoid basal cell carcinoma syndrome (Gorlin syndrome). The sphenoid bone consists of two main cartilaginous parts (hypophyseal cartilage) until the 7th or 8th month of gestation. The presphenoid will contribute to the anterior part of the sella turcica, while the postsphenoid forms the remainder. At birth, the sella is only a small depression; it begins to ossify soon after birth. Since 80% of the sella is occupied by the pituitary gland, it is not unusual for pituitary anomalies to cause abnormalities in the sella. In individuals with optic nerve gliomas the chiasmatic groove will appear scalloped, whereas in cases of calvarial enlargement it will appear elongated.4 Sellar abnormalities do not themselves require treatment. However, they are usually indicative of an underlying pathologic process that may require treatment. Prognosis therefore is dependent on the underlying cause. References (Anomalies of the Sella Turcica) 1. Pribam HW, duBoulay GH: Sella turcica. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 357. 2. DiChiro G, Nelson KB: The volume of the sella turcica. AJR Am J Roentgenol 87:989, 1962. 3. Oon CL: The size of the pituitary fossa in adults. Br J Radiol 36:294, 1963. 4. Swischuk LE: The normal pediatric skull: variations and artifacts. Radiol Clin North Am 10(2):277, 1972.

7.18 Anomalies of Foramen Magnum Definition

The foramen magnum is normally an oval-shaped opening in the occipital bone bound anteriorly by the basiocciput, laterally by the occipital condyles, and posteriorly by the supraocciput.1 Anomalies include either small or large size or a keyhole shape. Diagnosis

Magnetic resonance imaging best achieves diagnostic assessment of foramen magnum size or shape, although radiography or computed tomography may also be used (Fig. 7-30).2–4 Tables have been published indicating normal foramen magnum size.5 Effects of a small foramen magnum vary from producing no symptoms to being associated with weakness, apneic spells, hyperreflexia, hydrocephalus, and abnormal somatosensory potentials and/or polysomnograms.5 Achondroplasia is the most common syndrome in which a small foramen magnum occurs, but other skeletal dysplasias and disorders associated with scle-

Fig. 7-30. Foramen magnum size. Top: mean þ/1 standard deviation (SD) for transverse diameter. Bottom: mean þ/1 SD for sagittal diameter. (From Heckt et al.5)

rosis of the skull can also lead to a small foramen magnum. Patients with achondroplasia usually do not experience neurologic complications until the foramen magnum is 4 standard deviations (SD) or more below the mean,5 and 96% of achondroplastic patients with neurologic manifestations have foramen magnum sizes more than 3 SD below the mean.6 A small foramen magnum can be accompanied by a short cranial base, and anterior herniation of the brain through an open metopic suture has been known to occur in such cases.1 A large foramen magnum usually results from chronic increased intracranial pressure or from direct effects of an expanding process within the foramen magnum (syringomyelia, Arnold-Chiari malformation).3–9 Large foramen magnum has also been described in children with either Rubinstein-Taybi or Angelman syndrome.10,11 Asymmetry of the foramen magnum occurs with craniovertebral anomalies or premature synostosis of one or more of the occipital synchondroses.8 Children with the latter may tend to hold their heads

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obliquely. A keyhole-shaped foramen magnum has been described in the hydrolethalus syndrome.9,12

Table 7-13. Foramina and canals of the base of the cranium Foramen or Canal

Primary Structure Within

Etiology and Distribution

Foramen rotundum

Maxillary nerve, occasionally emissary veins

The foramen magnum is an oval-shaped orifice bound by the exoccipital, supraoccipital, and baso-occipital bones, which develop and grow by enchondral ossification. These bones are separated by two anterior and two posterior synchondroses that begin to fuse at 12 months and completely fuse by 3 to 4 years and 7 years, respectively.5 If enchondral ossification is abnormal, suture fusion premature, or both, a small foramen magnum is the result. Premature synostosis of one or two sutures may cause asymmetry.8

Foramen ovale

Mandibular nerve

Foramen spinosum

Middle meningeal artery and vein, meningeal branch of mandibular nerve

Foramen of vesalius

Vein connecting cavernous sinus and pterygoid plexus

Canal of Arnold

Lesser superficial petrosal nerve

Foramen lacerum

Meningeal branch of ascending pharyngeal artery and nerve of pterygoid canal

Prognosis, Prevention, and Treatment

Pterygoid canal

Nerve and artery of pterygoid canal

Prognosis for small foramen magnum is variable, but the most serious outcome of brain stem compression may be sudden death. Recommended treatment is suboccipital craniectomy.5 The prognosis for a large or abnormally shaped foramen magnum is dependent on the underlying cause.

Carotid canal

Internal carotid artery and nerve, small veins

Jugular foramen

Inferior petrosal sinus, glossopharyngeal nerve, internal jugular vein, vagus nerve, accessory nerve, meningeal branches of ascending pharyngeal and occipital arteries

Greater palatine foramen

Greater palatine artery and branch of sphenopalatine nerve

Lesser palatine foramen

Lesser palatine nerve and branches from greater palatine artery

References (Anomalies of Foramen Magnum) 1. McRae DL: Craniovertebral junction. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 260. 2. Deck MDF: Computed tomography and magnetic resonance imaging of the skull and brain. Clin Imaging 13:95, 1989. 3. Bliesener JA, Schmidt LR: Normal and pathologic growth of the foramen occipitale magnum shown in the plain radiograph. Pediatr Radiol 10:65, 1980. 4. Hone H, Watanabe K, Kusumoto S, et al.: Optimal positioning for CT examinations of the skull base. Eur J Radiol 7:225, 1987. 5. Hecht JT, Nelson FW, Butler IJ, et al.: Computerized tomography of the foramen magnum: achondroplastic values compared to normal standards. Am J Med Genet 20:355, 1985. 6. Wang H, Rosenbaum AE, Reid CS, et al.: Pediatric patients with achondroplasia: CT evaluation of the craniocervical junction. Radiology 164:515, 1987. 7. Cohen MM Jr, Kreiborg S: The central nervous system in the Apert syndrome. Am J Med Genet 35:36, 1990. 8. Coin CG, Malkasian DR: Foramen magnum. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 275. 9. Salonen R, Herva R, Reijo N: The hydrolethalus syndrome: delineation of a ‘‘new’’ malformation syndrome based on 28 patients. Clin Genet 19:321, 1981. 10. Hennekam RCM, VanDenBoogaard MJ, Sibbles BJ, et al.: RubinsteinTaybi syndrome in the Netherlands. Am J Med Genet (suppl)6:17, 1990. 11. William CA, Hendrickson JE, Cantu ES, et al.: Angelman syndrome in a daughter with del(15)(qllqI3) associated with brachycephaly, hearing loss, enlarged foramen magnum and ataxia in the mother. Am J Med Genet 32:333, 1989. 12. Krassikoff N, Konick L, Gilbert EF: The hydrolethalis syndrome. Birth Defects Orig Artic Ser XXIII(1):411, 1987.

7.19 Anomalies of the Other Basal Foramina and Canals Definition

Anomalies of other basal foramina can include abnormal configuration or size of openings in the basal part of the skull that transmit nerves, blood vessels, or both.

Diagnosis

There are at least 11 foramina and canals in the base of the cranium through which blood vessels and nerves enter or leave the intracranial space (Table 7-13).1 Increased intracranial pressure aneurysms, tumors, and arteriovenous malformations can all cause pathologic enlargement of these foramina. Congenital anomalies include asymmetry of paired foramina, communication with other foramina, and absence if the transmitted structure is absent. Diagnosis of these anomalies is achieved radiographically or by using basal tomography, although they usually produce incidental findings. Reference (Anomalies of the Other Basal Foramina and Canals) 1. Sondheimer FK: Basal foramina and canals. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 287.

7.20 Basilar Impression Definition

Basilar impression is a malformation or deformation of the cranial base consisting of indentation of the base of the skull at the craniospinal junction. Primary basilar impression is a malformation in which the base of the skull and the upper two cervical vertebrae fail to segment and exist as a bony mass within which the posterior fossa, brain stem, and upper cervical spinal cord may become compressed. Some degree of basilar impression may occur with platybasia, defined as a craniocervical angle of greater than 1408. Diagnosis

Basilar impression may be suspected when there is limited movement and shortening of the neck, but definitive diagnosis

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Craniofacial Structures

Fig. 7-31. Basilar impression. Platybasia with basilar impression at ages 10 months and 8 years in a male with Hajdu-Cheny syndrome. Note also the dolichocephaly, absence of frontal sinuses, and wormian bones. (Courtesy of Drs. Rodney I. Macpherson and G. Shashidhar Pai, Medical University of South Carolina, Charleston, SC.)

requires radiography, computed tomography scan, or magnetic resonance imaging scan (Fig. 7-31).1 In basilar impression, the odontoid moves cephalad and can protrude into the foramen magnum, thus compromising function of the spinal cord, brain stem, and cerebellum as well as impeding the flow of cerebrospinal fluid. Symptoms include pain, limitation of movement, increased intracranial pressure, hydrocephalus, and cranial nerve symptoms.2–4 Symptoms may appear suddenly or develop over several months. Etiology and Distribution

Primary basilar impression is caused by a congenital defect of osseous structures in the cervico-occipital region and can occur as an autosomal dominant trait.4 Secondary basilar impression is related to disease of the skull. It has been reported in association with Paget disease, histiocytosis X, rheumatoid arthritis, rickets, and hypoparathyroidism. It also occurs in several skeletal dysplasias and malformation syndromes (Table 7-14). The incidence in the general population is one per 3300, although it may be more common in Eskimos and in cultures where carrying heavy loads on the top of the head is practiced.5 Prognosis, Prevention, and Treatment

The prognosis is quite variable. Affected individuals may be asymptomatic, develop sudden or progressive symptoms, or die suddenly. Most patients present with symptoms in late childhood or early adulthood, which corresponds to the time of closure of the anterior synchondroses (6 years) and spheno-occipital synchondrosis (25 years) of the occipital bone.3 Treatment consists of immobilization or, in severe cases, decompression of the foramen

magnum, laminectomy of the first and second cervical vertebrae, and cervico-occipital fusion.1 Shunting for hydrocephalus may also be indicated. References (Basilar Impression) 1. Rush PJ, Berbrayer D, Reilly DJ: Basilar impression and osteogenesis imperfecta in a three year old girl: CT and MRI. Radiology 19:142, 1989. 2. McRae DL: Craniovertebral junction. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 260. 3. Adam AM: Skull radiograph measurements of normals and patients with basilar impression: use of Landzert’s angle. Surg Radiol Anat 9:225, 1987. 4. Bull JWD, Nixon WLB, Pratt RTC: The radiologic criteria and familial occurrence of primary basilar impression. Brain 78:229, 1955. 5. Teodori JB, Painter MJ: Basilar impression in children. Pediatrics 74:1097, 1984.

7.21 Cephalhematoma and Caput Succedaneum Cephalhematoma is a subperiosteal hemorrhage, which may enlarge after delivery and sometimes takes weeks to resolve, while the scalp edema of caput succedaneum is maximal in size at birth and usually resolves within a few days. Both lesions are believed to result from an injury to the cranial periosteum during labor in a traumatic delivery, but cephalhematomas are sometimes detected as echogenic bulges on the cranium during prenatal ultrasound evaluations, suggesting that they may also arise in utero. Traumatic subperiosteal hemorrhages occur most commonly in the outer

Skull

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Table 7-14. Syndromes with basilar impression Syndrome

Major Features

Causation Gene/Locus

Achondroplasia

Frontal bossing, large head, short stature, lordosis

AD (100800) FGFR3, 4p16.3

Ankylosing spondylitis

Iridocyclitis, sacroiliitis, bamboo spine, atrio-ventricular block

AD (106300) 6p21.3

Cleidocranial dysplasia

Large head, wide fontanels, delayed dentition, hypoplastic clavicles

AD (119600) CBFA1, 6p21

Crouzon

Brachycephaly, kleeblattschadel, ridged sutures, deafness, convex beaked nose, tooth anomalies, malocclusion

AD (123500) FGFR2, 10q26

Down

Hypotonia, mental retardation, single palm creases, distinctive face, atlanto-occipital spinal instability

Chromosomal Trisomy 21

Empty sella turcica with generalized dysplasia

Thick calvarium, sclerosis of skull, wormian bones, ear anomalies, prominent eyes, meningocele, abnormal gait

AD (130720)

Familial primary basilar impression

Syringomelia, Horner syndrome, limb muscle weakness, kyphoscoliosis

AD (109500)

Hajdu-Cheney (acroosteolysis)

Delayed fontanel closure, wormian bones, wide cranial sutures, short stature, oligodontia, vertebral anomalies

AD (102500)

Hyperparathyroidism (primary)

Hypercalcemia, primary chief cell hyperplasia

AD (145000) HRPT2, 1q25-q31, 11q13

Hypophosphatasia

Globular skull, short limbs, blue sclerae

AR (241510) AD (146300) ALPL, 1p36.1-p34

Klippel-Feil

Cervical vertebral fusions, malformed laryngeal cartilages, deafness

AD (148900) 8q22.2

Larsen

Multiple congenital joint dislocations, flat nasal bridge, prominent forehead, accessory carpal bones, broad thumbs, cylindrical fingers with short terminal phalanges, cleft palate

AD (150250) FLNB, 3p14.3

Mucopolysaccharidosis

Coarse facies, dysostosis multiplex congenita, corneal clouding, hernias, hepatosplenomegaly

AR, XLR Multiple loci

Osteogenesis imperfecta

Blue sclerae, fractures, deafness

AD (166200, 259400) Multiple loci: COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Pycnodysostosis

Osteosclerosis, short distal phalanges, delayed closure of fontanels

AR (166200) (259400) (259420) Cathepsin K, 1q21

Syringomelia

Bilateral Babinski sign, scoliosis, Arnold-Chiari malformation

AD (186700)

Thanatophoric dysplasia

Wide sutures, short limbs, narrow thorax, platyspondyly

AD (187600) FGFR3, 4p16.3

table of the parietal bone, giving rise to a soft, fluctuant mass. With time, its borders will become elevated and craterlike, as the raised periosteum begins to deposit bone at its borders. Calcified cephalhematomas resolve slowly over the course of the 1st year during the normal process of cranial remodeling with normal calvarial growth. Cephalhematoma is a hemorrhage, which occurs beneath the periosteum with no extension over a sutural margin, and definite palpable edges are usually evident. Among 16,292 fetuses undergoing comprehensive ultrasound examinations between 1993 and 1996, seven cephalhematomas were detected on exams done between 23 and 38 weeks (five occipital and two temporal). The diagnosis was confirmed at birth to be cephalhematoma in two cases, and caput succedaneum in the

remaining five cases, but it was not possible to make this distinction prenatally. The seven affected infants were not delivered by vacuum extraction or forceps, none had any signs of intracranial hemorrhage or skull fracture by ultrasound, and none required any treatment, including blood transfusion. Five of the seven cases had associated premature rupture of membranes, with oligohydramnios in four cases, suggesting this might have played a role.1 Cephalhematoma, subdural hematoma, and caput succedaneum have all been found more frequently in infants delivered by vacuum extraction than in infants delivered spontaneously.2,3 In a prospective randomized trial of 322 cases delivered via vacuum extraction, cephalhematomas were strongly associated with the

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Craniofacial Structures

station of the presenting part, asynclitism, and increasing application to delivery time, but none of these infants experienced any long-term complications or needed blood transfusions.4 There have also been reports of fetal death and stillbirth after prenatal diagnosis of fetal subdural hematomas following suspected or confirmed trauma.5–8 Thus, cephalhematomas can occur prenatally before the onset of labor, especially when there is premature rupture of membranes with prolonged oligohydramnios. Maternal abdominal trauma can result in serious subdural hematomas, which can be seen by ultrasound prenatally, and this type of intracranial hemorrhage may threaten fetal survival. Since vacuum extraction has been associated with cephalhematomas, there are concerns about whether this mode of delivery may result in more serious intracranial vascular injuries (subdural, cerebral, intraventricular, or subarachnoid hemorrhages). Among 583,340 liveborn singleton California infants weighing 2500 to 4000 grams, who were born to nulliparous women between 1992 and 1994, the rate of intracranial hemorrhage was significantly higher among infants delivered by vacuum extraction, forceps, or cesarean section during labor than among infants delivered spontaneously.9 There was an incremental increase in the rate of hemorrhage if more than one method of delivery was used. Since the rate of hemorrhage was not significantly higher among infants delivered by cesarean section before labor, much of the morbidity associated with operative vaginal delivery is thought to be due to an underlying abnormality of labor rather than the specific operative procedure. The rate of intracranial hemorrhage has decreased by three times (to less than 1%) since the substitution of plastic cups for metal cups in vacuum extractors during the 1980s.9 Cephalhematomas are benign lesions, which begin as soft fluctuant masses within the periosteum of the parietal bones and then slowly calcify over the 1st year of life. At the cranial vertex, there may be edema of the skin and subcutaneous tissues, the socalled caput succedaneum. Caput succedaneum can cross suture lines and is maximal at birth, resolving in just a few days. The subperiosteal hemorrhage associated with a cephalhematoma may manifest a subsequent crater-rim of bone at its outer borders, sometimes giving the impression of a depressed skull fracture, but cephalhematoma is a benign lesion.

7.22 Miscellaneous Anomalies of the Skull Paracondylar Process

A paracondylar process is an asymptomatic anatomic variant that is visible only on computed tomography and consists of a process of bone that arises from the lateral aspect of the condyloid process and extends toward the transverse process of the atlas. It is generally of no significance but has been reported in children with hemifacial microsomia. It is present in 7–8% of all human skulls.1 Bathrocephaly

Bathrocephaly is a skull deformation that appears as a steplike deformity at the back of the skull, and it is also termed an occipital shelf. It is not associated with craniosynostosis but can occur secondary to breech position in utero (Figs. 7-27 and Fig. 7-32). When associated with breech presentation (Section 7.15), the head is usually also dolichocephalic in shape. When associated with other Fig. 7-32. Schematic showing bathrocephaly, a steplike deformation of the skull (arrow) at the lambdoid suture.

References (Cephalhematoma and Caput Succedaneum) 1. Petrikovsky BM, Schneider E, Smith-Levitin M, et al.: Cephalhematoma and caput succedaneum: do they always occur in labor? Am J Obstet Gynecol 179:906, 1998. 2. Fall O, Ryden G, Finnstrom K, et al.: Forceps or vacuum extraction? A comparison of effects on the newborn infants. Acta Obstet Gynecol Scand 65:75, 1986. 3. Teng FY, Sayre JW: Vacuum extraction: does duration predict scalp injury? Obstet Gynecol 89:281, 1997. 4. Bofill JA, Rust OA, Devidas M, et al.: Neonatal cephalhematoma from vacuum extraction. J Reprod Med 42:565, 1997. 5. Demir RH, Ggleisher N, Myers S: A traumatic antepartum subdural hematoma causing fetal death. Am J Obstet Gynecol 160:619, 1989. 6. Gunn TR, Becroft DMO: Unexplained intracranial haemorrhage in utero: the battered fetus? Aust N Z J Obstet Gynaecol 24:17, 1984. 7. Winter TC, Mack LA, Cyr DR: Prenatal sonographic diagnosis of scalp edema/cephalhematoma mimicking an encephalhematoma mimicking an encephalocele. AJR Am J Roentgenol 161:1247, 1993. 8. Grylack L: Prenatal sonographic diagnosis of cephalhematoma due to pre-labor trauma. Pediatr Radiol 12:145, 1982. 9. Towner D, Castro MA, Eby-Wilkens E, et al.: Effect of mode of delivery in nulliparous women on neonatal intracranial injury. N Engl J Med 341:1709, 1999.

Fig. 7-33. Schematic of the bony exostoses of the inferior occiput (arrow) seen in the occipital horn syndrome (Ehlers-Danlos type IX).

Skull

abnormal fetal positions, such as transverse lie, face presentation, or brow presentation (Section 7.16), the forehead may be compressed. Hence, any constraining fetal position that retroflexes the head against the posterior neck and shoulders can result in bathrocephaly. Other anomalies related to breech presentation are often present, and these include dislocated hips, clubfoot, or uplifted ear lobes. In general, this anomaly is of no significance, and spontaneous improvement usually occurs. Prognosis is poor only if breech position is secondary to malformation or neurologic dysfunction.2 Occipital Horns

Occipital horns are bony protuberances situated on both sides of the foramen magnum and pointing caudad (Fig. 7-33). They have

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only been described in individuals with an X-linked syndrome that also includes obstructive uropathy, joint laxity, and other features of Ehlers-Danlos type IX.3 References (Miscellaneous Anomalies of the Skull) 1. Silverman FN: Caffey’s Pediatric X-Ray Diagnosis, ed. 8. Year Book Medical Publishers, Chicago, 1985, p 25. 2. Haberkorn CM, Smith DW, Jones KL: The ‘‘breech head’’ and its relevance. Am J Dis Child 133:154, 1979. 3. Lazoff SG, Rybak JJ, Parker BR, et al.: Skeletal dysplasia, occipital horns, intestinal malabsorption, and obstructive uropathy—a new hereditary syndrome. Birth Defects Orig Artic Ser XI(5):71, 1975.

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8 Facial Bones Karen Gripp and Luis Fernando Escobar

H

umans are very adept at recognizing one another. This ability is largely based on the identification of faces. The uniqueness of each human face, with the possible exception of monozygotic twins, allows for identification and recognition of an individual with deeper implications in human interaction and, more important, in social functioning. The recognition of an individual face, whose combination of features is remembered as belonging to a certain person, may be compared to the recognition of a syndrome diagnosis based on certain characteristics of the facial structures. The shape of individual facial structures can be recognized, but the combination of findings may lead to the identification of a facial ‘‘gestalt’’ that may be associated with a genetic syndrome. On a more formal level, anthropometric measurements of facial structures may be taken, and profiles of these measurements can be constructed. Facial indexes such as those developed by Blumenbach and Camper in the eighteenth century demonstrate the fascination that the facial bones provoked in early ‘‘dysmorphologists.’’ Attempts to objectively recognize the abnormal from the normal facial appearance have led to the development of dysmorphic indexes.1 Today, computer-driven facial recognition uses the correlation of the measurements to identify individual faces or to identify a pattern known to be characteristic for a specific syndrome. Based on consistent patterns of age-dependent growth and maturation of facial structures, facial photographs may be manipulated to predict the changes with age. The human facial form results from the interaction between the skeletal and soft tissue elements. The skeletal framework provides the structural support of the face and is largely responsible for size, shape, and proportions of each facial structure.2,3 Anomalies such as cyclopia or proboscis are clearly associated with structural abnormalities of the facial skeleton; however, more subtle facial anomalies may lack evident skeletal findings that would be identifiable only on facial radiographs or other imaging studies. Consistent differences in the facial bony structures may underlie the characteristic facial findings that would allow syndrome recognition. The face may be conveniently divided into thirds—the upper, middle, and lower—delimited by horizontal planes passing through the pupils of the eyes and the rima oris. The three parts correspond generally to the embryonic frontonasal, maxillary, and mandibular processes, respectively. The upper third of the face is predominantly of neurocranial composition. The middle third is

skeletally complex, composed in part of the cranial base, and involves both the nasal extension from the upper third of the face (frontonasal process) and the maxillary processes from the first branchial arch. The lower third is composed skeletally of the mandible. Although these three segments develop through similar embryologic processes, their individual origins differ. The form of the facial bones is not as dependent on brain development as are the calvarial bones. Anencephaly, for example, presents with no calvarial bones but relatively good formation of the cranial base and skeletal facial structures. The various facial bones are derived as portions of the neurocranium, chondrocranium, or viscerocranium. These skeletal elements have neural crest or paraxial mesodermal origins. The chondrocranium is the cartilaginous precursor of the cranial base and the capsules surrounding the nasal and auditory organs. The base of the skull becomes part of the neurocranium, the bony tissue that surrounds the brain. The cranial base ossifies endochondrally, while the vault undergoes intermembranous ossification. The viscerocranium is comprised of neural crest-derived bones of the jaws (maxilla and mandible) as well as the zygoma (part of the temporal bone), nasal, and lacrimal bones. The teeth, with the exception of their enamel, which is ectodermally derived, are also comprised of neural crest cells. Craniofacial development is an extremely complex process that requires a perfectly organized interaction and integration between multiple specialized tissues, such as ectoderm, neural crest, mesoderm, and pharyngeal endoderm. The complex mechanisms and molecular cascades continue to be an enigmatic process. It has not been until recent years that molecular biologists have been able to focus on specific mechanisms involved in craniofacial development.4–6 We are beginning to understand some of these mechanisms, such as those that involve fibroblast growth factor or nodal signaling and the role of homeobox genes. The complex interplay of numerous signaling cascades controls the proliferation and differentiation of specific cell populations. A thorough understanding of these developmental events is essential to defining the basis for the patterning of individual facial bones and their relative positioning. This chapter includes information regarding the most common defects that affect the facial skeleton. We review their 267

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frequency and their involvement in specific syndromic disorders. We limit our discussion to the frontal bones, orbits, zygomas, the nasal skeletal area, the maxillary structures, and the mandible.

into a triangular shape, leading to trigonocephaly. The orbits assume an excessively mesial position, which may be apparent as ocular hypotelorism.

References

Diagnosis

1. Escobar LF, Bixler D, Padilla LM: Quantitation of craniofacial anomalies in utero: fetal alcohol, Crouzon syndromes and Thanatophoric dysplasia. Am J Med Genet 45:25, 1993. 2. Friede H: Normal development and growth of the human neurocranium and cranial base. Scand J Plast Reconstr Surg 15:163, 1981. 3. Lavelle CL: An analysis of foetal craniofacial growth. Ann Hum Biol 1:269, 1974. 4. Trainor PA: Making headway: the roles of hox genes and neural crest cells in craniofacial development. Scientific WorldJournal 3:240, 2003. 5. David NB, Saint-Etienne L, Tsang M, et al.: Requirement for endoderm and FGF3 in ventral head skeleton formation. Development 129:4457, 2002. 6. Couly G, Creuzet S, Bennaceur S, et al.: Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head. Development 129:1061, 2002.

8.1 Premature Metopic Sutural Synostosis Definition

Premature metopic sutural synostosis is the premature fusion of the metopic suture in utero. It deforms the anterior cranial fossa

Premature metopic sutural synostosis is characterized by the presence of a keel-like ridge at the site of the metopic suture. The head, viewed from above, appears triangular (Fig. 8-1). Physical examination of the affected individual may show a vertical bony ridge of the forehead that coincides with the anatomic midline. Due to bony hypotelorism, the superolateral aspect of the orbits is positioned more mesially and posteriorly than normal. The occiput bulges with compensatory expansion to accommodate brain growth.1 In patients in whom metopic synostosis is suspected, radiologic confirmation is obligatory. Hypotelorism characterizes the anteroposterior skull films, in addition to low-set lateroinferior orbital angles. The roof of the orbits seems to be highly placed in relation to the horizontal plate of the ethmoid bone. Computerized tomography (CT) may show compression of the anterior cranial fossa and the cribriform plate in the midline.1 When 3-D CT study is used to identify metopic synostosis, it is important to note that physiologic metopic closure occurs between 3 and 9 months of age; closure earlier than 3 months should be suspected abnormal.2 The spectrum of facial morphology associated with metopic synostosis is broad, from minor prominence of the forehead to severe aesthetic deformity.

Fig. 8-1. A. Preoperative right lateral, frontal, and top views of the craniofacies in a patient with isolated premature metopic synostosis. B. Right lateral, frontal, and top views of patient 3 months after surgical correction. Note the reduction of hypotelorism. (From Marsh and Vannier.1)

Facial Bones

Two types of premature metopic sutural synostosis can be recognized. Isolated metopic synostosis occurs at a rate of approximately 0.3 per 1000 live births and is usually sporadic. In the second type, metopic synostosis is associated with multiple congenital anomalies.3 These anomalies include aortic stenosis, tetralogy of Fallot, omphalocele, cleft palate, hypospadias, multiple hemivertebrae, congenital abducens nerve palsies, absence of the corpus callosum, and agenesis of the septum pellucidum.1 It is not clear at present whether the different phenotypical combinations seen in these patients represent different conditions or belong together in a wide spectrum of abnormalities with a single etiology. Mental retardation is rarely seen as part of isolated early metopic sutural synostosis. There is no evidence that a disturbance in brain growth as a result of the cranial deformity contributes to the retardation occasionally seen. Syndromes that include metopic synostosis are listed in Table 8-1. Etiology and Distribution

As with any other type of early synostosis, early metopic fusion may lead to a sequence of developmental abnormalities. In this case, striking changes in the facial skeleton may result. Unfortunately, the mechanism that prematurely initiates this normal process of development is unknown. During fetal life the two frontal bones are separated by a sutural space, which consists of fibrous tissue and mesenchymal cells responsible for the growth of the frontal bones. This mesenchymal tissue has the potential to differentiate either into bone or into secondary cartilage.12 For the metopic suture, it is suggested that closure of the sutural space is due to the differentiation of the mesenchyme into chondroid tissue instead of bone. The chondroid tissue, then, is responsible for the growth of each frontal bone toward the other and constitutes the first bridge of union between the two bones.13 Active bone resorption prevents

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this primary union from closing prematurely. Any interruption either during mesenchymal differentiation or in the maintenance of an open sutural space can lead to premature metopic synostosis. It has been suggested that absence of interosseous movement might lead to sutural fusion. Experimental evidence seems to support this; immobilization of adjacent bone by cyanoacrylate glue, bone grafting, or periosteal grafting induces synostosis.14 This also would be consistent with the occurrence of metopic synostosis in infants with intrauterine constraint of the cranium due to uterine malformation or twinning.15 Teratogens causing trigonocephaly include valproic acid and hydantoin (Table 8-1).7,16 Metopic synostosis constitutes 4–10% of all cases of craniosynostosis,1,17,18 and male to female ratios of 3:4 and 2:3 have been reported.17 Prognosis, Treatment, and Prevention

Early surgical intervention strikingly improves the growth of the facial skeleton in isolated metopic synostosis.19–21 Bicoronal craniectomies can be helpful to free the frontal bones, with excision of the keel down to the frontonasal suture. Orbital advancement may be necessary to restore a normal brow contour. Straightening of the supraorbital bar and reshaping of the forehead using variations according to the deformity are very satisfactory. Following this procedure, hypotelorism tends to disappear clinically and diminishes radiologically.21 Recent forensic findings in Salzburg, Austria, suggest that the great musician Wolfgang Amadeus Mozart had premature synostosis of the metopic suture.22 This was characterized, in his case, by mild hypotelorism, reduction of the orbital volume, and a supraglabellar sulcus divided in the midline by a small protuberance that formed a ridge near the nasion. The prognosis of affected individuals is very encouraging, and, unless seen in multiple anomaly syndromes, metopic synostosis should

Table 8-1. Syndromes associated with premature metopic suture synostosis Causation Gene/Locus

Syndrome

Prominent Features

Baller-Gerold4

Growth deficiency, craniosynostosis, radial aplasia/hypoplasia, short curved ulna, missing small bones of the hands, imperforate anus, anteriorly placed anus, mental deficiency (50%)

Chromosome abnormalities5

Multiple congenital anomalies, learning differences

Abnormal karyotype

Deletion 9p6

Craniosynostosis, trigonocephaly, midfacial hypoplasia, short nose, anteverted nares, long philtrum, poorly formed ears, extra digital flexion creases, excess in whorl patterns, heart defect

(158170) Abnormal karyotype

Hydantoin, prenatal7

Growth deficiency, ocular hypertelorism, broad nasal bridge, short nose, clefting, hypoplasia of distal phalanges, low arch dermal ridges, digitalized thumb, short neck, rib anomalies, variable mental function

(132810) Hydantoin teratogenesis

Jacobsen8

Low-set ears, ptosis, congenital heart disease, hypospadias, labial and clitoral hypoplasia, joint contractures, hypotonia, mental retardation, thrombocytopenia

(147791) Monosomy 11q23-qter

Opitz-C9

Craniosynostosis, narrow bifrontal diameter, microcornea, short broad nose, long philtrum, thin lips, high arched palate, micrognathia, rhizomelic shortening and postaxial hexadactyly of all limbs, thin ribs, humeral and femoral shortening

(211750) Unknown

Saethre-Chotzen10

Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue syndactyly, hallux valgus

AD (101400) TWIST, 7p21

Trigonocephaly-short staturedevelopmental delay11

Marked frontal vertical ridge, narrow forehead, hypertelorism, growth retardation, variable mental development

XL (314320)

Trigonocephaly, isolated5

Craniosynostosis limited to the metopic region, giving a prow appearance to the forehead, normal brain development

AD (190440, 275600)

AR (218600)

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Craniofacial Structures

be considered a relatively benign form of craniofacial synostosis. No reports of prenatal diagnosis of metopic synostosis can be found in the literature, but ultrasonography may be helpful in detecting this abnormality via fetal cephalometry and detection of unusual craniofacial shape. Prevention methodology is limited to prenatal counseling. References (Premature Metopic Sutural Synostosis) 1. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. JL Marsh, MW Vonnier, WG Stevens, eds. CV Mosby, St. Louis, 1985, p 154. 2. Vu HL, Panchal J, Parker EE, et al.: The timing of physiologic closure of the metopic suture: a review of 159 patients using reconstructed 3D CT scans of the craniofacial region. J Craniofac Surg 12: 527, 2001. 3. Lajeunie E, Le Merrer M, Marchac D, et al.: Syndromal and nonsyndromal primary trigonocephaly: analysis of a series of 237 patients. Am J Med Genet 75:211, 1998. 4. Cohen MM Jr, Toriello HV: Is there a Baller-Gerold syndrome? Am J Med Genet. 61:63, 1996. 5. Azimi C, Kennedy SJ, Chitayat D, et al.: Clinical and genetic aspects of trigonocephaly: a study of 25 cases. Am J Med Genet 117A:127, 2003. 6. Deroover J, Fryns JP, Parloir C, et al.: Partial monosomy of the short arm of chromosome 9: a distinct clinical entity. Hum Genet 44:195, 1978. 7. Hanson JW, Myrianthopoulos NC, Sedgwick MHA, et al.: Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 89:662, 1976. 8. Penny LA, Dell’Aquila M, Jones MC, et al.: Clinical and molecular characterization of patients with distal 11q deletions. Am J Hum Genet 56:676, 1995. 9. Lalatta F, Clerici Bagozzi D, Salmoiraghi MG, et al.: ‘C’ trigonocephaly syndrome: clinical variability and possibility of surgical treatment. Am J Med Genet 37:451, 1990. 10. Paznekas WA, Cunningham ML, Howard TD, et al.: Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet 62:1370, 1998. 11. Say B, Mayer J: Familial trigonocephaly associated with short stature and developmental delay. Am J Dis Child 135:711, 1981. 12. Hall BK: Tissue interactions and chondrogenesis. In: Cartilage: Development, Differentiation and Growth, vol. 2. BK Hall, ed. Academic Press, New York, 1983, p 188. 13. Manzanares MC, Goret-Nicaise M, Dhem A: Metopic sutural closure in the human skull. J Anat 161:203, 1988. 14. Engstrom C, Kiliaridis S, Thilander B: Facial suture synostosis related to altered craniofacial bone remodelling induced by biochemical forces and metabolic factors. In: Normal and Abnormal Bone Growth: Basic and Clinical Research. AD Dixon, BG Sarnat, eds. Alan R. Liss, Inc., New York, 1985, p 379. 15. Graham JM Jr, Smith DW: Metopic craniosynostosis as a consequence of fetal head constraint: two interesting experiments of nature. Pediatrics 65:1000, 1980. 16. Lajeunie E, Barcik U, Thorne JA, et al.: Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg 95:778, 2001. 17. Cohen MM Jr: Craniosynostosis and syndromes with craniosynostosis: incidence, genetics, penetrance, variability and new syndrome updating. Birth Defects Orig Artic Ser XV(5B):13, 1979. 18. Shuper A, Merlob P, Grunebaum M, et al.: The incidence of isolated craniosynostosis in the newborn infant. Am J Dis Child 139: 85, 1985. 19. Dhellemmes P, Pellerin PH, Lejune JP, et al.: Surgical treatment of trigonocephaly. Childs Nerv System 2:228, 1986. 20. Anderson FM, Gwinn JL, Todt JC: Trigonocephaly: identity and surgical treatment. J Neurosurg 19:723, 1962. 21. Marchac D: Early surgery in craniofacial synostosis. In: Craniofacial Surgery. EP Caronni, ed. Little, Brown and Co., Boston, 1985, p 246. 22. Puech B, Puech PF, Tichy G, et al.: Craniofacial dysmorphism in Mozart’s skull. J Forensic Sci 34:487, 1989.

8.2 Orbital Hypotelorism Definition

Orbital hypotelorism is the decreased measurement between the bony orbits, determined by decreased bony interorbital measurement and decreased interpupillary measurement. Cyclopia represents the most severe form of orbital hypotelorism. Diagnosis

Orbital hypotelorism encompasses a wide spectrum of abnormalities ranging from mild reduction of the interorbital measurement to complete fusion of the orbits. Even though simple clinical inspection can detect orbital hypotelorism in the majority of cases, inner canthal measurements are very useful in the recognition of mild forms (Fig. 8-2).1 In contrast to orbital hypertelorism, inner canthal measurements are very helpful as an indicator of reduced space between interorbital walls. More accurate measurements can be made from the posteroanterior radiographs of the skull when direct evaluation is possible. Orbital hypotelorism can result from abnormalities in several developmental events. Although it may be seen as an isolated feature reflecting one end of the spectrum of continuous variation in facial structure, the clinician should methodically search for associated anomalies. Since orbital hypotelorism is consistently found in association with holoprosencephaly, this possibility should always be considered.2,3 Additional facial findings associated with holoprosencephaly include absence of the upper frenulum and a single upper medial incisor. These subtle findings can be present in otherwise healthy carriers of mutations predisposing to holoprosencephaly, for example, in sonic hedgehog (SHH), and may allow the identification of affected family members, suggesting an autosomal dominant inheritance pattern. The most severe form of orbital hypotelorism is seen in cyclopia, ethmocephaly, and cebocephaly, which are among the arrhinencephalic defects.4 Cyclopia is the fusion of the orbits into a single ring, which may encircle a wide range of intraorbital anomalies (Fig. 8-3). Several chromosomal abnormalities have been associated with cyclopia, including del 18p,5 del 2p,6 partial trisomy 3p, and partial trisomy 7q.7 In ethmocephaly, severe ocular hypotelorism occurs together with a blind-ended proboscis located between the eyes; this differs from cebocephaly, which presents with a blind-ended single nostril nose. In addition to the association with holoprosencephaly, orbital hypotelorism can be seen in maternal phenylketonuria, CoffinSiris, Langer-Giedion, Meckel-Gruber, and Williams syndromes (Table 8-2). Chromosomal abnormalities such as trisomy 13 and trisomy 20p have also been associated with reduction of the interorbital measurement.16 In some cases, clefting disorders (cleft lip and palate) are associated with some degree of orbital hypotelorism.17 An autosomal dominant form of ocular hypotelorism with submucosal cleft palate and hypospadias was recognized by Shilbach and Rott18 in a five-generation family with 10 affected individuals. Pashayan and Lewis19 described a patient with hypotelorism, nasomaxillary hypoplasia, and cleft lip and palate. The patient had normal neurologic structures and development. Another case was reported by Joss et al. in 2002.20 This rare entity was confirmed by Stark,21 who reported a similar case.

Facial Bones

271

Fig. 8-2. Standard curves for outer canthal, inner canthal, and interpupillary measurements. Data from a study population of 2403 newborns to children 14 years of age (56% male, 44% female; 2006 white, 206 black, 43 Asian). (From Feingold and Bossert.12)

Other developmental abnormalities that involve mechanical influences on the final position of the orbits include craniosynostotic processes such as premature closure of the metopic suture.

Etiology and Distribution

Hypotelorism results from excessive medial migration of the orbits due to inadequate development of the frontal-cribriform area, as a result of either metopic craniosynostosis or neural hypoplasia

272

Craniofacial Structures

Fig. 8-3. Hypotelorism associated with holoprosencephaly, absent nasal structures, and median cleft in trisomy 13 (left). At right is an infant with cyclopia and proboscis. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.) Table 8-2. Syndromes with orbital hypotelorism Causation Gene/Locus

Syndrome

Prominent Features

Coffin-Siris8

Growth deficiency, variable mental development, mild microcephaly, coarse facies with full lips, hypoplastic to absent fifth finger, radial dislocation at elbow, coxa valga, general hirsutism

(135900)

Holoprosencephaly9

Deficit of midline facial development, incomplete morphogenesis of the forebrain, cyclopia, olfactory placodes consolidated into single tubelike proboscis above the eye

Heterogeneous, including maternal diabetes (600725) SHH, 7q36 (603073) ZIC2, 13q32 (603714) SIX3, 2p21 (602630) TGIF, 18p11.3

Langer-Giedion10

Growth deficiency, mild to severe mental deficiency, microcephaly, heavy eyebrows, deep-set eyes, sparse scalp hair, redundancy of the skin, cone-shaped epiphyses, brittle nails, multiple exostoses, syndactyly, tendency to fractures

AD (150230) microdeletion 8q24.11-q24.13

Phenylketonuria, maternal11

Mental deficiency, growth deficiency, round facies, strabismus, smooth philtrum, small upturned nose, mandibular hypoplasia, congenital heart disease

Maternal metabolic disturbance

Kallmann12

Anosmia, hypogonadotropic hypogonadism, short stature, sensorineural hearing loss, mental retardation

Heterogeneous (147950, 308700, 244200) FGFR1, 8p11

Meckel-Gruber13

Growth deficiency, posterior encephalocele, microcephaly, cerebellar hypoplasia, microphthalmia, cleft palate, ear anomalies, polydactyly, bile duct proliferation, fibrosis and cysts of the kidneys and liver, cryptorchidism, incomplete development of external and/or internal genitalia

(AR 249000) 17q22-q23 and other loci

Smith-Lemli-Opitz14

Elevated 7-dehydrocholesterol, microcephaly, epicanthus, ptosis, cardiac defects, postaxial polydactyly, increase of whorls on dermatoglyphic pattern, hypospadias, syndactyly of toes 2 and 3, failure to thrive, mental retardation

AR (270400) DHCR7, 11q12-q13

Trisomy 1315

Holoprosencephaly, microcephaly, iris colobomata, microphthalmia, retinal dysplasia, cleft lip and palate, distal proximal triradii, camptodactyly, congenital heart disease, cryptorchidism, bicornuate uterus

Abnormal karyotype

Facial Bones

(the holoprosencephaly series). Since orbital hypotelorism is often part of a multiple congenital anomalies disorder, the incidence, sex ratio, and recurrence risk are variable, depending on the underlying cause. When hypotelorism occurs as part of the holoprosencephaly spectrum, the underlying cause for the holoprosencephaly may be identifiable. A chromosome anomaly or gene mutation may be identified, allowing for testing of at-risk family members and appropriate counseling. Human teratogens causing holoprosencephaly include maternal diabetes, alcohol, retinoic acid, and possibly drugs interfering with cholesterol metabolism.22,23 The autosomal recessive Smith-Lemli-Opitz syndrome,14 due to an enzymatic block of the last step of cholesterol biosynthesis, represents a rare cause of holoprosencephaly (Table 8-2). Prognosis, Treatment, and Prevention

Patients affected with cyclocephalic disorders have severe malformations of the brain that result in developmental delay. Depending on the extent of the defect, these individuals may not survive the neonatal period or infancy. The mild forms of orbital hypotelorism do not cause visual impairment and have few clinical implications. They usually do not require surgical correction, except for aesthetic reasons. Prenatal diagnosis is possible by ultrasonography, by interorbital measurement.6 The presence of orbital hypotelorism should alert the ultrasonographer to search for other fetal anomalies. Reproductive genetic counseling is the only means of prevention and should be individualized to each case. Recurrence figures can be estimated according to the inheritance pattern of the primary defect. References (Orbital Hypotelorism) 1. Feingold M, Bossert WH: Normal values for selected physical parameters. Birth Defects Orig Artic Ser X(13):1, 1974. 2. Sedano HO, Gorlin RJ: The oral manifestations of cyclopia. Oral Surg Oral Med Oral Pathol 16:823, 1963. 3. Roulatt V, Pruzansky S: Premaxillary agenesis, ocular hypotelorism, holoprosencephaly and extracranial anomalies in an infant with a normal karyogram. Cleft Palate J 17:197, 1980. 4. Cohen MM Jr: An update of holoprosencephalic disorders. J Pediatr 101:865, 1982. 5. Klein VR, Harrod MJE, Brown CEL, et al.: Prenatal diagnosis of cyclopia. Proc Greenwood Genet Center 6:138, 1987. 6. Grundy HO, Niemeyer P, Rupani MK, et al.: Prenatal detection of cyclopia associated with interstitial deletion 2p. Am J Med Genet 34:268, 1989. 7. Burrig KF, Gebaner J, Terinde R, et al.: Case of cyclopia with an unbalanced karyotype attributable to a balanced 3/7 translocation. Clin Gen 35:262, 1989. 8. Carey JC, Hall BD: The Coffin-Siris syndrome: five cases including two siblings. Am J Dis Child 132:667, 1978. 9. Cohen MM Jr: Malformations of the craniofacial region: evolutionary, embryonic, genetic, and clinical perspectives. Am J Med Genet 115: 245, 2002. 10. Ludecke HJ, Wagner MJ, Nardmann J: Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. Hum Molec Genet 4:31, 1995. 11. Sweeney E, Fryer A: Nasomaxillary hypoplasia and severe orofacial clefting in a child of a mother with phenylketonuria. J Inherit Metab Dis 25:77, 2002. 12. Dode C, Levilliers J, Dupont JM, et al.: Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33:463, 2003. 13. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997. 14. Cunniff C, Kratz LE, Moser A, et al.: Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet 68:263, 1997.

273

15. Delatycki M, Gardner RJ: Three cases of trisomy 13 mosaicism and a review of the literature. Clin Genet 51:403, 1997. 16. Taybi H: Radiology of Syndromes and Metabolic Disorders, ed 2. Year Book Medical Publishers, Chicago, 1983, p 444. 17. Ben-Hur N, Ashur H, Mieurreri M: An unusual case of median cleft lip with orbital hypotelorism—a missing link in the classification. Cleft Palate J 15:365, 1978. 18. Shilbach U, Rott HD: Ocular hypotelorism, submucosal cleft palate and hypospadias: a new autosomal dominant syndrome. Am J Med Genet 31:863, 1980. 19. Pashayan HM, Lewis MB: Hypotelorism, nasomaxillary hypoplasia and cleft lip and palate in a patient with normocephaly and normal intelligence—a case report. Cleft Palate J 17:62, 1980. 20. Joss SK, Paterson W, Donaldson MD, et al.: Cleft palate, hypotelorism, and hypospadias: Schilbach-Rott syndrome. Am J Med Genet 113:105, 2002. 21. Stark DB: Hypotelorism, nasomaxillary hypoplasia and cleft lip and palate in a patient with normocephaly and normal intelligence, a case report (letter). Cleft Palate J 17:262, 1980. 22. Cohen MM, Shiota K: Teratogenesis of holoprosencephaly. Am J Med Genet 109:1, 2002. 23. Edison RJ, Muenke M: Central nervous syndrome and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 350: 1579, 2004.

8.3 Orbital Hypertelorism Definitions

Orbital hypertelorism is the excessive separation of the medial walls of the bony orbits. As with other growth parameters, the interorbital measurement is age-related, with an increase from approximately 16 mm at birth to approximately 27 mm in adult life. Orbital hypertelorism is present when the interorbital measurement exceeds 2 standard deviations (SD) above the mean. In the adult, the upper limit of normal is approximately 30 mm. Ocular Hypertelorism

Ocular hypertelorism is the increased space between the eyes as determined by interpupillary measurement. Determination of ocular hypertelorism using interpupillary measurement requires that the eyes be properly aligned. Alternatively, ocular hypertelorism can be assumed if the interorbital measurement is greater than 2 SD above the mean and the eyes are of normal size. Telecanthus

Telecanthus is the increased measurement between the inner canthi but with normally spaced eyes. Telecanthus results from lateral displacement of the inner canthus and lacrimal punctae. The iris is shifted medially from its normally central position in the palpebral aperture. Graphs with the normal range of intraorbital, interpupillary, and inner canthal measurements have been prepared by several groups of investigators (Fig. 8-2).1–6 Diagnosis

The term hypertelorism was probably introduced in 1924 by Greig7 to describe a discrete condition with excessive separation of the eyes. It is often used indiscriminately to convey the impression that the eyes are widely spaced. The experienced observer can usually detect true orbital hypertelorism and ocular hypertelorism by simple inspection (Fig. 8-4). This, however, is not always the case. The clinician can be confused by the impression of hypertelorism produced by

274

Craniofacial Structures

(Fig. 8-5). It often represents the mildest form of midline facial clefting. Over 200 malformation syndromes include orbital hypertelorism; Table 8-3 lists the most common of these syndromes. Orbital and ocular hypertelorism usually coexist. It is possible, however, for the eyes to be displaced laterally by encroachment into the orbital space by tumor, neural tissue, or ethmoid air cells, with normal interorbital measurement.35 Etiology and Distribution

Fig. 8-4. Isolated ocular hypertelorism in a 9-year-old male without associated defects (Greig hypertelorism).

telecanthus in the presence of normal interorbital and interpupillary measurements. Diagnosis of orbital hypertelorism requires radiologic studies to confirm the presence of a wide separation of the orbits. Because of involvement of soft tissue, the determination of the measurement between the bony orbital walls is difficult. Several quantitative methods such as inner canthal measurement, interpupillary measurement, canthal index, and circumference interorbital index have been used in an attempt to establish the position of the orbits in relation to each other.1 Of the various methods for determining orbital hypertelorism, the preferable one probably is the interorbital measurement as determined directly from posteroanterior skull radiographs.4 Values 2 SD or greater above the mean compared with Tessier data are diagnostic of orbital hypertelorism. The use of computed tomography (CT) to measure interorbital space has been investigated.8 However, the high cost may limit its use for assessment of orbital hypertelorism. On the other hand, CT scanning allows study of the orbital contents with respect to the bony orbit. It allows independent measurement for each globe, which is necessary to uncover asymmetric displacement that could lead to binocular stereoscopic vision and other visual complications. Orbital hypertelorism may be an isolated craniofacial characteristic, but this is uncommon.9,10 Usually it is a component of one of numerous multiple congenital anomaly syndromes

During early stages of embryonic life, the eyes extend laterally as evaginations of the forebrain. Differential growth, occurring prior to ossification of the bones of the skull, results in convergence toward the facial midline from this primitive lateral position. Aberrations in this differential growth affect the position of the orbits. Since orbital hypertelorism is a characteristic finding in several craniofacial malformation syndromes that involve different pathogenicities, there is no identifiable single mechanism that leads to the disorder. Three main mechanisms have been postulated to produce orbital hypertelorism.4,36 The first possible mechanism is a time-specific deficiency in differential growth, with a primary effect on the forebrain and optic primordia or their supporting tissues. The second possible mechanism is migration being interrupted due to the presence of a midline lesion, such as a nasoencephalocele, which inhibits the progressive medial approximation of the orbits. A third proposed mechanism is the occurrence of a parallel pathologic process on the cranial base (secondary to craniosynostosis, for example) that could separate the orbits during intrauterine life and persist through early postnatal growth. Isolated hypertelorism is rare and usually occurs in a sporadic form. Apparently dominant and recessive cases have been reported; however, the sexes appear to be equally affected. Syndromic hypertelorism has many causes (Table 8-3), and the recurrence risks depend on the cause. As the genes causally involved in these syndromes are identified, it becomes clear that many of them encode transcription factors active in early embryologic development. The gene product encoded by the cleidocranial dysplasia gene is a transcription factor essential for cell proliferation and differentiation,37 whereas the transcription factor encoded by the Greig syndrome gene (GLI3) acts as a repressor of signaling through FGF838 and sonic hedgehog (see Section 8.2). Of note, the protein product encoded by the gene involved in Gorlin syndrome (Table 8-3) is a cell membrane bound receptor for sonic hedgehog. In contrast to these molecules involved in transcription and the sonic hedgehog signaling pathway, mutations affecting proteins involved in the cytoskeletal organization, such as filamin A (OPD spectrum disorders, Table 8-3), are more likely to result in structural malformations by abnormal cell migration.29 In a review of patients with a primary presenting diagnosis of hypertelorism, excluding patients with syndromic craniosynostosis or cleft lip, the most common cause was frontonasal dysplasia, followed by craniofrontonasal dysplasia.39 Numerous chromosome aberrations cause orbital hypertelorism. These include XXXXY syndrome, trisomy 22, trisomy 13, deletion 4p, deletion 5p, and deletion 17p. Teratogenic exposures associated with hypertelorism include hydantoin, warfarin, and aminopterin. Prognosis, Treatment, and Prevention

The prognosis of the patient with bony orbital hypertelorism depends on the primary defect. Multiple congenital anomaly

Facial Bones

275

Fig. 8-5. Ocular hypertelorism in a 26-month-old male with Aarskog syndrome showing triangular face, broad forehead, and widow’s peak (A); in an infant girl with bifid nose (B); in an infant girl with median cleft face (C); and in an adult with frontonasal dysplasia showing broad nose and widow’s peak (D). (B and C courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

syndromes that severely affect the orbital area may represent major surgical challenges requiring multiple interventions. Orbital hypertelorism is classified into three different categories according to the interorbital measurement. Each category is treated surgically in a different manner. First-degree orbital hypertelorism (interorbital distance [IOD] between 30 and 34 mm) can be corrected by rhinoplasty, correction of the epicanthal folds, or both. Second-degree orbital hypertelorism (IOD between 34 and 40 mm) can be corrected by extracranial osteotomy. Thirddegree orbital hypertelorism (IOD greater than 44 mm) requires an intracranial approach.40 Surgical correction rests on transposition of the portion of the orbit that must be moved to effect a movement of the globe. This procedure can be done with excellent

results during early infancy. Early intervention results in a normal appearance, which minimizes the psychological problems for the patient. Prognosis should be individualized according to the primary defect involved. Prenatal diagnosis of orbital hypertelorism is possible with real-time ultrasonography. Normal standards have been established by different investigators, with similar results.41–43 Figure 8-6 shows a coronal section of the fetal craniofacies at 18 weeks gestation from our normal sample. Landmarks for determining the interorbital measurement have been identified. In the presence of fetal orbital hypertelorism, along with an accurate last menstrual period date, the clinician should investigate the possibility of associated birth defects.

Table 8-3. Syndromes associated with orbital hypertelorism Causation Gene/Locus

Syndrome

Prominent Features

Aarskog11

Moderate short stature, rounded facies, ptosis, slight downward-slanting palpebral fissures, small nose, anteverted nostrils, hypodontia, brachydactyly, mild interdigital webbing, mild pectus, shawl scrotum

XL (305400) FGD1, Xp11.21

Acrocallosal12

Growth and mental deficiency, agenesis of the corpus callosum, preaxial polydactyly, syndactyly, prominent forehead and occiput, hypoplastic midface

AR (200990)

Acrodysostosis13

Growth deficiency and mental deficiency, brachydactyly, low nasal bridge, upturned small nose, short and broad hands

(101800)

Cat eye14

Mental deficiency, inferior coloboma of the iris, micrognathia, cardiac defects, anal atresia, rectovesicular fistula, renal agenesis

(115470) Partial tetrasomy 22 due to inv dup (22)(q11)

Cleidocranial dysplasia15

Wide, late-closing fontanel; depressed nasal bridge; supernumerary teeth; hypoplastic clavicles; minor skeletal abnormalities; mild short stature

AD (119600) CBFA1(RUNX2), 6p21

Craniofrontonasal16

Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal grooves and splits in nails

XL (304110) EFNB1, Xq12

Coffin-Lowry17

Downslanting palpebrae, open mouth with thick lips, growth and mental deficiency, pectus anomalies, wide hands with tapering digits, hyperextensible joints, drop attacks

XL (303600) RSK2, Xp22.2-p22.1

Donnai-Barrow18

Diaphragmatic hernia, exomphalos, absent corpus callosum, iris coloboma, myopia, sensorineural deafness

AR (222448)

Escobar19

Small stature, inner canthal folds, micrognathia, cleft palate, expressionless face, multiple large joint pterygia, camptodactyly, syndactyly, cryptorchidism

AR (265000)

Frontonasal dysplasia20

Lateral displacement of inner canthi, widow’s peak, broad nasal bridge, hypoplasia to absence of the prolabium, premaxilla

(136760)

Gorlin21

Macrocephaly, odontogenic keratocysts, basal cell nevi, palmar pits, mental retardation, medulloblastoma

AD (109400) PTCH, 9q22.3

Greig cephalopolysyndactyly22

High forehead, frontal bossing, macrocephaly, broad nasal root, postaxial polydactyly, broad thumbs, syndactyly, preaxial polydactyly of toes

AD (175700) GLI3, 7p13

Killian/Teschler-Nicola23

Obesity, short stature, seizures, hypotonia, deafness, sparse anterior scalp hair, delayed dental eruption, large ears, flat broad nasal root, coarse face, long philtrum, thin upper lip, short neck, broad hands with short digits, diaphragmatic hernia

Tetrasomy 12p

Larsen24

Flat facies; depressed nasal ridge; prominent forehead; dislocations of elbow, wrist, and knee; dysplastic epiphyseal centers; spatulate thumbs; short nails; short metacarpals; talipes equinovarus; cervical vertebrae hypoplasia

Heterogeneous (150250, 245600, 245650) 3p21.1-p14.1 for AD form

Lenz-Majewski25

Short stature, variable mental development, prominent forehead, late closure of fontanels, proptosis, choanal stenosis, cutis laxa, cutaneous syndactyly, sparse hair, dysplastic enamel, proximal symphalangism, absent middle phalanges, long and flared metaphyses

(151050)

Multiple lentigines (LEOPARD)26

Lentigines, prominent ears, ptosis, short neck, pulmonic stenosis, ECG abnormalities, short stature

AD, allelic to Noonan (151900) PTPN11, 12q24.1

Neu-Laxova27

Microcephaly, lissencephaly, absence of corpus callosum, absence of olfactory bulbs, absence of lids, flattened nose, gaping mouth, micrognathia, short neck, transparent scaling skin, ichthyosis, short limbs, syndactyly of fingers and toes, poorly mineralized bones, cataracts, microphthalmia, absence of eyelashes and scalp hair

AR (256520)

Noonan28

Short stature, variable mental impairment, epicanthal folds, ptosis, downslanting palpebrae, low-set and abnormally shaped ears, webbed neck, shield chest, pectus carinatum and/or excavatum, cubitus valgus, pulmonary valve stenosis, cryptorchidism, bleeding tendency, multiple giant cell lesions

AD (163950) Heterogeneous PTPN11, 12q24.1

Oto-palato-digital (OPD) spectrum29

OPD type 2: growth deficiency, large anterior fontanel, wide sutures, prominent forehead, flat nasal bridge, small mouth, cleft palate, small mandible, flexed overlapping fingers, short thumbs, syndactyly, bowed long bones, subluxed joints, narrow chest

XL (311300, 304120, 309350, 305620) Allelic to Melnick-Needles, frontometaphyseal dysplasia, and periventricular heterotopia FLNA, Xq28

Hypertelorism-hypospadias (Opitz)30

Variable mental development, widow’s peak, laryngeal abnormalities, hypospadias, cryptorchidism, bifid scrotum, hernias

AD (145410) 22q11.2 XL (300000) MID1, Xp22.3 (continued )

276

Facial Bones

277

Table 8-3. Syndromes associated with orbital hypertelorism (continued) Causation Gene/Locus

Syndrome

Prominent Features

Robinow31

Moderate short stature, macrocephaly, frontal bossing, proptosis, small triangular mouth, micrognathia, hyperplastic alveolar ridges, short forearms, hemivertebrae, small penis or clitoris, cryptorchidism

AD (180700) AR (268310) Allelic to brachydactyly type B ROR2, 9q22

Sotos32

Overgrowth, macrocephaly, prominent forehead, prognathism variable mental development, large hands and feet, accelerated phalangeal centers, premature eruption of teeth

AD (117550) NSD1, 5q35

Teebi33

Heavy eyebrows, downslanting palpebrae, depressed nasal bridge, short nose, mild syndactyly, shawl scrotum

AD (145420)

Weaver34

Accelerated growth and maturation, long philtrum, large ears, mild hypertonia, spasticity, camptodactyly, broad thumbs, thin deep-set nails, limited elbow and knee extension, relatively loose skin, thin hair, umbilical hernia

AD (277590) Unknown in most; NSD1, 5q35 point mutation in some cases

Fig. 8-6. Coronal ultrasonographic view of the fetal facial skeleton at 18 weeks of gestation. Note localization of landmarks for evaluation of interorbital measurement.

References (Orbital Hypertelorism) 1. Feingold M, Bossert WH: Normal values for selected physical parameters. Birth Defects Orig Artic Ser X(13):1, 1974. 2. Merlob P, Sivan Y, Reisner SH: Anthropometric measurements of the newborn infant (27 to 41 gestational weeks). Birth Defects Orig Artic Ser XX(7):1, 1984. 3. Laestadius ND, Aase JM, Smith DW: Normal inner canthal and outer orbital dimensions. J Pediatr 74:465, 1969. 4. Tessier P: Orbital hypertelorism. 1. Successive surgical attempts, materials and methods. Causes and mechanisms. Scand J Plast Reconstr Surg 6:135, 1972. 5. Hall JG, Froster-lskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 6. Saul RA, Stevenson RE, Rogers RC, et al.: Growth references from conception to adulthood. Proc Greenwood Genet Center, Suppl 1, 1988.

7. Greig DM: Hypertelorism: a hitherto undifferentiated congenital craniofacial deformity. Edinburgh Med J 31:350, 1924. 8. Costaras M, Pruzansky S, Broadbent BH Jr.: Bony interorbital distance (BIOD), head size, and level of the cribriform plate relative to orbital height: I. Possible pathogenesis of orbital hypertelorism. J Craniofac Genet Dev Biol 2:5, 1982. 9. Myrianthopoulos NC: Epidemiology of craniofacial malformations: foundations of craniofacial genetics. In: Clinical Dysmorphology of Oral-Facial Structures. M Melnick, ED Shields, NJ Burzynski, eds. John Wright, PSG, Boston, 1982, p 12. 10. Morin JD, Hill JC, Anderson MC, et al.: A study of growth in the interorbital region. Am J Ophthalmol 56:895, 1963. 11. Fryns JP: Aarskog syndrome: the changing phenotype with age. Am J Med Genet 43:420, 1992. 12. Koenig R, Bach A, Woelki U, et al.: Spectrum of the acrocallosal syndrome. Am J Med Genet 108:7, 2002. 13. Robinow M, Pfeiffer RA, Gorlin RJ, et al.: Acrodysostosis: a syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am J Dis Child 121:195, 1971. 14. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’: decentric small marker chromosome probably derived from a 22 (tetrasomy 22pter;q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 57:148, 1981. 15. Cooper SC, Flaitz CM, Johnston DA, et al.: A natural history of cleidocranial dysplasia. Am J Med Genet 104:1, 2001. 16. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Craniofrontonasal syndrome: study of 41 patients. Am J Med Genet 61:147, 1996. 17. Hunter AGW: Coffin-Lowry syndrome: a 20-year follow-up and review of long-term outcomes. Am J Med Genet 111:345, 2002. 18. Gripp KW, Donnai D, Clericuzio CL, et al.: Diaphragmatic herniaexomphalos-hypertelorism syndrome: a new case and further evidence of autosomal recessive inheritance. Am J Med Genet 68:441, 1997. 19. Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes: a review and report of eleven patients. Am J Med Genet 12:377, 1982. 20. Sedano HO, Cohen MM Jr, Jirasek J, et al.: Frontonasal dysplasia. J Pediatr 76:906, 1970. 21. Evans DGR, Ladusans EJ, Rimmer S, et al.: Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet 30:460, 1993. 22. Debeer P, Peeters H, Driess S, et al.: Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. Am J Med Genet 120A:49, 2003. 23. Schaefer GB, Jochar A, Muneer R, et al.: Clinical variability of tetrasomy 12p. Clin Genet 51:102, 1997. 24. Larsen LJ, Schottstaedt ER, Bost FC: Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr 37:574, 1950.

278

Craniofacial Structures

25. Robinow M, Johanson AJ, Smith TH: The Lenz-Majewski hyperostotic dwarfism: a syndrome of multiple congenital anomalies, mental retardation, and progressive skeletal sclerosis. J Pediatr 91:417, 1977. 26. Digilio MC, Conti E, Sarkozy A, et al.: Grouping of multiplelentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389, 2002. 27. Neu RL, Kajii T, Gardner LI, et al.: A lethal syndrome of microcephaly with multiple congenital anomalies in three siblings. Pediatrics 47: 610, 1971. 28. Allanson JE, Hall JG, Hughes HE, et al.: Noonan syndrome: the changing phenotype. Am J Med Genet 21:507, 1985. 29. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum Disorders Clinical Collaborative Group: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 30. Opitz JM: G syndrome (hypertelorism with esophageal abnormality and hypospadias, or hypospadias-dysphagia, or ‘Opitz-Frias’ or ‘Opitz-G’ syndrome)—perspective in 1987 and bibliography. Am J Med Genet 28:275, 1987. 31. Robinow M, Silverman FN, Smith HD: A newly recognized dwarfing syndrome. Am J Dis Child 117:645, 1969. 32. Allanson JE, Cole TRP: Sotos syndrome: evolution of facial phenotype subjective and objective assessment. Am J Med Genet 65:13, 1996. 33. Teebi AS: New autosomal dominant syndrome resembling craniofrontonasal dysplasia. Am J Med Genet 28:581, 1987. 34. Weaver DD, Graham CB, Thomas IT: A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly. J Pediatr 84:547, 1974. 35. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. CV Mosby, St. Louis, 1985, p 184. 36. DeMyer W: The median cleft face syndrome. Differential diagnosis of cranium bifidum occultum and hypertelorism in median cleft nose, lip and palate. Neurology 17:961, 1967. 37. Coffman JA: Runx transcription factors and the developmental balance between cell proliferation and differentiation. Cell Biol Int 27:315, 2003. 38. Aoto K, Nishimura T, Eto K, et al.: Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev Biol 251:320, 2002. 39. Tan ST, Mulliken JB: Hypertelorism: nosologic analysis of 90 patients. Plast Reconstr Surg 99:317, 1997. 40. Psillakis JM: Surgical treatment of hypertelorbitism. In: Craniofacial Surgery. EP Caronni, ed. Little, Brown and Company, Boston, 1985, p 190. 41. Mayden KL, Tortora M, Berkowitz RL: Orbital diameters: a new parameter for prenatal diagnosis and dating. Am J Obstet Gynecol 144:289, 1982. 42. Jeanty P, Cantraine F, Cousaert E, et al.: The binocular distance: a new way to estimate fetal age. J Ultrasound Med 3:241, 1984. 43. Escobar LF, Bixler D, Padilla M, et al.: Fetal craniofacial morphometrics in utero. Evaluation at 16 weeks of gestation. Obstet Gynecol 72:677, 1988.

8.4 Midline Facial Skeletal Clefting Definition

Midline facial skeletal clefting is a sagittally oriented fissure dividing the craniofacial structures at the midline. Midline facial clefts result from failure of the facial processes to fuse during the embryonic stage. Diagnosis

Midline facial clefting (MFC) is classified according to the morphologic characteristics. Table 8-4 lists the different types of facial bone involvement as shown by computed tomography

Table 8-4. Facial bone abnormalities in midline facial clefts Tessier1 type

0

Keel-shaped maxillary alveolus, reduction of median and paramedian midfacial height, thickening of the nasal septum, broad and flat maxilla, orbital hypertelorism, widening of anterior cranial fossa

1

Clefting of the maxilla with or without cleft palate, maxillary hypoplasia, flattening of the nasal dorsum, asymmetry of the ptyrigoid plates, keel-shaped alveolus

2

Alveolar cleft that extends to soft and hard palate, deviation of the nasal septum

3

Deviation of the nasal septum, no septation between nasal cavity and the cleft side of the maxilla, cleft extending to the medial portion of the orbital floor and into the inferior orbital rim, orbit and anterior cranial fossa inferiorly displaced

4

Palatal cleft from the maxilla to the infraorbital foramen, medial septation separating the nasal cavity from the orbit, maxillary sinus and mouth present

5

From narrow to broad cleft of the maxilla to the infraorbital foramen and maxillary sinus, cleft entering the inferolateral orbital rim

12

Flattening of the frontal process of the maxilla, orbital hypertelorism, flattening of the frontal bone, obtuse nasofrontal angle

13

Bony cleft beginning in the region of the nasal bone and extending superiorly through the full height of the frontal bone; posteriorly, cleft extends through the cribiform plate and ethmoid sinus as far as the lesser wing and body of the sphenoid

14

Median frontal cleft defect sometimes with herniation of a frontal encephalocele, flattened glabella, shortening of the anterior dimension of the middle cranial fossa

Tessier types 6–11 involve regions other than the craniofacial midline. Therefore, they are not included here. Further information is given by David et al.2

(CT) scanning. Initially recognized by soft tissue abnormalities, midline facial clefts vary from mild broadening of the philtrum, or a true medial cleft lip (MFC 0), to severe orbital hypertelorism, with anterior cranium bifidum occultum. Recognition of the degree of skeletal involvement requires radiologic techniques such as CT. CT and tridimensional reconstruction are essential in evaluating accurately the severity of the defect and in planning reconstructive procedures (Fig. 8-7). In addition, cephalometric analysis of the skeletal craniofacies is helpful in delineating skeletal morphology. Midline facial clefts are characterized by the combination of two or more of the following: (1) true ocular hypertelorism, (2) broadening of the nasal root, (3) median facial cleft affecting the nose or both nose and upper lip and at times the palate, (4) unilateral or bilateral clefting of the alae nasi, (5) lack of formation of the nasal tip, (6) anterior cranium bifidum occultum, and (7) V-shaped hair prolongation onto the forehead, generally over the area of the cranium bifidum.3 Distinction has to be made between median and paramedian craniofacial clefts and also between median clefts and the group of frontoethmoidal meningoencephaloceles, which are associated with a normal craniofacial skeleton that is displaced in position (Fig. 8-8).4,5 However, encephaloceles are sometimes associated with true craniofacial clefts with markedly abnormal skulls. Since frontoethmoidal meningoencephaloceles lack the frontal

Facial Bones

279

Fig. 8-8. Ten-month-old female with frontoethmoidal meningoencephalocele. She was exposed prenatally to hydantoin and had a unilateral constriction ring of the arm and nail hypoplasia.

Fig. 8-7. Three-year-old patient with facial cleft. Note the facial skeletal defect as seen via 3-D CT reformat sequence. (From David et al.2)

hairline indicator, this sign may be helpful in distinguishing the two entities. Other entities that include ocular hypertelorism must be carefully differentiated from mild forms of midline facial clefts. Syndromes including ocular hypertelorism usually affect other areas of the body in addition to the midline of the face. Etiology and Distribution

Severe midline facial clefting is associated with gross malformations of the head and rarely presents in an isolated form. As suggested by Sedano and Gorlin3 in 1988, frontonasal malformation may represent the reaction of part, or parts, of an embryo as a unit to both normal and abnormal stimuli. The spectrum of frontonasal malformations involves individual entities that may include midfacial clefts as a major characteristic (Table 8-5). Examples are craniofrontonasal dysplasia, ophthalmofrontonasal dysplasia, and Greig cephalopolysyndactyly. Midline craniofacial clefting has been reported to occur in hemifacial microsomia (sporadic), Treacher

Collins syndrome (autosomal dominant), and acrofrontofacionasal dysostosis (autosomal recessive). In addition, it can be seen as part of some multiple congenital anomaly syndromes or can represent a single developmental event in a malformation sequence, as was suggested by Toriello and collaborators.11 Midline facial clefting appears to result from insult during the embryonic period.3 The developmental basis for these defects was investigated by Darab and coworkers.12 They were able to produce a spectrum of defects ranging from narrow midline nasal-groove defects to frank midfacial clefting in mouse embryos exposed to methotrexate during day 9 of pregnancy (corresponding to week 4 of human gestation). Affected embryos showed dilation and congestion of blood vessels in the frontonasal process, suggesting that vascular damage may be responsible for initiating the sequence of events leading to midline facial clefting. Caution is suggested, since mice may be highly sensitive to teratogenic clefting and this may not be the case in humans. The majority of midline facial clefts are sporadic, with a somewhat low recurrence risk. The recurrence risk, however, can be substantial if the clefts are associated with other anomalies in a recognized malformation syndrome. A particularly interesting example is the craniofrontonasal syndrome, due to mutations in the EFNB1 gene located in the pericentromeric region of the X chromosome.13 In contrast to other X-linked disorders, craniofrontonasal syndrome affects females more severely, and males show milder manifestations, such as hypertelorism only. Prognosis, Treatment, and Prevention

The child with midfacial cleft should be approached by a multidisciplinary team of professionals. The evaluation and treatment of these children should include audiology, genetics, maxillofacial prosthetics, neurology, neurosurgery, ophthalmology, oral and maxillofacial surgery, orthodontics, pediatrics, psychiatry, psychology, radiology, social work, and speech pathology. Some centers have the advantage of including physical anthropology. This ‘‘team’’ approach has greatly improved the prognosis for the child with midfacial clefts. Surgical reconstruction in childhood has become routine at a few centers. Initially, surgeons were reluctant to do major reconstructive surgery on young children, preferring to wait until most of the facial growth had occurred. The current change to earlier surgery has probably been motivated by concern for the patient’s psychological adjustments. However, depending

280

Craniofacial Structures

Table 8-5. Syndromes associated with midline facial skeletal clefting Syndrome

Prominent Features

Causation Gene/Locus

Craniofrontonasal6

Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal grooves and splits in nails

XL (304110) EFNB1, Xq28

Facio-auriculo-vertebral spectrum7

Macrostomia, microtia, periauricular tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate, hypoplasia of one side of face

Unknown, sporadic (164210, 257700)

Frontonasal dysplasia8

Ocular hypertelorism, lateral displacement of inner canthi, widow’s peak, deficit in midline frontal bone, notched broad nasal tip, medial cleft lip, broad nasal root, nasal tags, mental deficiency

Unknown, sporadic (136760)

Oto-palato-digital (OPD) spectrum9

Frontometaphyseal dysplasia: coarse facies; prominent supraorbital ridges; partial anodontia; high palate; small mandible; wide foramen magnum; flared pelvis; mixed conductive and sensorineural hearing loss; flexion defects of fingers, wrists, elbows, knees, and ankles

XL (305620, 311300, 304120, 309350) FLNA, Xq28 Allelic to Melnick-Needles, OPD types 1 and 2, and periventricular heterotopia

Greig cephalopolysyndactyly10

High forehead, frontal bossing, macrocephaly, hypertelorism, broad nasal root, postaxial polydactyly of hands, broad thumbs, preaxial polydactyly of feet, broad halluces, syndactyly

AD (175700) GLI3, 7p13

on the severity of the defects, multiple procedures may be required. This process may take from a few months to years. Between 15% and 20% of patients with midfacial clefts have some degree of developmental delay. This can, in most cases, be reasonably attributed to other causes, such as extreme prematurity, perinatal difficulties, or multiple other congenital anomalies.14 Prevention of midline facial clefting is limited to reproductive genetic counseling and prenatal testing for pregnancies at risk. Prenatal diagnosis by ultrasonography has been accomplished in the past, and ultrasonography is a relatively good indicator of the severity of the defect.15,16 Since no chromosomal abnormality has been identified, amniocentesis has limited diagnostic value. In specialized centers, fetoscopy remains as an important backup procedure for confirmation of midline facial clefts. References (Midline Facial Skeletal Clefting) 1. Tessier P: Anatomical classification facial, cranio-facial and laterofacial clefts. J Maxillofac Surg 4:69, 1976. 2. David DJ, Moore MH, Cooler RD: Tessier clefts revisited with a third dimension. Cleft Palate J 26:163, 1989. 3. Sedano HO, Gorlin RJ: Frontonasal malformation as a field defect and in syndromic associations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 65:804, 1988. 4. David DJ, Sheffield L, Simpson D, et al.: Frontoethmoidal meningoencephaloceles, morphology and treatment. Br J Plast Surg 37:271, 1984. 5. Moore MH, David DJ, Cooler RD: Hairline indicators of craniofacial clefts. Plast Reconstr Surg 82:589, 1988. 6. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Craniofrontonasal syndrome: study of 41 patients. Am J Med Genet 61:147, 1996. 7. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 8. Sedano HO, Cohen MM Jr, Jirasek J, et al.: Frontonasal dysplasia. J Pediatr 76:906, 1970. 9. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum Disorders Clinical Collaborative Group: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 10. Debeer P, Peeters H, Driess S, et al.: Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. Am J Med Genet 120A:49, 2003.

11. Toriello HV, Radecky LL, Sharda J, et al.: Frontonasal ‘‘dysplasia,’’ cerebral anomalies, and polydactyly. Report of a new syndrome and discussion from a developmental field perspective. Am J Med Genet (suppl)2:89, 1986. 12. Darab DJ, Minkoff R, Sciote J, et al.: Pathogenesis of median clefts in mice treated with methotrexate. Teratology 36:77, 1987. 13. Wieland I, Jakubiczka S, Muschke P, et al.: Mutations of the Ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet 74:1209, 2004. 14. Stewart RE: The value of establishing the genetic component in etiology of craniofacial anomalies. Birth Defects Orig Artic Ser XVI(5): 27, 1980. 15. Chevernak FA, Tortora M, Mayden K, et al.: Antenatal diagnosis of median cleft syndrome: sonographic demonstration of cleft lip and hypertelorism. Am J Obstet Gynecol 149:94, 1984. 16. Gianluigi P, Reece EA, Romero R, et al.: Prenatal diagnosis of craniofacial malformations with ultrasonography. Am J Obstet Gynecol 155: 45, 1986.

8.5 Absence and Hypoplasia of the Zygoma Definition

Absence and hypoplasia of the zygoma is the impaired development of the zygomatic bone leading to deficiency of the midface and orbital floor. Hypoplasia/aplasia of the zygoma represents an anomaly of the first branchial arch and has wide phenotypic variability. Diagnosis

Hypoplasia of the malar bones and zygomatic arches is usually recognizable on simple clinical inspection of the affected individual (Fig. 8-9). Striking deficiency of the midface in the zygomatic area is characteristic. The deficient facial skeleton is reflected in soft tissue abnormalities such as tongues of hair protruding onto the cheeks, lateral canthal colobomas, downward obliquity of the palpebral fissures, lower lid colobomas, lower lid ciliary agenesis, and a small face with prominent nose. Facial anomalies of this type are usually seen in well-defined entities such as Treacher Collins syndrome and ablepharon-macrostomia.1,2

Facial Bones

281

a defect of the inferior rim and floor of the orbit, with inferolateral herniation.3,4 Total absence of the zygomatic bones and zygomatic arches is rare, and, in many cases, a remnant of zygomatic bone can be found appended to the sphenoid tubercle, without connection to the maxilla or the frontal or temporal bone. Zygomatic absence is responsible for the absence of the lateral orbital rim, with formation of the lateral orbital wall by the hypoplastic greater wing of the sphenoid.5 In the ablepharon-macrostomia syndrome, radiologic studies may show profound hypoplasia of the malars, infraorbital rims, and lateral walls and absent zygomatic arches. Other entities that include zygomatic hypoplasia or absence are Goldenhar (hemifacial microsomia), Nager (preaxial acrofacial dysostosis), and Miller (postaxial acrofacial dysostosis) syndromes (Table 8-6). Clinical caution is suggested since the occurrence of incomplete and or asymmetric forms may lead to diagnostic difficulties. Etiology and Distribution

Fig. 8-9. Top: Frontal (A) and lateral (B) view of patient with hypoplasia of zygomatic bone. Bottom: Frontal view of 13-month-old female with Treacher Collins syndrome showing downslanting palpebral fissures, sagging (cleft) lower lids, and hypoplasia of the zygoma. (A and B from Jackson et al.2)

Due to the wide spectrum of abnormalities associated with absence or hypoplasia of the zygoma, radiologic studies are essential in establishing the areas involved and in evaluating the extent of the defect. This is best accomplished by the Waters radiologic view and frontal tomograms that demonstrate deficiency of the malar bones and partial or complete absence of the zygomatic arches. In addition, modification of the orbital shape with an inferolateral elongation can be observed. The hypoplasia can be described in relation to the three articulations of the zygoma: zygomaticotemporal, zygomaticofrontal, and zygomaticomaxillary. Impairment in the development of the temporal process of the zygoma, in conjunction with impairment of the zygomatic process of the temporal bone, results in partial to complete absence of the zygomatic arch. Impairment of the frontal process causes absence of the anterior portion of the lateral orbital wall. Impairment along the maxillary articulation results in

It is important to emphasize that absence or hypoplasia of the zygoma does not occur as an isolated malformation. It is the result of a deficient growth and aberrant tissue interaction between several embryologic craniofacial structures. Opitz21 suggested that these abnormalities constitute part of the mandible, zygoma, ear ossicles developmental field (MZEDF), which may imply that whenever one of the three structures becomes anomalous, abnormal growth will occur in the other two. Positive statistical correlations exist between the frequency of aberrant development of these three structures, supporting a developmental field concept.22 This idea is particularly attractive when one observes the close clinical linkage between syndromes that affect the structures derived from the first branchial arches. These include mandibulofacial dysostosis; ablepharon-macrostomia; otocephaly; and Goldenhar, Miller, and Nager syndromes. Etiologically, the primary developmental defect that leads to abnormalities of the zygoma is unknown; however, damage to the stapedial artery has been suggested to cause failure of migration of the neural crest cells, leading to deficient growth of the zygomatic structures.23 This appears to be a plausible explanation, but it fails to account for the occurrence of bilateral defects. Nevertheless, the possibility that some cases of first branchial arch deficiency are due to this mechanism or to similar mechanisms of vascular origin cannot be dismissed. If the vascular theory holds true, this may lead to excessive and/or premature deficiencies in the amounts of cell death in the first and second arch. Among the cell populations that may be particularly affected are the first arch epithelial placode cells.24 The appearance of single ossification centers for each of the zygomatic bones at approximately the 8th week of gestation has led to the suggestion that any arrest in chondrogenesis could result in absence or hypoplasia of the zygoma.2 This suggested mechanism would support the idea of failure of cell differentiation due to the absence of an appropriate extracellular matrix during the early developmental stages.25 The gene causally involved in mandibulofacial dysostosis has been identified as TCOF1. It encodes a nucleolar phosphoprotein named treacle, whose biologic function remains poorly defined. Investigation of a mouse model showed that heterozygous Tcof1 deletion leads to perinatal death from severe craniofacial anomalies caused by a massive increase of apoptosis in the prefusion neural folds. These studies, in combination with the mutations identified in patients with Treacher

Table 8-6. Syndromes associated with absence or hypoplasia of the zygoma Syndrome

Prominent Features

Causation Gene/Locus

Bloom6

Growth deficiency, microcephaly, dolichocephaly, small nose, butterfly telangiectatic erythema involving the midface region exacerbated by sunlight

AR (210900) RECQL3, 15q26.1

Chondrodysplasia punctata7

Growth deficiency, short limbs, epiphyseal stippling, low nasal bridge, downward-slanting palpebral fissures, variable joint contractures, scoliosis, follicular atrophoderma, ichthyosis

Multiple loci XL (302960) EBP, Xp11.23 XL (302950) ARSE, Xp22.3 AD (118650) AR (215100) PEX7, 6q22-q24

Deletion 22q11.28

Cleft palate, conotruncal heart malformation, thymic hypoplasia, abnormal external ear, prominent nasal tip, hypoplastic alae nasi, learning difficulties

(192430) Microdeletion, 22q11.2

Diamond-Blackfan anemiamicrotia-cleft palate9

Macrocytic anemia, short stature, downslanting palpebral fissures, microtia, cleft palate, micrognathia

AD (606164)

Facio-auriculo-vertebral spectrum10

Macrostomia, unilateral hypoplasia of malar and mandibular region, microtia, periauricular tags, epibulbar dermoid, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate, cardiac and renal malformation

Unknown, sporadic (164210, 257700)

Hallermann-Streiff11

Small stature, brachycephaly, frontal bossing, thin calvarium, delayed ossification of sutures, micrognathia, anterior displacement of the temporomandibular joint, microphthalmia, cataracts, small nose with hypoplasia of the cartilage, microstomia, hypoplasia of the teeth, partial anodontia

Unknown, sporadic (234100)

Marshall12

Short stature, depressed nose with flat nasal bridge, anteverted nares, flat midface, myopia, cataracts, calvarial thickening, irregular distal femoral and proximal tibial epiphyses, bowing of the radius and ulna

AD (154780) Allelic to Stickler type 2 COL1A11, 1p21

Miller13

Downslanting palpebral fissures, eyelid coloboma, ectropion, micrognathia, cleft lip and/or palate, postaxial limb deficiencies, syndactyly, accessory nipple

AR (263750) Most sporadic, AD rarely reported

Mohr14

Short stature, conductive deafness, low nasal bridge, broad nasal tip, slightly bifid, midline cleft of tongue, hypoplasia of the maxilla and body of the mandible, duplication of hallux and first metatarsals, duplication of tarsal bones, polydactyly, metaphyseal flaring

AR (252100)

Nager15

Normal intelligence, short stature, conductive deafness and articulation problems, downslanting palpebral fissures, micrognathia, absence of the lower eyelashes, periauricular tags, atresia of external ear canal, hypoplasia to aplasia of the thumb, proximal radioulnar synostosis, short forearms

AD, AR (154400)

Oto-palato-digital (OPD) spectrum16

OPD type 1: variable mental deficiency, short stature, moderate conductive deafness, thick base of skull, facial bone hypoplasia, absence of frontal and sphenoid sinuses, partial anodontia, impacted teeth, small trunk, pectus excavatum, small iliac crests, joint contractures, broad distal phalanges, accessory ossification center at the base of the second metatarsal

XL (311300, 304120, 309350, 305620) FLNA, Xq28 Allelic to Melnick-Needles, frontometaphyseal dysplasia and periventricular heterotopia

Pycnodysostosis 17

Small stature, osteosclerosis with tendency toward transverse fracture, delayed closure of sutures, persistence of anterior fontanel, lack of frontal sinus, facial hypoplasia, irregular permanent teeth, dysplasia to loss of acromion of the clavicle, acro-osteolysis of distal phalanges, wrinkled skin over dorsa of distal fingers

AR (265800) CTSK, 1q21

Seckel18

Growth deficiency, mental deficiency, microcephaly, receding forehead, prominent nose, downward-slanting palpebral fissures, clinodactyly of fifth finger, proximal radial hypoplasia with dislocation of radial head, hypoplasia of proximal fibula

AR (210600) ATR, 3q22-q24 heterogeneous

Townes-Brocks19

Hemifacial microsomia with preauricular tags, abnormal ear shape, sensorineural hearing loss, thumb anomalies, imperforate anus, renal malformations

AD (107480) SALL1, 16q21.1

Treacher Collins20

Downslanting palpebral fissures, cleft in zygomatic bone, lower lid coloboma, partial to total absence of lower eyelashes, malformed auricles, external ear malformation, conductive deafness, cleft palate, extension of scalp hair onto lateral cheek

AD (154500) TCOF1, 5q32-q33

282

Facial Bones

Collins syndrome, suggest that the protein is crucial for the survival of cephalic neural crest cells, and that haploinsufficiency is disease causing.26 Prognosis, Treatment, and Prevention

The prognosis for patients with zygomatic anomalies and related disorders is very good. In a small number of cases, neonatal complications cause insults to the central nervous system, but the majority of patients have normal intelligence. Treatment of these anomalies is primarily surgical and is designed to build the zygomatic bones and zygomatic arches. If other anomalies are involved, the correction can be made at the same time these are corrected depending on the degree of involvement. These procedures are usually performed during childhood with excellent results. Jackson and collaborators1 have used bilateral full-thickness vascularized skull grafts raised on the anterior one-third of the temporalis muscle to correct the skeletal anomalies in the ablepharon-macrostomia syndrome. The grafts are contoured to form the zygomatic arch and to augment the lateral orbital wall. Only cranial bone grafts may be used on the anterior aspect of the orbital rim. Considering that, in most severe forms, two malar bones and two zygomatic arches have to be reconstructed and that partial resorption may occur, the donor sites for bone grafts may be insufficient. In such cases, cranial vault and tibia are used to preserve ribs and iliac crest for additional procedures that may be required. Distraction osteotomy may be used as a primary procedure or after bone grafting.27 As was mentioned previously, zygomatic deficiency is not an isolated birth defect, and careful consideration of syndromic associations must be made. Recurrence figures must be calculated for the primary diagnosis. In mandibulofacial dysostosis, for example, the recurrence risk for the offspring of an affected individual will be 50%, with high penetrance and equal distribution between sexes. Prenatal diagnosis of zygomatic hypoplasia in association with mandibulofacial dysostosis has been accomplished via fetoscopy and ultrasonography.28,29 Fetal cephalometry with ultrasound should be attempted to establish the degree of deficient growth. Prenatal counseling is at present the only means of prevention. References (Absence and Hypoplasia of the Zygoma) 1. Jackson IT, Shaw KE, Pinal-Matorras F: A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence. Br J Plast Surg 41:410, 1988. 2. Kay ED, Kay CN: Dysmorphogenesis of the mandible, zygoma and mandible, ear ossicles in hemifacial microsomia and mandibulofacial dysostosis. Am J Med Genet 32:27, 1989. 3. Tessier P: Anatomical classification of facial, craniofacial and laterofacial clefts. J Maxillofac Surg 4:69, 1976. 4. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. JL Marsh, MW Vannier, WG Stevens, eds. CV Mosby, St. Louis, 1985, p 256. 5. Raulo Y: Treacher Collins syndrome: analysis and principles of surgery. In: Craniofacial Surgery. EP Caronni, ed. Little, Brown and Co, Boston, 1985, p 372. 6. Ellis NA, German J: Molecular genetics of Bloom’s syndrome. Hum Molec Genet 5:1457, 1996. 7. Spranger JW, Opitz JM, Bibber U: Heterogeneity of chondrodysplasia punctata. Hum Genet 11:190, 1971. 8. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 44:261, 1992.

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9. Gripp KW, McDonald-McGinn DM, La Rossa D, et al.: Bilateral microtia and cleft palate in cousins with Diamond-Blackfan anemia. Am J Med Genet 101:268, 2001. 10. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 11. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med Genet 41:488, 1991. 12. Griffith AJ, Sprunger LK, Sirko-Osadsa DA, et al.: Marshall syndrome associated with a splicing defect at the COL11A1 locus. Am J Hum Genet 62:816, 1998. 13. Miller M, Fineman R, Smith DW: Postaxial acrofacial dysostosis syndrome. J Pediatr 95:970, 1979. 14. Toriello HV: Heterogeneity and variability in the oral-facial-digital syndromes. Am J Med Genet (suppl)4:149, 1988. 15. Aylsworth AS, Lin AE, Friedman PA: Nager acrofacial dysostosis: maleto-male transmission in 2 families. Am J Med Genet 41:83, 1991. 16. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum Disorders Clinical Collaborative Group: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 17. Gelb BD, Shi GP, Chapman HA, et al.: Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236, 1996. 18. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497, 2003. 19. Kohlhase J, Wischermann A, Reichenbach H, et al.: Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet 18:81, 1998. 20. Splendore A, Silva EO, Alonso LG, et al.: High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes. Hum Mutat 16:315, 2000. 21. Opitz JM: The developmental field concept in clinical genetics. J Pediatr 101:805, 1982. 22. Kumakawa K, Funasaka S: Middle ear malformation with normal external meatus; correlation of ossicular anomalies with anomalies of auricle, jaw and face. Nippon Jibiinkoka Gakkai Kaiho 88:30, 1985. 23. Poswillo D: The embryological basis of craniofacial dysplasia. Postgrad Med J 53:517, 1977. 24. Sulik KK, Johnson MC, Smiley SJ, et al.: Mandibulofacial dysostosis (Treacher Collins syndrome): a new proposal for its pathogenesis. Am J Med Genet 27:359, 1978. 25. Herring SW, Powlatt UF, Pruzansky S: Anatomical abnormalities in mandibulofacial dysostosis. Am J Med Genet 3:225, 1979. 26. Dixon J, Brakebush C, Fassler R, et al.: Increased levels of apoptosis in the prefusion of neural folds underlie the craniofacial disorder, Treacher Collins syndrome. Hum Mol Genet 9:1473, 2000. 27. McCarthy JG, Hopper RA: Distraction osteogenesis of zygomatic bone grafts in a patient with Treacher Collins syndrome: a case report. J Craniofac Surg 13:279, 2002. 28. Nicolaides KH, Johanston D, Donnai D, et al.: Prenatal diagnosis of mandibulofacial dysostosis. Prenat Diagn 4:201, 1984. 29. Crane JP, Beaver HA: Midtrimester sonographic diagnosis of mandibulofacial dysostosis. Am J Med Genet 25:251, 1986.

8.6 Midface Retrusion and Hypoplasia Definition

Midface retrusion and hypoplasia is the underdevelopment or posterior positioning of the midface. Affecting the inferior portion of the orbits, nasal bones, and maxilla, the human midface growth deficiency gives these individuals a semilunar configuration of the anterior portion of the craniofacial profile.1 Retrusion or hypoplasia of the midface suggests a complex growth deficiency involving neural tissue, cranial base, and branchial arches.

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Diagnosis

For practical purposes, the facial skeleton is divided into three main areas: the upper face, composed of the frontal bones and upper part of the orbits; the midface, composed of the lower portion of the orbits, nasal bones, and maxilla; and the lower face, consisting mainly of the mandible. Abnormalities in any one of these areas distort the normal shape of the craniofacies as a whole. Each is a unique area of growth and development, with relatively independent clinical delineation. Of the three facial areas, the midface may be the most fascinating multistructural complex of facial development. It represents the central point of union of the growing and migrating craniofacial processes (branchial arches), with the final developmental result based on normal growth of the cranial base and brain. In some instances, pathologic processes of the upper and lower skeletal face will modify the shape of the midface (Fig. 8-10). Acrocephalosyndactyly syndromes are good examples of such modification.2 The middle one-third of the skeletal face constitutes the structural support of the nose, which is an important element in facial aesthetics. Alterations of the anteroposterior dimensions of the midface lead to changes in facial convexity and in dental occlusion.1 Evaluation of patients with midface retrusion includes external measurements, lateral radiographs, cephalometry, and study of dental occlusion. A complete dimensional study of the whole face is necessary not only to analyze the relationship between the maxilla and the rest of the facial skeleton but also to determine alterations of the upper or lower one-third of the face.3 Cephalometry is an accurate method of assessing alterations in the anterior projection of the face. It also provides documentation of the preoperative and postoperative findings in affected individuals. Fixed anatomic points, such as the cranial base, the Frankfurt plane, and other facial planes, are used in the regular cephalometric evaluation. Excellent normative data have recently been published for all postnatal ages.4 Dental models have been used to confirm the cephalometric measurements; these may help the clinician to evaluate malocclusion problems and to plan cor-

rective surgical procedures. The cast is cut and different segments are mobilized to determine what type of procedure will produce the most favorable result.1 Midfacial hypoplasia or retrusion may cause obstruction of the nasal airway and inability to feed adequately. This is seen in syndromes such as the Antley-Bixler syndrome, in which patients show choanal atresia and feeding difficulties.5 Since the infant is usually a nose breather, obstruction of the nasal airway in the neonatal period requires rapid recognition and treatment. Orotracheal intubation is usually required. Some patients with midface hypoplasia and/or retrusion have isolated hypoplasia of the maxilla, which provides support to the upper lip. This is usually a hereditary feature (autosomal dominant) and is commonly associated with prognathism. The majority of cases of maxillary hypoplasia result from congenital anomaly syndromes, such as Crouzon, Apert, and Binder syndromes6 (Table 8-7). Etiology and Distribution

Midface hypoplasia or retrusion is seen not as an isolated finding but only as part of a multiple congenital anomaly syndrome. In the absence of a traumatic or infectious cause, a genetic or environmental origin should be investigated.28 The inheritance of midface hypoplasia should be considered in the context of the entity with which it is seen. The growth and development of the midface are not completely understood. It has been suggested that the three areas of the face (upper, middle, and lower one-third) may have relatively independent mechanisms of growth and development, the midface being the most complex of the three.29 Insufficient information is available at present to define a single mechanism that results in midface hypoplasia; perhaps it would be unwise to seek a single cause. This fascinating area of structures may be a developmental field in which growing parts of an embryo are controlled and coordinated in a spatially ordered, temporally synchronized, and epimorphically hierarchical manner. Several authors have attempted to delineate a developmental field by anthropometric analysis. This attempt is based on the

Fig. 8-10. Preoperative (A) and postoperative (B) profile of patient with midface retrusion. (From OrtizMonasterio and Musolas.1)

Table 8-7. Syndromes associated with midface retrusion and hypoplasia Causation Gene/Locus

Syndrome

Prominent Features

Achondroplasia7

Rhizomelia, megalocephaly, small foramen magnum, short cranial base, low nasal bridge, prominent forehead, narrowing of lumbar interpedicular distance, lumbar lordosis, short trident hand

AD (100800) FGFR3, 4p16.3

Angelman8

Growth deficiency, mental retardation, ataxia, seizure disorder, inappropriate laughter, microbrachycephaly, widely spaced teeth

(105830) Mat del 15q11-q13 Pat UPD 15q UBE3A

Antley-Bixler9

Growth deficiency, variable mental development, brachycephaly, choanal stenosis/atresia, craniosynostosis, depressed nasal bridge, radiohumeral synostosis, arachnodactyly, femoral bowing, femoral fractures

AR (207410) Abnormal steroid biogenesis in some cases

Apert10

Craniosynostosis, high forehead, flat facies, irregular supraorbital horizontal groove, shallow orbits, hypertelorism, severe syndactyly hands and feet, broad distal phalanges of thumb, mental retardation

AD (101200) FGFR2, 10q26

Cohen11

Truncal obesity, hypotonia, high nasal bridge, short philtrum, downslanting palpebral fissures, prominent maxillary central incisors, large ears, chorioretinal dystrophy, narrow hands and feet

AR (216550) COH1, 8q22

Deletion 1p3612

Mental retardation, expressive language most severely affected, deep-set eyes, prominent supraorbital ridges, seizure disorder

Subtelomeric deletion

Deletion 18q13

Mental retardation, hypotonia, behavior problems, short stature, narrow external ear canal, microcephaly, hypoplastic labia majora, cryptorchidism

Monosomy for variable 18q region

Deletion 22q11.214

Cleft palate, conotruncal heart malformation, thymic hypoplasia, abnormal external ear, prominent nasal tip, hypoplastic alae nasi, learning difficulties

(192430) 22q11.2 microdeletion

Crouzon15

Bicoronal or pansynostosis, proptosis, beaked nose

AD (123500) FGFR2, 10q26

Facio-auriculo-vertebral spectrum16

Macrostomia, unilateral facial hypoplasia, microtia, periauricular tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate

Unknown, sporadic (164210, 257700)

Prenatal alcohol17

Growth deficiency, fine motor dysfunction, poor eye-hand coordination, variable microcephaly, short palpebral fissures, short nose, smooth philtrum, thin smooth upper lip, joint anomalies, small distal phalanges

Teratogen

Prenatal valproate18

Narrow bifrontal diameter, high forehead, epicanthal folds, low nasal bridge, short nose, congenital heart disease, long and thin fingers and toes, meningomyelocele, cleft lip

Teratogen

Prenatal fluconazole19

Phenocopy of Antley-Bixler syndrome

Teratogen, interference with steroid biogenesis

Hallermann-Streiff 20

Small stature, brachycephaly with parietal bossing, thin calvarium, delayed ossification of the sutures, microphthalmia, small nose, microstomia, hypoplasia of the teeth, atrophy of the skin, hypotrichosis

AD (234100)

Pfeiffer21

Brachycephaly, coronal synostosis, hypertelorism, broad distal phalanges of the thumb, medial deviation of thumbs and broad first toes

AD (101600) FGFR1, 8p11 FGFR2, 10q26

Rieger22

Iris dysplasia, short philtrum, thin upper lip, hypodontia, failure of involution of periumbilical skin

AD (180500) PITX2, 4q25-q26

Rubinstein-Taybi23

Short stature, small cranium, palpebral downslant, beaked nose, epicanthal folds, strabismus, malformed auricles, broad thumbs, broad toes, cryptorchidism, mental retardation

(180849) Microdeletion or mutation CREBBP, 16p13.3

Saethre-Chotzen24

Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue syndactyly, hallux valgus

(101400) TWIST, 7p21

Stickler25

Flat facies, depressed nasal bridge, epicanthal folds, clefts of hard and/soft palate, micrognathia, deafness, retinal detachment, cataracts, hypotonia, marfanoid habitus, flat vertebrae

AD (108300, 604841, 184840) COL2A1, 12q31 COL11A1, 1p21 COL11A2, 6p21

Trisomy 2126

Hypotonia, short stature, brachycephaly, upslanting palpebral fissures, small ears, cardiac defects, single palmar crease, clinodactyly

Abnormal karyotype, trisomy 21

Turner27

Small stature, ovarian dysgenesis, transient congenital lymphedema, broad chest, widely spaced nipples, pectus excavatum, abnormal auricles, inner canthal folds, excessive pigmented nevi, renal malformation, congenital heart disease

Abnormal karyotype, 45,X

285

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Craniofacial Structures

concept of spatial relationship between structures belonging to the same growth field, which represents an area of convergence and concentration of several growth forces.30,31 Positive results were obtained by Siebert,29 who suggested a positive delineation of the midface developmental field. However, the representative variables used (inner canthal measurement, outer orbital measurement, nose breadth, and mouth width) are soft tissue measurements that probably do not truly reflect the growth of the skeletal midface. More studies are needed to elucidate the mechanisms involved in the aberrant growth of the middle one-third of the skeletal face. Prognosis, Treatment, and Prevention

The treatment of hypoplasia of the midface is surgical, and the central section of the face must be advanced; a horizontal osteotomy of the maxilla closely following the trace of a LeFort I fracture is indicated. When the facial hypoplasia extends to the floor of the orbit, to the nose, and to the malar eminence, the osteotomy varies according to the amount of advancement required and the particular areas of the face that must be mobilized. Ortiz-Monasterio and Musolas1 have suggested the use of Tessier osteotomies types 2.4 and 5, which follow the course of a LeFort III fracture. These procedures are complemented by cartilage or bone grafts to the pyriform area that will be useful in the restoration of the facial convexity. Distraction osteogenesis has been used in combination with LeFort procedures to increase the amount of midfacial advancement in a single surgical procedure.32,33 Further refinement of this technique allows for distraction in more than one plane.34 Midface advancement is a rewarding technique, with excellent functional correction and improvement of facial aesthetics. The prognosis must be individualized according to the associated congenital malformations, but in general it is considered very good. Prenatal studies of the midface have rarely been reported.29 Recent advances in ultrasonography have raised the possibility of accurately measuring the midface at early gestational ages.35 The presence of midface hypoplasia during a fetal sonogram should alert the ultrasonographer to the possibility of associated fetal anomalies. Midface hypoplasia is not an independent entity. Prevention of this condition is related to the individual situation, with prenatal counseling apparently the only method available at present. References (Midface Retrusion and Hypoplasia) 1. Ortiz-Monasterio F, Musolas A: Midface retrusion. World J Surg 13:410, 1989. 2. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. CV Mosby, St. Louis, 1985, p 209. 3. Ricketts RM: Divine proportion in facial esthetics. Symposium on maxillo-facial surgery. Clin Plast Surg 9:401, 1982. 4. Saksena SS, Bixler D, Yu PL: A Clinical Atlas of Roentgencephalometry in Norma Lateralis. Alan R. Liss, Inc., New York, 1987, p 5. 5. Escobar LF, Bixler D, Sadove M, et al.: Antley-Bixler syndrome from a prognostic perspective: report of a case and review of the literature. Am J Med Genet 29:829, 1988. 6. Gross-Kieselstein E, Har-Even Y, Navon P, et al.: Familial variant of maxillonasal dysplasia? J Craniofac Genet Dev Biol 6:331, 1986. 7. Bellus GA, Hefferon TW, Ortiz de Luna RI, et al.: Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet 56:368, 1995. 8. Buntinx IM, Hennekam RCM, Brouwer OF, et al.: Clinical profile of Angelman syndrome at different ages. Am J Med Genet 56:176, 1995. 9. Antley RM, Bixler D: Trapezoidocephaly, midface hypoplasia and cartilage abnormalities with multiple synostoses and skeletal fractures. Birth Defects Orig Artic Ser XI(2):397, 1975.

10. Wilkie AOM, Slaney SF, Oldridge M, et al.: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165, 1995. 11. Cohen MM Jr, Hall BD, Smith DW, et al.: A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular and limb anomalies. J Pediatr 83:280, 1973. 12. Heilstedt HA, Ballif BC, Howard LA, et al.: Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome. Am J Hum Genet 72:1200, 2003. 13. Kline AD, White ME, Wapner R, et al.: Molecular analysis of the 18qsyndrome—and correlation with phenotype. Am J Hum Genet 52:895, 1993. 14. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 44:261, 1992. 15. Reardon W, Winter RM, Rutland P, et al.: Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 8:98, 1994. 16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 17. Jones KL, Smith DW: The fetal alcohol syndrome. Teratology 12:1, 1975. 18. Kozma C: Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet 98:168, 2001. 19. Aleck KA, Bartley DL: Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet 72:253, 1997. 20. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med Genet 41:488, 1991. 21. Cohen MM Jr: Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. Am J Med Genet 45:300, 1993. 22. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996. 23. Hennekam RCM, Tilanus M, Hamel BCJ, et al.: Deletion at chromosome 16p13.3 as a cause of Rubinstein-Taybi syndrome: clinical aspects. Am J Hum Genet 52:255, 1993. 24. Pantke OA, Cohen MM Jr, Witkop CJ Jr, et al.: The Saethre-Chotzen syndrome. Birth Defects Orig Artic Ser XI(2):190, 1975. 25. Snead MP, Yates JRW: Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353, 1999. 26. Korenberg JR, Chen XN, Schipper R, et al.: Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Nat Acad Sci 91:4997, 1994. 27. Saenger P: Turner’s syndrome. N Engl J Med 335:1749, 1996. 28. Hopkin GB: Hypoplasia of the middle third of the face associated with congenital absence of the anterior nasal spine, depression of the nasal bones, and angle class III malocclusion. Br J Plast Surg 16:146, 1963. 29. Siebert JR: Prenatal growth of the median face. Am J Med Genet 25:369, 1986. 30. Lauder GV: Form and function: structural analysis in evolutionary morphology. Paleobiology 7:430, 1981. 31. Cheverud JM: Phenotypic, genetic, and environmental morphology integration in the cranium. Evolution 36:499, 1982. 32. Alonso N, Munhoz AM, Fogaca W, et al.: Midfacial advancement by bone distraction for treatment of craniofacial deformities. J Craniofac Surg 9:114; discussion 119, 1998. 33. Toth BA, Kim JW, Chin M, et al.: Distraction osteogenesis and its application to the midface and bony orbit in craniosynostosis syndromes. J Craniofac Surg 9:100; discussion 119, 1998. 34. Satoh K, Mitsukawa N, Hosaka Y: Dual midfacial distraction osteogenesis: Le Fort III minus I and Le Fort I for syndromic craniosynostosis. Plast Reconstr Surg 111:1019, 2003. 35. Escobar LF, Bixler D, Padilla LM, et al.: A morphometric analysis of the fetal craniofacies by ultrasound: fetal cephalometry. J Craniofac Genet Dev Biol 10:19, 1990.

Facial Bones

8.7 Agnathia Definition

Agnathia is the complete absence of the mandible. This rare condition can be viewed as the most severe form of micrognathia (reduction in mandibular size). However, agnathia and micrognathia probably have different etiologies. Diagnosis

Using simple clinical inspection, the dysmorphologist is frequently able to detect changes in mandibular shape and size. In agnathia, the missing lower one-third of the facial skeleton causes striking morphologic changes (Fig. 8-11). Affected individuals have severe soft tissue anomalies, such as microstomia, cleft lip and/or palate, and ear abnormalities ranging from absence or misplacement of the external auricle to abnormalities of the inner ear. Some patients also have holoprosencephaly and upper respiratory tract anomalies.1 Two groups of patients with agnathia are now recognized: those who have varying degrees of cyclopia, with holoprosencephalic brain, and those without cyclopialike facial malformations.2 The former is a rare lethal condition that has been reported to occur in association with microstomia, aglossia, synotia, and brain Fig. 8-11. Infant with agnathia without holoprosencephaly.

287

malformations. It usually occurs with developmental abnormalities of other systems that lead to early neonatal death.1 The second group is considered less severe and consists of agnathia without holoprosencephaly. Affected patients usually have microstomia, aglossia, blind mouth, middle ear anomalies, cleft lip, cleft palate, and downward-slanting palpebral fissures (Fig. 8-11). Most pregnancies with agnathic fetuses are associated with polyhydramnios, which probably result from fetal inability to swallow because of persistence of the oropharyngeal membrane. As a consequence, premature labor is frequent, with only rare cases reaching 38 weeks of gestation. The neonate shows a blindending mouth, which impedes the passing of an oropharyngeal tube to establish an airway. Early recognition of this situation may prompt the clinician to perform a tracheostomy. Ear positioning is variable, and the use of the term otocephaly does not seem justified. Patients with fusion of the ears in the midline are rare.3 Inner ear anomalies have been reported to occur in about 40% of cases.4 Etiology and Distribution

It seems possible that two different mechanisms are responsible for agnathia holoprosencephaly and agnathia without brain anomalies (otocephaly).1,5,6 Agnathia is considered to be a defect in the ventral portion of the first branchial arch and may be secondary to defective neural crest migration or proliferation or to a mesodermal deficiency in the arch itself.6 Persistence of the oropharyngeal membrane occurs. Bixler and collaborators1 have suggested that a defect in prechordal mesoderm formation and/or its interactions accounts for agnathia-holoprosencephaly. Subsequent effects on neural crest cells may result. A graded series of defects resulting from abnormal formation of the prosencephalon and the mandible occurs. Agnathia without holoprosencephaly is a very rare abnormality, with sporadic occurrence. Autosomal recessive inheritance has been suggested by Pauli et al.2 based on their observation of two affected stillborn siblings. However, an unbalanced chromosome abnormality was later identified in this family.7 Animal models (mouse and guinea pig) have also indicated the existence of an inherited type of agnathia without holoprosencephaly; however, this evidence is not conclusive at the present time.8 Agnathia with holoprosencephaly seems to have a higher incidence than agnathia without holoprosencephaly, with only 24 cases of the latter identified in the 25 years prior to 1985.1 In patients with agnathia with holoprosencephaly, situs inversus may also be present.9 Sex ratios are equal, and excessive incidence has not been described in any racial group. Prognosis, Treatment, and Prevention

As was mentioned previously, agnathia without holoprosencephaly seems to carry a better prognosis than agnathia with holoprosencephaly. In general, the prognosis in both situations is poor; however, there are no adequate data concerning survival rates. In the presence of airway obstruction, the clinician should consider a tracheostomy, since this is the only means of ensuring good ventilatory support. Once the patient is stable, evaluation for surgical correction of associated anomalies is indicated, with the planning of feeding methods to support the child. Reports of prenatal diagnosis of this condition can be found in the literature.10,11 The authors used prenatal radiographs to identify agnathia and polyhydramnios. The use of ultrasonography, which can demonstrate polyhydramnios and agnathia with

288

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holoprosencephaly, has been found to be preferable. Computer tomography has also been used for prenatal diagnosis.12 Since most of the cases are sporadic, no biochemical, DNA, or chromosomal markers have been useful in the diagnosis of agnathia. There appears to be no effective means of prevention at present.

Rarely seen as an isolated characteristic, hypoplasia of the mandible can be familial.2 However, it is more common as part of a multiple congenital anomaly syndrome, with which it follows the corresponding mode of inheritance. More than 130 syndromes and 47 chromosomal anomalies have been reported to include micrognathia as a consistent feature (Table 8-8).

References (Agnathia)

Etiology and Distribution

1. Bixler D, Ward R, Gale DD: Agnathia-holoprosencephaly: a developmental field complex involving face and brain. Report of 3 cases. J Craniofac Genet Dev Biol 1:241, 1985. 2. Pauli RM, Pettersen JC, Arya S, et al.: Familial agnathia-holoprosencephaly. Am J Med Genet 14:677, 1983. 3. Johnson W, Cook JB: Agnathia associated with pharyngeal isthmus atresia and hydramnios. Arch Pediatr 78:211, 1961. 4. Le Marec B, Bourdiniere J, Le Clech G, et al.: A propos d’un cas d’tocephalie (A case of otocephaly). J Genet Hum 24(suppl):253, 1976. 5. Opitz JM: Letter to the editor. Clin Genet 17:238, 1980. 6. Johnston MC, Sulik KK: Some abnormal patterns of development in the craniofacial region. Birth Defects Orig Artic Ser XV(8): 23, 1979. 7. Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255, 1989. 8. Juriloff DM, Sulik KK, Roderick TH, et al.: Morphogenesis of spontaneously occurring otocephaly in a newly developed mouse mutant. Teratology 21:47A, 1980. 9. Ozden S, Bilgic R, Delikara N, et al.: The sixth clinical report of a rare association: agnathia-holoprosencephaly-situs inversus. Prenat Diagn 22:840, 2002. 10. Ursell W: Hydramnios associated with congenital microstomia, agnathia and synotia. J Obstet Gynecol Br Commonwealth 79:185, 1972. 11. Cayea PD, Bieber FR, Ross MJ, et al.: Sonographic findings in otocephaly (synotia). J Ultrasound Med 4:377, 1985. 12. Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathiaholoprosencephaly: three-dimensional imaging by helical computed tomography. Prenat Diagn 21:68, 2001.

8.8 Micrognathia Definition

Micrognathia is the reduction in size of one or all parts of the mandible. Micrognathia should be differentiated from retrognathia, in which the mandible is of normal size but is posteriorly positioned in relation to the skull base. Diagnosis

Malformations of the mandible are among the most common malformations known to humans. Among these, micrognathia may be the most common.1 Severe micrognathia can be detected by the clinician by simple inspection (Fig. 8-12). Mild forms may be difficult to detect, however, and can be easily confused with retrognathia. Roentgenocephalometry is extremely helpful in the differentiation between true micrognathia and retrognathia, and it also provides a substantial amount of information necessary for objective decisions concerning treatment. Mandibular hypoplasia may induce other anomalies, as is the case in the Pierre Robin sequence. Here, acting as a single initiating defect, the small mandible keeps the tongue in a posterior location, impairing the closure of the posterior palatal shelves in the midline. This results in cleft palate.

Micrognathia is believed to result from hypoplasia of the neural crest cell population in the first branchial arch. The bony elements of the lower jaw are neural crest-derived. From two different ossification centers that appear at about the 6th week of gestation, each side of the mandible is formed by posteroanterior ossification spreading over the framework provided by Meckel’s cartilage. At birth, the mandible consists of two halves, with a fibrous union at the symphysis. Complete ossification of the mandible and the fibrous union occurs within the 1st year of life. Evidence for the supportive role of Meckel’s cartilage during growth of the mandible is shown by the effects of the lathyrogen B-aminoproprionitrile (BAPN) on facial growth.39 Administration of BAPN to pregnant rats at about day 15 of gestation reduces the length of the mandible in the fetuses. In some instances, micrognathia may be due to mechanical influences during growth and development. The best example of this situation is the mandibular hypoplasia seen in the oligohydramnios sequence, in which compression impedes normal growth and development of the mandible. Teratogenic factors also have been suggested to play a role in the etiology of micrognathia. Observations in fetuses of mothers who received radiotherapy during pregnancy showed an increased incidence of mandibular hypoplasia.40 Administration of the antiniacin agent 6-aminonicotinamide and the glutamine analogue diazo-oxo norleucine to rats during gestational day 15 produced severe growth retardation of Meckel’s cartilage, thereby producing an inadequate framework for mandibular development.41 Anomalies of the mandible with or without ear abnormalities are considered to occur with a frequency greater than one of every 100 newborn babies.1 Micrognathia does not follow a sex preferential pattern. The mode of inheritance, if any, should be evaluated in the context of the disorder of which micrognathia constitutes a part. Prognosis, Treatment, and Prevention

The prognosis of the patient with mandibular hypoplasia depends on associated birth defects. Cases of isolated micrognathia or even Pierre Robin sequence have an excellent prognosis. The neonate with airway obstruction may require tracheotomy and feeding gastrostomy. Surgical mandibular advancement was previously not recommended for use during infancy.42 This has changed due to the availability of distraction osteogenesis. This technique has been used successfully in children as young as 6 months.43 As the distraction devices become smaller, they can be implanted in even younger infants. This technique may be used to prevent tracheotomy or to allow for decannulation in tracheotomy-dependent patients.44 When there is a stable airway and nutrition can be maintained, orthognathic surgery can be deferred until mid- to late adolescence depending on the sex, since females can undergo such surgery earlier. Micrognathia has been clearly identified in the prenatal period via ultrasonography.45,46 The routine ultrasonographic

Facial Bones

289

Fig. 8-12. Mild micrognathia in a 12-year-old male with MPS 1-H/I-S compound (A), moderate micrognathia in an infant with cerebrocostomandibular syndrome (B and C), and severe micrognathia associated with radial reduction defects in a 5-year-old boy with Nager syndrome (D). (B and C courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

examination between 16 and 18 gestational weeks should allow delineation of the morphology of the mandible. Prenatal recognition of micrognathia is helpful in that it allows the neonatologist, facial surgeon, otolaryngologist, and anesthetist to be prepared for possible complications during and after delivery. References (Micrognathia) 1. Melnick M: Anomalies of branchial-arch-derived otomandibular structures. In: Clinical Dysmorphology of Oral-Facial Structures. M Melnick, ED Shields, NJ Burzmski, eds. John Wright, PSG, Boston, 1982, p 336. 2. Warkany J: Congenital Malformations. Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 622. 3. Hall JG, Reed SD, Driscoll EP: Part 1. Amyoplasia: a common, sporadic condition with congenital contractures. Am J Med Genet 15: 571, 1983. 4. Ellis NA, German J: Molecular genetics of Bloom’s syndrome. Hum Molec Genet 5:1457, 1996.

5. Wagner T, Wirth J, Meyer J, et al.: Autosomal sex reversal and camptomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79:1111, 1994. 6. Dignan PSJ, Martin LW, Zenni EJ Jr: Pierre Robin anomaly with an accessory metacarpal of the index fingers: the Catel-Manzke syndrome. Clin Genet 29:168, 1986. 7. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’: Decentric small marker chromosome probably derived from a 22 (tetrasomy 22pter;q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 57:148, 1981. 8. Plotz FB, van Essen AJ, Bosschaart AN, et al.: Cerebro-costo-mandibular syndrome. Am J Med Genet 62:286, 1996. 9. Pena SDJ, Shokeir MHK: Autosomal recessive cerebro-oculo-facioskeletal (COFS) syndrome. Clin Genet 5:285, 1974. 10. Cohen MM Jr, Hall BD, Smith DW, et al.: A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular and limb anomalies. J Pediatr 83:280, 1973.

Table 8-8. Syndromes associated with micrognathia Causation Gene/Locus

Syndrome

Prominent Features

Amyoplasia congenita3

Round face; small upturned nose; midline capillary hemangioma; severe flexion contractures at metacarpophalangeal joints, with mild contractures at interphalangeal joints, hips usually dislocated, adducted, or abducted

Unknown, sporadic (108110)

Bloom4

Growth deficiency, mild microcephaly with dolichocephaly, small nose, facial telangiectatic erythema that involves the butterfly midface region exacerbated by sunlight

AR (210900) RECQL3, 15q26.1

Campomelic dysplasia5

Growth deficiency, large brain with gross cellular disorganization, small flat-appearing face, cleft palate, short palpebral fissures, anterior bowing of tibiae, short fibula, absence of mineralization of the sternum, hypogenitalism, XY gonadal dysgenesis

AR (211970) SOX9, 17q24-q25

Catel-Manzke6

Hyperphalangy of index finger, postnatal growth deficiency, cleft palate, malformed ears, cardiac defects, clinodactyly

(302380) Majority of cases are sporadic affected males

Cat eye7

Cognitive delay, mild hypertelorism, inferior coloboma of the iris, preauricular pits and tags, cardiac defects (TAPVR), imperforate anus, renal agenesis

(115470) partial tetrasomy 22 (isochromosome 22pter-q11)

Cerebro-costo-mandibular8

Cognitive delay, growth deficiency, glossoptosis, cleft soft palate, bell-shaped small thorax, anomalous rib insertion with ‘‘rib gaps’’

AD (117650)

Cerebro-oculofacio-skeletal (COFS)9

Reduced white matter of brain with gray mottling, microcephaly, large pinnae, blepharophimosis, microphthalmia, cataracts, nystagmus, camptodactyly, flexion contractures of elbows and knees, hirsutism, kyphosis

AR (214150, 126340) ERCC6, 10q11 ERCC2, 19q13

Cohen10

Truncal obesity, hypotonia, high nasal bridge, short philtrum, downslanting palpebral fissures, prominent maxillary central incisors, large ears, chorioretinal dystrophy, narrow hands and feet

AR (216550) COH1, 8q22

Cornelia de Lange11

Short stature, cognitive delay, initial hypertonicity, low-pitched weak cry, long curly eyelashes, small nose, bushy eyebrows, synophrys, hirsutism, micromelia, genital anomalies

AD (122470) Most cases sporadic NIPBL, 5p13.1

Deletion 22q11.212

Cleft palate, conotruncal heart malformation, thymic hypoplasia, abnormal external ear, prominent nasal tip, hypoplastic alae nasi, learning difficulties

(192430) microdeletion 22q11.2

Diamond-Blackfan anemia-microtiacleft palate13

Macrocytic anemia, short stature, downslanting palpebral fissure, microtia, cleft palate, micrognathia

Dominant (606164)

Dubowitz14

Prenatal growth deficiency, variable mental deficiency, short attention span, microcephaly, short palpebral fissures, round nasal tip, prominent dysplastic ears, eczema

AR (223370)

Escobar15

Multiple pterygia, short stature, inner canthal folds, cleft palate, emotionless face, scoliosis, camptodactyly, syndactyly, genital anomalies

AR (265000)

Facio-auriculo-vertebral spectrum16

Macrostomia, unilateral facial hypoplasia, microtia, periauricular tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate

Unknown, sporadic (164210, 257700)

Hallermann-Streiff17

Small stature, brachycephaly with parietal bossing, thin calvarium, delayed ossification of the sutures, microphthalmia, small nose, microstomia, hypoplasia of the teeth, atrophy of the skin, hypotrichosis

Unknown, sporadic (234100)

Lethal multiple pterygium18

Generalized amyoplasia, multiple pterygia, contractures, growth deficiency, epicanthal folds, ocular hypertelorism, flat nose, cryptorchidism, mild neck edema and loose skin

AR (253290) Heterogeneous

Marshall-Smith19

Accelerated linear growth and skeletal maturation, long cranium, prominent forehead, bluish sclerae, broad proximal and middle phalanges with narrow distal phalanges, hypertrichosis, respiratory problems

Unknown (602535)

Meckel-Gruber20

Growth deficiency, occipital encephalocele, microcephaly, ear anomalies, cleft palate, microphthalmia, polydactyly, cystic renal dysplasia, cryptorchidism

AR, multiple loci (606361) 8q24 (603194) 11q13 (249000) 17q22-q23 (continued )

290

Table 8-8. Syndromes associated with micrognathia (continued) Causation Gene/Locus

Syndrome

Prominent Features

Melnick-Needles (Oto-palatodigital spectrum)21

Melnick-Needles: prominent eyes, late closure of fontanels, short upper arms and distal phalanges, bowing of radius and tibia, coxa valga, small thoracic cage, pectus excavatum, iliac flaring; often male lethal

XL (309350, 311300, 304120, 305620) FLNA, Xq28 Allelic to OPD1, OPD2, frontometaphyseal dysplasia, periventricular heterotopia

Miller22

Downslanting palpebral fissures, eyelid coloboma, ectropion, cleft lip and/or palate, postaxial limb deficiencies, syndactyly, accessory nipple

AR (263750) Most sporadic, AD rarely reported

Miller-Dieker23

Lissencephaly, heterotopias, absent or hypoplastic corpus callosum, small brain stem, hypotonia, seizures, microcephaly, small nose, late eruption of primary teeth, cryptorchidism

(247200) Microdeletion 17p13.3

Moebius24

Mask-like facies with sixth and seventh nerve palsy, hypoplasia to absence of the central brain nuclei, myopathy

(157900) Majority of cases sporadic, few familial

Nager25

Normal intelligence, short stature, conductive deafness and articulation problems, malar hypoplasia, palpebral downslant, absence of lower eyelashes, periauricular tags, atresia of external ear canal, hypoplasia to aplasia of the thumb, proximal radioulnar synostosis, short forearms

AD, AR (154400)

Nijmegen breakage26

Microcephaly, short stature, palpebral upslant, long nose, immune dysfunction, chromosome breakage, malignancies, neurodegeneration

AR (251260) NBS1, 8q21

Pallister-Hall27

Hypothalamic hamartoblastoma, hypopituitarism, flat midface, anteverted nares, laryngeal cleft, bifid epiglottis, multiple frenuli, abnormal lung lobation, nail dysplasia, postaxial polydactyly, anal defects

AD (146510) GLI3, 7p13 Allelic to Greig

Progeria28

Alopecia, hypoplasia of nails, loss of subcutaneous fat, periarticular fibrosis, skeletal hypoplasia, dysphasia, dental anomalies, atherosclerosis

AD (176670) LMNA, 1q21.2

Prenatal accutane29

Bilateral microtia, anotia, U-shaped palatal cleft, ocular hypertelorism, conotruncal heart defects, hydrocephaly, cerebellar hypoplasia, agenesis of the vermis, thymic abnormalities

Teratogen

Seckel30

Prenatal growth deficiency, microcephaly, receding forehead, prominent nose, mental retardation

AR, heterogeneous (210600) ATR, 3q22 (606744) 18p11-q11

Splenogonadal fusion31

Fused spleen and gonad, limb defects, deep and narrow palate, multiple unerupted teeth

(183300) Sporadic, mostly males, possibly due to vascular event

Stickler32

Flat facies, depressed nasal bridge, epicanthal folds, clefts of hard and/soft palate, deafness, retinal detachment, cataracts, hypotonia, marfanoid habitus, flat vertebrae

AD (108300) COL2A1, 12q31 (604841) COL11A1, 1p21 (184840) COL1A2, 6p21

Treacher Collins33

Downslanting palpebral fissures, cleft in zygomatic bone, lower lid coloboma, partial to total absence of lower eyelashes, external ear malformation, conductive deafness, cleft palate, extension of scalp hair onto lateral cheek

AD (154500) TCOF1, 5q21-q33

Trisomy 834

Variable cognitive deficiency, strabismus, hypertelorism, full lips, cupped ears, camptodactyly, limited supination, long slender trunk, narrow pelvis

Abnormal karyotype

Trisomy 935

Growth deficiency, severe mental deficiency, narrow bifrontal diameter, prominent upper lip, low-set ears, joint anomalies, hypoplastic phalanges, congenital heart disease

Abnormal karyotype

Trisomy 1836

Growth deficiency, hypertonicity, prominent occiput, small mouth, clenched hand, overlapping fingers, cardiac defects, renal malformation, rocker-bottom feet

Abnormal karyotype

Deletion 4p37

Growth deficiency, hypotonia, severe mental deficiency, strabismus, hypertelorism, prominent glabella, posterior midline scalp defects, periaurcular tags, clefting, genital anomalies

Abnormal karyotype

Deletion 13q38

Growth deficiency, mental deficiency, microcephaly, hypertelorism, microphthalmia, retinoblastoma, webbed neck, congenital heart disease, hypospadias, lumbar agenesis

Abnormal karyotype

291

292

Craniofacial Structures

11. Allanson JE, Hennekam RCM, Ireland M: De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes. J Med Genet 34:645, 1997. 12. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 44:261, 1992. 13. Gripp KW, McDonald-McGinn DM, La Rossa D, et al.: Bilateral microtia and cleft palate in cousins with Diamond-Blackfan anemia. Am J Med Genet 101:268, 2001. 14. Tsukahara M, Opitz JM: Dubowitz syndrome: review of 141 cases including 36 previously unreported patients. Am J Med Genet 63:277, 1996. 15. Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes: a review and report of eleven patients. Am J Med Genet 12:377, 1982. 16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 17. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med Genet 41:488, 1991. 18. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809, 1984. 19. Williams DK, Carlton DR, Green SH, et al.: Marshall-Smith syndrome: the expanding phenotype. J Med Genet 34:842, 1997. 20. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997. 21. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum Disorders Clinical Collaborative Group: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 22. Miller M, Fineman R, Smith DW: Postaxial acrofacial dysostosis syndrome. J Pediatr 95:970, 1979. 23. Allanson JE, Ledbetter DH, Dobyns WB: Classical lissencephaly syndromes: does the face reflect the brain? J Med Genet 35:920, 1998. 24. Baraitser M: Genetics of Moebius syndrome. J Med Genet 14:415, 1977. 25. Aylsworth AS, Lin AE, Friedman PA: Nager acrofacial dysostosis: maleto-male transmission in 2 families. Am J Med Genet 41:83, 1991. 26. Van der Burgt I, Chrzanowska KH, Smeets D, et al.: Nijmegen breakage syndrome. J Med Genet 33:153, 1996. 27. Kang S, Allen J, Graham JM Jr, et al.: Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet 34:441, 1997. 28. Eriksson M, Brown WT, Gordon LB, et al.: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293, 2003. 29. Sulik KK, Cook CS, Webster WS: Teratogens and craniofacial malformations: relationships to cell death. Development 103(suppl):213, 1988. 30. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497, 2003. 31. Bonneau D, Roume J, Gonzalez M, et al.: Splenogonadal fusion limb defect syndrome: report of five new cases and review. Am J Med Genet 86:347, 1999. 32. Snead MP, Yates JRW: Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353, 1999. 33. Splendore A, Silva EO, Alonso LG, et al.: High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes. Hum Mutat 16:315, 2000. 34. Riccardi VM: Trisomy 8: an international study of 70 patients. Birth Defects Orig Artic Ser XIII(3C):171, 1977. 35. Cantu ES, Eicher DJ, Pai GS, et al.: Mosaic vs. nonmosaic trisomy 9: report of a liveborn infant evaluated by fluorescence in situ hybridization and review of the literature. Am J Med Genet 62:330, 1996.

36. Baty BJ, Blackburn BL, Carey JC: Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet 49:175, 1994. 37. Battaglia A, Carey JC, Cederholm P, et al.: Natural history of WolfHirschhorn syndrome: experience with 15 cases. Pediatrics 103:830, 1999. 38. Tranebjaerg L, Nielsen KB, Tommerup N, et al.: Interstitial deletion 13q: further delineation of the syndrome by clinical and highresolution chromosome analysis of five patients. Am J Med Genet 29:739, 1988. 39. Diewert VM: Correction between alterations in Meckel’s cartilage and induction of cleft palate with B-aminoproprionitrile in the rat. Teratology 24:43, 1981. 40. Fogh-Andersen P: Rare clefts of the face. Acta Chir Scand 129:275, 1965. 41. Diewert VM: Contributions of differential growth of cartilages to changes in craniofacial morphology. In: Factors and Mechanisms Influencing Bone Growth. Alan R. Liss, Inc, New York, 1982, p 229. 42. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. JL Marsh, MW Vannier, WG Stevens, eds. CV Mosby, St Louis, 1985, p 260. 43. Denny AD, Talisman R, Hanson PR, et al.: Mandibular distraction osteogenesis in very young patients to correct airway obstruction. Plast Reconstr Surg 108:302, 2001. 44. Perlyn CA, Schmelzer RE, Sutera SP, et al.: Effect of distraction osteogenesis of the mandible on upper airway volume and resistance in children with micrognathia. Plast Reconstr Surg 109:1809, 2002. 45. Malinger G, Rosen N, Achiron R, et al.: Pierre Robin sequence associated with amniotic band syndrome ultrasonographic diagnosis and pathogenesis. Prenat Diagn 7:455, 1987. 46. Rotten D, Levaillant JM, Martinez H, et al.: The fetal mandible: a 2D and 3D sonographic approach to the diagnosis of retrognathia and micrognathia. Ultrasound Obstet Gynecol 19:122, 2002.

8.9 Congenital Asymmetry of the Facial Skeleton Definition

Congenital asymmetry of the facial skeleton is a quantitative discrepancy in size between the right and left sides of the facial skeleton. The facial midline is determined by the sagittal line drawn from the vertex (highest midpoint of the craniofacies) through the nasion and subnasale points to the gnathion (lowest medial point of the mandible). Diagnosis

Asymmetry of the facial skeleton and of the human skull as a whole to a degree that can be readily appreciated is so common that it has to be recognized as the rule.1 Such normal or anatomic asymmetry must be distinguished from pathologic asymmetry (Fig. 8-13). This difficult task is facilitated by quantitative procedures that can validate clinical observations. Useful techniques include anthropometry, cephalometry, tridimensional computed tomography (CT), and for the prenatal period fetal cephalometry via ultrasound. These techniques not only describe the severity of the asymmetry but provide information necessary to plan adequate corrective treatment. During the neonatal period, one should be particularly careful in distinguishing between facial asymmetry resulting from molding of the cranial bones during the birth process and true malformation of the facial skeleton. Facial asymmetry resulting from excessive molding of the cranium or from displacement of the mandible during breech or face presentations is very common and is usually self-correcting. Morphometric analysis of the face is helpful in establishing the role of skeletal abnormalities in facial

Facial Bones

293

Fig. 8-13. Facial asymmetry in a 31-month-old male with hemifacial microsomia (A), an infant with asymmetric crying face (B), and a teenage girl with Parry-Romberg syndrome (C and D). (Courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

asymmetry. However, the precise diagnosis requires roentgenographic examination of the craniofacial skeleton, and sometimes more sophisticated technology such as CT, tridimensional imaging (TDI), and magnetic resonance imaging (MRI). With the anteroposterior radiographs of the skull, one can use cephalometric measurements to quantify the extent of the defect and the particular facial areas involved. CT, TDI, and MRI are very useful in distinguishing between congenital (‘‘developmental’’) skeletal facial asymmetry and acquired skeletal facial asymmetry due to pathologic processes and trauma. Radiologic analysis assessing asymmetry of the facial skeleton should include three planes as described by Murray and collaborators.2 The frontal plane view, which is evaluated with an anteroposterior cephalometric radiograph, demonstrates asymmetry of

the mandible, maxilla, pyriform apertures, and orbits. This radiographic view also discloses obliquity and rotation of the plane formed by the two mandibular midlines, dental and skeletal. The dental midline is rotated toward the normal side, while the skeletal midline is rotated toward the abnormal side. The sagittal plane view can demonstrate discrepancies in the ramus height and relationships of the maxilla, mandible, and base of the skull. A panoramic view may reveal anomalies in height and shape of the mandibular rami and the temporomandibular joint (TMJ). The transverse plane is evaluated with a submental vertex radiologic plate to demonstrate the shape and width of the mandibular body, asymmetry in the zygomatic arches, and medial and anterior displacement of the TMJ. The most common cause of congenital facial asymmetry probably is the group of disorders known as the otocraniofacial

294

Craniofacial Structures

syndromes.3 These involve unilateral and bilateral developmental malformations of the skeletal craniofacial structures that may arise from a growth deficiency of the first and second branchial arches. They include conditions such as mandibulofacial dysostosis and hemifacial microsomia. With an incidence of one in 4000, hemifacial microsomia represents a wide spectrum of abnormalities of the facial skeleton.4 Different classifications have been suggested according to the severity of the defects.5 In type I, the malformation of the facial skeleton is slight and mandibular growth is compromised; however, the anatomic development of the TMJ is not impaired. Type II shows a pronounced malformation of the facial skeleton. The body and ramus of the lower jaw, along with the TMJ, are underdeveloped on the affected side. Rudiments of the condylar and coronoid processes are situated below the malar arch and frontally to the site of the natural position of the articular fossa. Underdevelopment of the temporal bone, the mastoid process, and the articular fossa and tubercle also can be observed. Type III is also characterized by pronounced malformation of the facial skeleton. The body of the mandible on the affected side is underdeveloped and ends in a rudiment of the ramus. The TMJ is absent. Radiologic studies usually show pronounced asymmetry and disfigurement of the facial skeleton. The underdeveloped side of the face is flattened, involving the orbit, malar bone, and frontal and occipital bones. The affected malar bone is considerably lower than the analogous bone on the intact side. The body of the lower jaw is hypoplastic and deformed, and the ramus appears as a pointed rudiment.

Etiology and Distribution

Asymmetry of the facial skeleton rarely occurs as an isolated anomaly. In the majority of cases, it represents one component of a multiple anomaly syndrome, usually resulting from an insult in the early development of the branchial arches or brain. One must understand that in the human, various insults to the fetus can produce unilateral facial skeletal defects. Growth of the facial skeleton is influenced by multiple factors, including brain growth.6 Asymmetrical growth of the brain produces rotation of the face on the cranium, which progresses with age and further growth. As the temporal lobes of the cerebrum show a greater asymmetric development, increased displacement of the nasomaxillary segment on the affected side occurs, and this in turn produces a rotation of the face. This seems to apply to a few conditions that include facial asymmetry in their phenotype; however, it cannot be generalized. Vascular theories to explain unilateral birth defects have gained popularity.7–9 Robinson and collaborators7 suggested that a vascular accident interrupting the blood flow to developing facial structures could result in tissue ischemia, necrosis, or both. The severity of the resulting defects would be directly proportional to the magnitude and duration of tissue injury, allowing for a wide phenotypic variability. It has been suggested that a lesion in the stapedial artery, the second aortic arch vessel, can produce unilateral craniofacial defects. Animal models seem to support this theory.9 Vascular theories may also be supported by the increased incidence of hemifacial

Table 8-9. Syndromes associated with congenital asymmetry of the facial skeleton Causation Gene/Locus

Syndrome

Prominent Features

Apert13

Craniosynostosis, high forehead, flat facies, irregular supraorbital horizontal groove, shallow orbits, hypertelorism, severe syndactyly hands and feet, broad distal phalanges of thumb, mental retardation

AD (101200) FGFR2, 10q26

Craniofrontonasal14

Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal grooves and splits in nails

XL (304110) EFNB1, Xq12

Cat eye15

Mental deficiency, inferior coloboma of the iris, micrognathia, cardiac defects, anal atresia, rectovesicular fistula, renal agenesis

(115470) Partial tetrasomy 22 due to inv dup (22)(q11)

Facio-auriculo-vertebral spectrum16

Macrostomia, unilateral facial hypoplasia, micrognathia, microtia, periauricular tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate, renal and cardiac abnormalities

Unknown, sporadic (164210, 257700)

Hemimaxillofacial dysplasia17

Unilateral enlargement of maxillary alveolar bone and gingival, hypoplastic teeth, hypertrichosis of ipsilateral facial skin

Unknown

Hemifacial hyperplasia with strabismus18

Abnormal growth of the facial skeleton, zygomatic deficiency, convergent strabismus, amblyopia of the affected side, submucous cleft palate

AD (141350)

Hemifacial microsomia with radial defects19

Similar facial findings to those seen in hemifacial microsomia, periauricular pits or skin tags, shortening of the mandibular ramus, radial limb defects, triphalangeal thumbs, duplication of the thumb

AD (141400)

McCune-Albright20

Fibrous dysplasia in bone, irregular patches of pigment of trunk, precocious puberty, hyperthyroidism, hyperparathyroidism, acromegaly, Cushing, hyperprolactinemia, short stature

(174800) GNAS1, 20q13.2

Muenke21

Uni- or bicoronal synostosis, macrocephaly, hearing loss, learning differences

AD (602849) FGFR3, 4p16.3

Saethre-Chotzen22

Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue syndactyly, hallux valgus

AD (101400) TWIST, 7p21

Townes-Brocks23

Hemifacial microsomia with preauricular tags, abnormal ear shape, sensorineural hearing loss, thumb anomalies, imperforate anus, renal malformations

AD (107480) SALL1, 16q21.1

Wildervanck24

Ear anomalies, preauricular tags, pseudopapilledema, Duane anomaly, Klippel-Feil anomaly

(314600) Sporadic, most cases female

Facial Bones

microsomia in offspring of diabetic mothers10,11 and in products of twin or higher-order multiple pregancies.12 Several single-gene defects are known to cause skeletal facial asymmetry as part of the clinical picture (Table 8-9). An autosomal dominant form of isolated facial asymmetry has been described in the past; however, in this case the asymmetry is localized to the maxillomandibular region, without involvement of the upper face and midface.25 Other causes of congenital facial asymmetry include premature unilateral closure of the coronal suture, other craniosynostosis, TMJ anomalies, coronoid process hyperplasia, septic processes of the mandible, and trauma.9 Since skeletal facial asymmetry is not a primary birth defect, its occurrence is usually dependent on another underlying defect in facial embryogenesis. At present, no conclusive studies of sex distribution are available. Prognosis, Treatment, and Prevention

Advancements in surgical methodology have improved the prognosis for patients with facial asymmetry. Mildly affected individuals in whom there is no concern regarding appearance during childhood need no treatment until adolescence. At this time an assessment of the residual asymmetry at the end of growth can be made and appropriate surgery undertaken.4 For many years it was believed that the skeletal problems affecting the jaws and facial skeleton, even in severe cases, should not be surgically corrected until adolescence, mainly to avoid interference with growth. Surgery in the adolescent patient has been directed most often to the centralization of the mandible with bone grafting. Recent years have seen increased interest in earlier restoration of facial symmetry through surgery in the preschool period. Surgical procedures may include the use of costochondral grafts. These grafts with growth potential are placed into the vertical ramus of the mandible to correct any deficiency. Osteotomies, especially in the midface, are sometimes unavoidable. Distraction osteotomy of the mandible has been used successfully in young patients; however, on follow-up it became clear that the affected side grew at a slower rate than the contralateral side, and initial overcorrection was considered.26 A further definitive operation may be required at the end of growth. Prenatal diagnosis of this condition has been accomplished with ultrasonography.27 Fetal craniofacial asymmetry may be the first indication of a multiple congenital anomaly syndrome. At 16 weeks of gestation, an ultrasonographic coronal section may identify differences between both sides of the facial skeleton. Level two ultrasound may indicate the presence of other defects. Prenatal counseling should be available to all couples with a previously affected child. References (Congenital Asymmetry of the Facial Skeleton) 1. Brash JA: The Etiology of Irregularity and Malocclusion of the Teeth. Dental Board of the United Kingdom, London, 1956, p 31. 2. Murray JE, Kaban LB, Mulliken JB, et al.: Analysis and treatment of hemifacial microsomia. In: Craniofacial Surgery. E Caronni, ed. Little, Brown and Co, Boston, 1985, p 377. 3. Pruzansky S: Otocraniofacial syndromes: clinical studies on mandibulofacial dysostosis, hemifacial microsomia, and variants. In: Craniofacial Surgery. E Caronni, ed. Little, Brown and Co, Boston, 1985, p 351. 4. Poole MD: Hemifacial microsomia. World J Surg 13:396, 1989. 5. Bezrukov VM, Plotnikov NA, Gun’ko VI, et al.: Surgical correction of deformation of the facial skeleton in patients with hemifacial microsomia. Acta Chir Plast 30:202, 1988.

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6. Trenouth MJ: Asymmetry of the human skull during fetal growth. Anat Rec 211:205, 1985. 7. Robinson LK, Hoyme HE, Edwards DK, et al.: Vascular pathogenesis of unilateral craniofacial defects. J Pediatr 111:236, 1987. 8. Bavnick JNB, Weaver DD: Subclavian artery supply disruption sequence: Hypothesis of vascular etiology for Poland, Klippel-Feil and Mo¨bius anomalies. Am J Med Genet 23:903, 1986. 9. Poswillo D: The pathogenesis of the first and second branchial arch syndromes. Oral Surg 35:301, 1973. 10. Ewart-Toland A, Yankowitz J, Winder A, et al.: Oculoauriculovertebral abnormalities in children of diabetic mothers. Am J Med Genet 90:303, 2000. 11. Wang R, Martinez-Frias ML, Graham JM Jr: Infants of diabetic mothers are at increased risk for the oculo-auriculo-vertebral sequence: A case-based and case-control approach. J Pediatr 141:611, 2002. 12. Lawson K, Waterhouse N, Gault DT, et al.: Is hemifacial microsomia linked to multiple maternities? Br J Plast Surg 55:474, 2002. 13. Wilkie AOM, Slaney SF, Oldridge M, et al.: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165, 1995. 14. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Craniofrontonasal syndrome: study of 41 patients. Am J Med Genet 61:147, 1996. 15. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’: Decentric small marker chromosome probably derived from a 22 (tetrasomy 22pter;q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 57: 148, 1981. 16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 17. Miles DA, Lovas JL, Cohen MM Jr: Hemimaxillofacial dysplasia: a newly recognized disorder of facial asymmetry, hypertrichosis of the facial skin, unilateral enlargement of the maxilla, and hypoplastic teeth in two patients. Oral Surg Oral Med Oral Pathol 64:445, 1987. 18. Kurnit D, Hall JG, Shurtleff DB, et al.: An autosomal dominantly inherited syndrome of facial asymmetry, esotropia, amblyopia, and submucous cleft palate (Bencze syndrome). Clin Genet 16:301, 1979. 19. Moeschler J, Clarren SK: Familial occurrence of hemifacial microsomia with radial limb defects. Am J Med Genet 12:371, 1982. 20. Schwindinger WF, Francomano CA, Levine MA: Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G-protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci U S A 89:5152, 1992. 21. Gripp KW, McDonald-McGinn DM, Gaudenz K, et al.: Identification of a genetic cause for isolated unilateral coronal synostosis: a unique mutation in the fibroblast growth factor receptor 3. J Pediatr 132:714, 1998. 22. Paznekas WA, Cunningham ML, Howard TD, et al.: Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet 62:1370, 1998. 23. Kohlhase J, Wischermann A, Reichenbach H, et al.: Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet 18:81, 1998. 24. Balci S, Oguz KK, Firat MM, et al.: Cervical diastematomyelia in cervicooculo-acoustic (Wildervanck) syndrome: MRI findings. Clin Dysmorphol 11:125, 2002. 25. Burchfield D, Escobar V: Familial facial asymmetry (autosomal dominant hemihypertrophy?). Oral Surg Oral Med Oral Pathol 50: 321, 1980. 26. Hollier LH, Kim JH, Grayson B, et al.: Mandibular growth after distraction in patients under 48 months of age. Plast Reconstr Surg 103:1361, 1999. 27. Tamas DE, Mahony BS, Bowie JD, et al.: Prenatal sonographic diagnosis of hemifacial microsomia (Goldenhar-Gorlin syndrome). J Ultrasound Med 5:461, 1986.

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9 Eye Elias I. Traboulsi

O

cular malformations can occur in isolation or accompany other systemic abnormalities in the context of malformation syndromes. Several ocular malformations can coexist, resulting in complex but well-defined clinical ocular phenotypes such as persistent hyperplastic primary vitreous or aniridia. Other malformations such as Peters anomaly and the morning glory disc anomaly are extremely variable in clinical appearance and have been given a number of descriptive names over the years because of a failure to recognize the spectrum in their morphology. Major ocular malformations are diagnosed at or shortly after birth because of abnormal appearance of the eye or poor vision. Less severe anomalies are usually diagnosed during routine ocular examinations. Infants with multiple congenital anomalies are usually screened for ocular defects, which may be diagnostic. Some ocular anomalies can be classified according to the presumed faulty ocular developmental process that has lead to their formation (Table 9-1); others result from faulty induction, distribution, or resorption of specific embryonic cellular masses such as the neural crest cells in anterior segment dysgenesis (Axenfeld-Rieger spectrum). The number of genes that have been linked to individual ocular malformations is increasing, and a partial list is given in Table 9-2. The management of congenital ocular malformations is challenging but often rewarding. Substantial improvement in visual outcome is possible in many cases in which early recognition of the anomaly results in correction of refractive errors, institution of strabismus and amblyopia therapy as needed, and application of surgical techniques to clear the visual axis where ocular media opacification such as corneal opacities, cataracts, or hyaloid membrane remnants exist. Embryology

The embryonic eye first appears as a depression (optic pit) in the developing forebrain when the neural groove is still open. After complete closure of the neural groove, the optic pits derived from neural ectoderm move away from the brain and toward the surface ectoderm and form the single-layered optic vesicles. The connection between the optic vesicle and the forebrain constricts, forming the optic stalk. Subsequent invagination of the optic vesicle creates the optic cup, whose cells will contribute to the development of the retinal pigment epithelium, neurosensory retina,

ciliary epithelium, iris neuroepithelium, and constrictor and dilator pupillary muscles; the inner layer of the optic cup gives rise to the neurosensory retina, while the outer layer gives rise to the retinal pigment epithelium. There remains a potential space between the two layers that fills with fluid in retinal detachment. At 6 weeks, the inferiorly located embryonic fissure, through which the mesodermal primordium of the hyaloid system of blood vessels has entered, starts to close in the equatorial region and proceeds posteriorly and anteriorly. Failure of closure of the embryonic fissure results in typical inferior uveoretinal colobomas, which can be localized to the posterior segment of the eye or to the iris (a uveal structure and the most anterior part of the fissure to close), or may extend from the optic disc anteriorly to involve the iris. Although all retinal layers, including the rod and cone photoreceptors, are distinguishable by week 12, they are not well-developed until the 8th month of gestation. The macula continues to mature postnatally, and the infant does not attain full visual potential until age 2 to 4 years. Lens development begins as a focal thickening of surface ectoderm overlying the optic cup. When the neuroectodermally derived optic vesicle approximates the surface ectoderm and starts to invaginate, the lens placode is incorporated into this structure, forming the lens vesicle that separates from the surface ectoderm by 35 days. The posterior epithelial cells of the lens primordium elongate and differentiate into primary lens fibers. After filling the lens cavity, the nuclei of these cells disappear and protein synthesis ceases. The anterior lens epithelium continues to form secondary lens fibers that accumulate concentrically around the embryonic nucleus throughout life. The lens capsule is the basement membrane of the anterior lens epithelium. Most of the remaining anterior segment structures are derived from neural crest. Neural crest cells form in the dorsal midline between the brain and surface ectoderm after closure of the neural groove and subsequently move rostrally to form a cellular cluster situated between the optic cup and the overlying surface ectoderm. These cells migrate in three successive waves into the anterior segment of the eye, contributing to the development of the cornea, angle structures, iris, and ciliary region. The sclera, choroidal tissues, and surrounding orbital soft tissue and bone as well as many structures of the head and face are also derived from neural crest cells. 297

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Craniofacial Structures Table 9-1. Malformation syndromes of the eye Failure of optic vesicle to form

Iridohyaloidal vessels

Anophthalmia

Atypical coloboma Persistent pupillary membrane

Failure of optic vesicle to invaginate

Congenital cystic eye Failure of fetal fissure to close

Colobomatous microphthalmia

Congenital falciform fold of the retina Persistent hyperplastic primary vitreous Patent and persistent hyaloid artery Congenital nonattachment of the retina

Uveal coloboma

Failure of ganglion cells to develop

Colobomatous microphthalmia with cyst

Optic nerve hypoplasia

Neuroectodermal abnormality with major effect on development of the iris

Failure of posterior sclera and/or lamina cribrosa to form

Aniridia

Optic pit

Failure of normal separation of lens vesicle from surface ectoderm with ensuing abnormalities of the cornea, iris, and lens

Morning glory disc anomaly

Peters anomaly

Contractile peripapillary coloboma Choristomatous malformations

Sclerocornea

Epibulbar dermoid

Congenital anterior staphyloma1

Medulloepithelioma

Anterior polar cataracts Congenital aphakia Posterior keratoconus Von Hippel internal ulcer

Failure of lid fissure to form

Cryptophthalmia Ankyloblepharon

Congenital cornea guttata with anterior polar cataracts

Failure of lacrimal passages to form

Neural crest abnormalities with anterior segment dysgenesis

Congenital nasolacrimal duct obstruction

Atresia of punctae and canaliculi Congenital dacryocystocele

Axenfeld anomaly Rieger anomaly

Abnormalities of collagen structure

Infantile glaucoma

Nanophthalmos

Congenital hereditary endothelial dystrophy

Megalocornea

Congenital ectropion of the iris

Congenital hereditary stromal dystrophy

Congenital microcornea

Cornea plana

Ectopia lentis et pupillae Iridoschisis Congenital cysts of the iris Failure of regression of fetal vasculature and hyaloidal blood vessels

Mittendorf dot

Failure of extraocular muscles to develop

Aplasia of extraocular muscles Abnormalities of forebrain development with resultant ocular malformations

Cyclopia

Bergmeister papilla

Development of the vitreous begins with the appearance of the hyaloid vasculature, which, along with the mesenchymal cells and fibrillar material, forms the primary vitreous. The hyaloid vessels anastomose anteriorly with the system of blood vessels around the lens and form the tunica vasculosa lentis that completely envelops and provides nutrients to the developing lens, the most metabolically active part of the embryonic eye. The secondary vitreous, an avascular and more compact fibrillar network,

begins to replace the primary vitreous at 8 weeks. It starts from the periphery of the globe and goes toward the center, compressing the primary vitreal structures that regress, leaving in the newborn and adult eye a hollow, hornlike structure: the canal of Cloquet. Occasionally, and in otherwise normal eyes, remnants of the primary vitreous persist as Mittendorf dots on the posterior lens capsule or as a small fibrous veil over the optic disc, forming the so-called Bergmeister papilla.

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Table 9-2. Selected congenital ocular malformations and their responsible genes Gene

Inheritance

Ocular Malformation

SOX2

AR

Anophthalmia

RAX

AD

Microphthalmia

CHX10

AR

Microphthalmia, cataracts, and iris abnormalities

PAX2

AD

Oculorenal syndrome

PAX6

AD

Aniridia, Peters anomaly, anterior segment dysgenesis, foveal hypoplasia, autosomal dominant keratitis, congenital cataract

PITX2

AD

Axenfeld-Rieger syndrome, iridogoniodysgenesis, Peters anomaly

PITX3

AD

Anterior segment mesenchymal dysgenesis and cataracts, congenital cataracts

FOXC1

AD

Anterior segment dysgenesis

FOXC2

AD

Lymphedema-distichiasis, familial distichiasis

FOXL2

AD

Blepharophimosis syndrome

9.1 Anophthalmia Definition

Anophthalmia is the apparent absence of the globe in an orbit that otherwise contains normal adnexal elements. Diagnosis

The lids in anophthalmia are structurally normal except for a decreased horizontal dimension. Normal conjunctiva lines the inside of the lids and orbit, and there is a functioning lacrimal gland. Rudiments of optic vesicle-derived structures and structures derived from the mesoderm and/or neural crest may be found on histopathologic sectioning of the orbit in consecutive or degenerative anophthalmia (clinical anophthalmia) but not in primary or true anophthalmia. The orbit is shallow and orbital volume remains small with increasing age, presumably because of absence of the trophic action of the globe on the orbit (Fig. 9-1). Clinical anophthalmia may be unilateral or bilateral. Etiology and Distribution

When unilateral, there may be contralateral microphthalmia. True or primary anophthalmia is extremely rare and results from failure of the optic vesicle to bud from the cerebral vesicle; the optic nerves and tract are usually absent. In secondary anophthalmia usually there are associated severe forebrain malformations such as holoprosencephaly, and affected fetuses are usually aborted. Consecutive or degenerative anophthalmia results from regression or degeneration of the optic vesicle. Inherited isolated anophthalmia is usually autosomal recessive.1 Driggers et al. reported a child with isolated bilateral anophthalmia and an apparent balanced chromosomal translocation: 46,XX,t(3;11)(q27;p11.2).2 Fantes et al. found that this child had, in fact, a submicroscopic deletion that eliminated the SOX2 gene on chromosome 3 and went on to show nonsense mutations in SOX2 in four of 11 subjects with bilateral anophthalmia.3 SOX2

Fig. 9-1. Clinical anophthalmia. Infant with apparent bilateral anophthalmia with small orbits and normal adnexae (top). Middle and bottom photos show another infant who appears anophthalmic with lids closed. Extreme microphthalmia is evident when lids are separated.

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lies within an intron of a nonexpressed gene, SOX2OT, and is expressed in neuroectoderm early in development. SOX2 protein interacts cooperatively with PAX6 in the induction of lens development and delta-crystallin expression. Traboulsi et al. found a null mutation in SOX2 in a girl with bilateral clinical anophthalmia and absence of the optic nerves, chiasm, and optic tracts (unpublished data). Anophthalmia may be part of multisystem malformation syndromes such as the Waardenburg recessive anophthalmia syndrome or the Lenz microphthalmia syndrome. Waardenburg anophthalmia syndrome is characterized by mental retardation; unilateral or bilateral clinical absence of the globe; distal limb abnormalities in the form of syndactyly, camptodactyly, or hypodactyly; and other inconsistent malformations.4 Lenz syndrome is X-linked and is characterized by microphthalmia or clinical anophthalmia, simple ears, cardiovascular and urogenital anomalies, and distal limb abnormalities such as clinodactyly or duplication of the thumb.5 Anophthalmia also occurs in the Sjo¨gren-Larsson syndrome with mental retardation and other neurologic abnormalities. Prognosis, Prevention, and Treatment

Treatment of anophthalmia consists of maintenance of orbital volume and conjunctival fornical depth by insertion of ocular prostheses of increasing sizes into the orbit. References (Anophthalmia) 1. Kohn G, el Shawwa R, el Rayyes E: Isolated ‘‘clinical anophthalmia’’ in an extensively affected Arab kindred. Clin Genet 33:321, 1988. 2. Driggers RW, Macri CJ, Greenwald J, et al.: Isolated bilateral anophthalmia in a girl with an apparently balanced de novo translocation: 46,XX,t(3;11)(q27;p11.2). Am J Med Genet 87:201, 1999. 3. Fantes J, Ragge NK, Lynch SA, et al.: Mutations in SOX2 cause anophthalmia. Nat Genet 33:461, 2003. 4. Traboulsi EI, Nasr A, Fahd SD, et al.: Waardenburg’s recessive anophthalmia syndrome. Ophthal Paediatr Genet 4:13, 1984. 5. Traboulsi EI, Lenz W, Gonzales-Ramos M, et al.: The Lenz microphthalmia syndrome. Am J Ophthalmol 105:40, 1988.

9.2 Microphthalmia and Typical Uveal Coloboma Definition

In microphthalmia there is a reduction in the volume of the eye. The corneal diameter is usually less than 10 mm, and the anteroposterior globe diameter is less than 20 mm. Diagnosis

There is a wide spectrum of malformations ranging from a mild decrease in the diameter of the eye to extreme microphthalmia or clinical anophthalmia in which remnants of optic vesicle-derived structures can only be found on serial histologic section of the orbit.1 Etiology and Distribution

In a prospective study of 50,000 pregnancies in the United States, the incidence of microphthalmia/clinical anophthalmia was found to be 0.22 per 1000 births; the incidence of coloboma was 0.26 per 1000. About 0.6–1.9% of blind adults have microphthalmia/ coloboma, and 3.2–11.2% of blind children have microphthalmia.2 The diagnosis of microphthalmia can generally be made by inspection of the eye (Fig. 9-2). The cornea is small but may be of normal size in posterior microphthalmos.3 Microcornea can occur in the absence of microphthalmia as a dominant or recessive trait.

Fig. 9-2. Bilateral colobomas of the iris in a patient with the Lenz microphthalmia syndrome. Note smaller palpebral fissure and iris on the left.

There may be a coloboma of the iris, choroid, and/or optic nerve. Cataracts may be present. Microphthalmic eyes usually have high hypermetropic refractive errors but may be myopic. The diagnosis of borderline cases can be confirmed by measuring the diameter of the eye using ultrasonography. The normal adult eye measures between 21.50 and 27.00 mm. Microphthalmia can be unilateral or bilateral and may or may not be associated with uveal coloboma, hence its general classification into colobomatous and noncolobomatous. Asymmetric reduction of the volume of the eyes is common in bilateral cases. Large colobomas may produce a white reflex from the pupil (leukocoria) and have been confused with retinoblastoma. The ocular complications of microphthalmia/coloboma include high refractive errors, angle-closure glaucoma, cataracts, macular or optic nerve involvement, subretinal neovascularization, and, rarely, retinal detachment. Colobomas result from failure of closure of the fetal fissure in the invaginated optic vesicle. This process is usually completed by week 6 of gestation. Since the fetal fissure is located inferiorly, ‘‘typical’’ colobomas are inferonasal and may involve the iris, ciliary body, and/or inferior choroid. The optic nerve head may also be included in the colobomatous defect. Eyes with colobomas may be of normal size but are generally microphthalmic. A posterior or inferior cyst may form in the area of defective closure, producing microphthalmia with cyst. Patients with this condition can present with a bulging of the inferior lid and a superior displacement of the globe by the cyst.4–9 The pathogenetic mechanisms leading to microphthalmia are unclear. The coordinated expression of a large number of developmental genes is necessary for normal ocular and optic nerve development, and the pathways and interactions between these genes are currently being elucidated. Degeneration of the developing optic vesicle results in secondary or consecutive anophthalmia. Microphthalmia can be isolated or familial or can occur in a number of single gene, chromosomal, and embryopathic multisystem malformation syndromes (Tables 9-1 and 9-3).10,11 It is estimated that 15–30% of patients with microphthalmia/coloboma have the CHARGE syndrome.12 In a review of 1313 cases of microphthalmia/ coloboma, Fujiki et al. found that 15% were autosomal recessive, 22% were autosomal dominant, and the rest were isolated.13 Dominant microphthalmia/coloboma may be isolated or may be associated with congenital cataracts or with myopia and ectopic pupils. Variable expressivity is the rule in familial occurrences, with some family

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Table 9-3. A practical classification of microphthalmia/coloboma Isolated microphthalmia (AD) Colobomatous: isolated uveoretinal coloboma; microphthalmia with cyst

Microphthalmia with multiple congenital anomaly syndromes CHARGE syndrome (AD)

Noncolobomatous

Duker syndrome

Microphthalmia with ocular anomalies

Oculo-dento-osseous dysplasia (AD, AR)

Lenz microphthalmia syndrome (XR) Microphthalmia with cataract (AD, AR) Microphthalmia with myopia and corectopia (AD) Microphthalmia with ectopia lentis Microphthalmia with congenital retinal detachment (AR) Persistent hyperplastic primary vitreous (sporadic)

Cryptophthalmia syndrome (AD, AR) Cerebro-oculo-facial syndrome (AR) Goltz syndrome or focal dermal hypoplasia (XD) Lowe syndrome (XR) Meckel-Gruber syndrome (AR)

Aicardi syndrome

Basal cell nevus syndrome of GorlinGoltz (AD)

Microphthalmia with mental retardation

Congenital contractural arachznodactyly (AD)

Microphthalmia with mental retardation (AD, AR, XR)

Rubinstein-Taybi syndrome

Microphthalmia with mental retardation and congenital spastic diplegia (Sjogren-Larsson)

Cross syndrome (AR) Fanconi syndrome (AR) Diamond-Blackfan syndrome (AR) Epidermal nevus syndrome

Microphthalmia with craniofacial malformations

Facio-auriculo-vertebral syndrome

Microphthalmia in chromosomal anomalies

Hallermann-Streiff syndrome

T-13 (Patau)

Amniotic band syndrome

4p- (Wolf-Hirschhorn)

Transverse facial cleft

18q-

Microphthalmia with cleft lip/palate

T-18 (Edwards)

Microphthalmia with microcephaly

‘‘Cat eye’’ syndrome (marker 22)

Microphthalmia with microcephaly and retinal folds (XR, AR) Microphthalmia with hydrocephalus and congenital retinal nonattachment (Warburg syndrome) Microphthalmia with malformations of the hands and feet

Other chromosomal aberrations14,18 Microphthalmia and intrauterine insults

Maternal drug intake: thalidomide, alcohol, isotretinoin, others Maternal vitamin A deficiency Maternal phenylketonuria Maternal fever or radiation exposure

Microphthalmia with polydactyly Waardenburg anophthalmia syndrome (AR) Subgroup of CHARGE syndrome (bifid thumbs)

members exhibiting severe microphthalmia and others only small asymptomatic uveal colobomas in normal-sized eyes, hence the importance of ocular examination of all family members. Because of incomplete penetrance, Fujiki et al. estimated that, in families with dominant microphthalmia/coloboma, unaffected individuals have an 8.6% chance of having an affected offspring.13 Warburg and Friedrich14 reviewed the chromosomal abnormalities and Gregory-Evans et al. reviewed the gene mutations associated with microphthalmia/coloboma.11 Percin et al. described mutations in the homeobox gene CHX10 (14q24.3) in two families with autosomal recessive, nonsyndromic microphthalmia, iris abnormalities, and coloboma.15

Intrauterine infections: Cytomegalovirus, Epstein-Barr virus, varicella, herpes simplex, rubella, toxoplasma

Like other homeobox proteins, CHX10 is a transcription factor that binds to specific DNA sequences in the regulatory regions of other genes and affects their transcription during development. Chx10 mutations were previously found in the ocular retardation mouse model, which is characterized by microphthalmia, a thin hypocellular retina and optic nerve aplasia.16 One form of autosomal recessive complex microphthalmia was found by Bessant et al. to map to 14q32.17 Phenotypic features included sclerocornea (eight of eight patients) with secondary corneal vascularization (six of eight patients) and staphyloma formation (three of eight patients), elevated intraocular pressure (five of eight patients), and short axial length (five of five measured).17,18 These

302

Craniofacial Structures

authors ruled out CHX10 and OTX2 as candidate genes in this pedigree. Lehman et al. reported a large Mexican-American pedigree with isolated X-linked recessive colobomatous microphthalmia that maps to either the proximal p or q arm of the X chromosome.19 Microphthalmia can result from intrauterine infection with cytomegalovirus, Epstein-Barr virus, rubella, toxoplasma, herpes simplex, and varicella. Maternal intake of thalidomide, alcohol, isotretinoin, and other medications can lead to microphthalmia in the offspring. Maternal fever or radiation exposure can also result in microphthalmia. Prognosis, Prevention, and Treatment

The treatment of microphthalmia/coloboma depends on the severity of ocular involvement. Errors of refraction should be corrected. Cataract extraction is performed if the retina is attached and the size of the eye is not extremely small. Corneal transplantation can be performed if the cornea is opaque, but with mediocre results.20 Prostheses are fit over very small blind eyes for cosmetic purposes. Genetic counseling should be provided after examination of all available family members to determine the possible mode of inheritance in familial cases. The empiric risk of recurrence in a sibling is 2% if both parents are unaffected and increases to 14% if one parent is affected. The yield of chromosomal studies is poor for isolated microphthalmia/coloboma but increases significantly if there is associated mental retardation and at least one other congenital malformation. Prenatal diagnosis with ultrasonography should be possible if the size of the eye is significantly reduced.21 Hypothalamic dysfunction has been reported in patients with microphthalmia, and the potential for developing hypopituitarism should be included in the counseling of these patients. References (Microphthalmia and Typical Uveal Coloboma) 1. Pagon R: Ocular coloboma. Surv Ophthalmol 25:223, 1981. 2. Bateman J: Microphthalmos. Int Ophthalmol Clin 24:87, 1984. 3. Spitznas M, Gerke E, Bateman JB: Hereditary posterior microphthalmos with papillomacular fold and high hyperopia. Arch Ophthalmol 101:413, 1983. 4. Waring GO 3rd, Roth AM, Rodrigues MM: Clinicopathologic correlation of microphthalmos with cyst. Am J Ophthalmol 82:714, 1976. 5. Porges Y, Gershoni-Baruch R, Leibu R, et al.: Hereditary microphthalmia with colobomatous cyst. Am J Ophthalmol 114:30, 1992. 6. McLean CJ, Ragge NK, Jones RB, et al.: The management of orbital cysts associated with congenital microphthalmos and anophthalmos. Br J Ophthalmol 87:860, 2003. 7. Makley TA Jr, Battles M: Microphthalmos with cyst. Report of two cases in the same family. Surv Ophthalmol 13:200, 1969. 8. Leatherbarrow B, Kwartz J, Noble JL: Microphthalmos with cyst in monozygous twins. J Pediatr Ophthalmol Strabismus 27:294, 1990. 9. Gupta PC, Peralta D, Parker M, et al.: Bilateral microphthalmia with cyst, facial clefts, and limb anomalies: a new syndrome with features of Waardenburg syndrome, cerebro-oculo-nasal syndrome, and craniotelencephalic dysplasia. Am J Med Genet 117A:72, 2003. 10. Warburg M: Update of sporadic microphthalmos and coloboma. Noninherited anomalies. Ophthalmic Paediatr Genet 13:111, 1992. 11. Gregory-Evans CY, Williams MJ, Halford S, et al.: Ocular coloboma: a reassessment in the age of molecular neuroscience. J Med Genet 41:881, 2004. 12. Tellier AL, Cormier-Daire V, Abadie V, et al.: CHARGE syndrome: report of 47 cases and review. Am J Med Genet 76:402, 1998. 13. Fujiki K, Nakajima A, Yasuda N, et al.: Genetic analysis of microphthalmos. Ophthalmic Paediatr Genet 1:139, 1982.

14. Warburg M, Friedrich U: Coloboma and microphthalmos in chromosomal aberrations. Chromosomal aberrations and neural crest cell developmental field. Ophthalmic Paediatr Genet 8:105, 1987. 15. Ferda Percin E, Ploder LA, Yu JJ, et al.: Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Nat Genet 25:397, 2000. 16. Burmeister M, Novak J, Liang MY, et al.: Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat Genet 12:376, 1996. 17. Bessant DA, Khaliq S, Hameed A, et al.: A locus for autosomal recessive congenital microphthalmia maps to chromosome 14q32. Am J Hum Genet 62:1113, 1998. 18. Bessant DA, Anwar K, Khaliq S, et al.: Phenotype of autosomal recessive congenital microphthalmia mapping to chromosome 14q32. Br J Ophthalmol 83:919, 1999. 19. Lehman DM, Sponsel WE, Stratton RF, et al.: Genetic mapping of a novel X-linked recessive colobomatous microphthalmia. Am J Med Genet 101:114, 2001. 20. Feldman ST, Frucht-Pery J, Brown SI: Corneal transplantation in microphthalmic eyes. Am J Ophthalmol 104:164, 1987. 21. Feldman E, Shalev E, Weiner E, et al.: Microphthalmia-prenatal ultrasonic diagnosis: a case report. Prenat Diagn 5:205, 1985.

9.3 Cyclopia and Synophthalmia Definition

Cyclopia (a single midline eye) and synophthalmia (fusion of the eyes) encompass a spectrum of ocular malformations stemming from an abnormality in the development of the forebrain and frontonasal processes.1 Diagnosis

The eyes, orbits, and most of the midfacial structures may be absent. The eyes and orbits may be normal but closely set and with a single nostril, or the malformation may fit into the spectrum between these extremes. Cyclopia and synophthalmia are two distinct ocular malformations in this spectrum. The anterior part of the brain and the mesodermal midline structures are always abnormal in infants with synophthalmia or cyclopia. The process may involve only one side of the face. Etiology and Distribution

Cyclopia is very rare and seems to occur preferentially in females. It has been reported in female siblings.2 Affected fetuses are usually aborted in the third trimester of gestation. The holoprosencephalic conditions with and without cyclopia are discussed in Section 15.4. The globe in cyclopia may be relatively normal except for retinochoroidal coloboma and retinal dysplasia; however, the globe is usually severely malformed, with a rudimentary dysplastic retina and undifferentiated mesodermal tissue without an optic nerve. Intermediate degrees of abnormalities can occur. Rarely an anophthalmic median orbit is found. In synophthalmia there is a variable degree of fusion of the two developing optic vesicles (Fig. 9-3). All structures may be single except for the presence of a large duplicated lens. Conversely, all structures may be duplicated except for a single optic nerve.3 The optic nerve may also be duplicated. In less severe forms of this spectrum of malformations, there may be two separate eyes in a single median orbit or two separate orbits set very close together in the midface. In such cases, the forebrain is always affected with bilateral or unilateral arrhinencephaly.

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Fig. 9-3. Two infants with cyclopia and alobar holoprosencephaly. A proboscis is located above the synophthalmia. (Courtesy of Dr. Charles I. Scott Jr, A. I. duPont Hospital for Children, Wilmington, DE, and Dr. Will Blackburn, Fairhope, AL.)

It is believed that the spectrum of holoprosencephaly/cyclopia/ synophthalmus anomalies result from a disturbance in the activity of the prosencephalic organizing center, with gross underdevelopment of the telencephalon and structures derived from the frontonasal processes and overgrowth of the maxillary processes that meet in the midline. A number of developmental genes are involved in this process. Mutations in sonic hedgehog (SHH) cause holoprosencephaly with or without cyclopia, with significant phenotypic variations among family members carrying the same mutation.4 Cyclopia has also been reported with mutations in SIX3,5 in patients with rearrangements of chromosome 3,6 in trisomy 13,7 as well as with other chromosomal abnormalities.8 Prognosis, Prevention, and Treatment

There is no specific treatment for this condition. References (Cyclopia and Synophthalmia) 1. Torczynski E, Jacobiec FA, Johnston MC, et al.: Synophthalmia and cyclopia: a histopathologic, radiographic, and organogenetic analysis. Doc Ophthalmol 44:311, 1977. 2. Balci S, Onol B, Ercal MD, et al.: Autosomal recessive alobar holoprosencephaly with cyclops in three female sibs: prenatal ultrasonographic diagnosis at 18th week. Clin Dysmorphol 2:165, 1993. 3. Liu DP, Burrowes DM, Qureshi MN: Cyclopia: craniofacial appearance on MR and three-dimensional CT. AJNR Am J Neuroradiol 18:543, 1997. 4. Roessler E, Belloni E, Gaudenz K, et al.: Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357, 1996. 5. Pasquier L, Dubourg C, Blayau M, et al.: A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. Eur J Hum Genet 8:797, 2000. 6. Dallapiccola B, Ferranti G: Duplication 3p and cyclopia. Clin Genet 37:490, 1990. 7. Tomoda K, Shea JJ, Shenefelt RE, et al.: Temporal bone findings in trisomy 13 with cyclopia. Arch Otolaryngol 109:553, 1983. 8. Howard RO: Chromosomal abnormalities associated with cyclopia and synophthalmia. Trans Am Ophthalmol Soc 75:505, 1977.

9.4 Cryptophthalmos Definition

Cryptophthalmos is a hidden eye behind skin continuing from the forehead onto the cheek and with no recognizable lid structures. Diagnosis

In typical cryptophthalmos, the eyes are usually malformed, with anomalies ranging from anterior segment dysgenesis to microphthalmia. Francois divided cryptophthalmos into three types.1 In the first typical and complete form, the eyelids are absent and skin extends continuously from the forehead to the cheek, passing in front of the orbit, where it forms a small depression (Fig. 9-4). The eyebrows are poorly developed or nonexistent. The anterior hairline at the temporal area extends forward to fuse with the malformed brow. The eyelashes, Meibomian glands, lacrimal glands, and lacrimal punctae are absent. The eyeball can be palpated through the skin, to which it is usually adherent. There is reaction to light with contraction of the orbicularis, but the eye is usually microphthalmic with major dysplasia, usually more marked in the anterior segment, which is comprised of the conjunctiva, cornea, anterior chamber angle, iris, and lens. There is no conjunctival sac, and incision of the skin often opens directly into the eye. In the second incomplete, atypical, or partial form of cryptophthalmos, there are rudimentary lid structures, and a conjunctival sac may be present temporally. The eyeball is usually microphthalmic and covered with skin. In the third and least severe abortive form, the upper eyelid is adherent to the superior aspect of the globe, does not carry lashes, and continues over the cornea as an epidermal membrane. The free part of the cornea may be vascularized, opaque, or keratinized. The lower eyelid is normal but may lack a lacrimal punctum. The globe is generally of normal size.

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Fig. 9-4. Left: unilateral cryptophthalmia, syndactyly, nasal anomalies, and genital anomalies in a newborn female with cryptophthalmia syndrome. Right: cryptophthalmia syndrome in a 29-year-old mentally retarded female showing partial absence of the eyebrows and eyelashes, rudimentary eyelids, broad nasal root, nasal coloboma, and repaired cleft lip and palate. (Left figure courtesy of Dr. I. T. Thomas, Bowman Gray School of Medicine, Winston-Salem, NC.)

Cases in which there is typical cryptophthalmos on one side and abortive cryptophthalmos on the other side indicate that the two anomalies are equivalent. Cases have been reported with typical cryptophthalmos on one side and a dermoid, microphthalmia, or lid coloboma on the other side. A fourth type of isolated cryptophthalmos also exists, in which the lids are formed with a full complement of adnexal accessories. The lid fissure is displaced inferiorly close to the inferior orbital rim, but the conjunctival sac is rudimentary and the globe is not visible. There is a wide upper lid that adheres to the underlying malformed globe, and there is a short lower lid. The family reported twice by Coover2 (the same family was also reported by Magruder3) and the mother and daughter reported by Saal et al. are examples of this apparently distinct autosomal dominant syndrome in which cryptophthalmos is not accompanied by mental retardation or other congenital anomalies.4 Etiology and Distribution

Cryptophthalmos is most often accompanied by systemic anomalies and inherited in an autosomal recessive fashion, hence the term cryptophthalmos syndrome, cryptophthalmos-syndactyly syndrome, syndromic cryptophthalmos, and Fraser syndrome. The most prominent features of the cryptophthalmos syndrome include mental retardation; dyscephaly with skull malformations mostly in the region of the temples and forehead; anomalies of the auricles, ear canal, or inner ear; anomalies of the nose; laryngeal atresia; total or partial syndactyly of the toes and/or fingers; renal

anomalies; and malformations of the genital organs, especially in females. Other less common malformations include anal atresia and umbilical hernias or a low-set umbilicus. In a review of 86 cases of cryptophthalmos from the world literature, Thomas et al. set forth major and minor criteria for diagnosis of the cryptophthalmos syndrome.5 The major criteria are cryptophthalmos, syndactyly, abnormal genitalia, and a history of a sib with the cryptophthalmos syndrome (Fig. 9-4). Minor criteria include malformations of the nose, ears, and larynx; cleft lip/palate; skeletal defects; umbilical hernias; renal agenesis; and mental retardation. To qualify for a diagnosis of the cryptophthalmos syndrome, patients should satisfy either two major criteria and one minor criterion, or one major criterion and four or more minor criteria. Accompanying congenital anomalies may be severe, especially renal malformations such as renal agenesis or dysplasia, resulting in spontaneous abortions, stillbirths, or neonatal deaths. Indeed, the diagnosis of the cryptophthalmos syndrome should be considered even in the absence of cryptophthalmos if the other constellation of abnormalities is present. Cryptophthalmos is not necessary for the diagnosis of Fraser syndrome.6 There appears to be at least two genetic types of cryptophthalmos: syndromic (with congenital malformations of other systems) and isolated (without other malformations). Syndromic cryptophthalmos is inherited in an autosomal recessive fashion. Sporadic cases of isolated cryptophthalmos may be recessively inherited or may be due to new dominant mutations. Autosomal dominant transmission is most likely in the family reported by Saal and co-workers.4

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The pathogenesis of cryptophthalmos is unclear. The lid fissure forms in the 6th month of gestation after the upper and lower eyelids have developed their complements of tarsus, Meibomian glands, and lashes. Defects in lid differentiation and in lid separation have been postulated to result in cryptophthalmos. McGregor et al. determined that a locus FS1 at chromosome 4q21 is associated with Fraser syndrome and identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix blastocoelar protein found in sea urchin.7 Fraser syndrome appears to be caused by disrupted epithelial integrity in utero. Prognosis, Prevention, and Treatment

Surgical incision in the area of the palpebral fissure may open directly into the anterior segment of the eye. The absence of a conjunctival sac and hence of a normal ocular surface makes the prognosis for a clear corneal graft very poor. Furthermore, the globe in typical cryptophthalmos is often malformed, rendering visual prognosis very guarded even if a good reaction to light is elicited through the skin covering the eyes. In partial or abortive cryptophthalmos, surgical intervention may result in cosmetic and functional improvement. References (Cryptophthalmos) 1. Francois J: Malformative syndrome with cryptophthalmos. Int Ophthalmol Clin 8:817, 1968. 2. Coover DH: Two cases of cryptophthalmia. Ophthalmoscope 8:259, 1910. 3. Magruder AC: Cryptophthalmos. Am J Ophthalmol 4:48, 1921. 4. Saal HM, Traboulsi EI, Gavaris P, et al.: Dominant syndrome with isolated cryptophthalmos and ocular anomalies. Am J Med Genet 43: 785, 1992. 5. Thomas IT, Frias JL, Felix V, et al.: Isolated and syndromic cryptophthalmos. Am J Med Genet 25:85, 1986. 6. Meinecke P: Cryptophthalmos-syndactyly syndrome without cryptophthalmos. Clin Genet 30:527, 1986. 7. McGregor L, Makela V, Darling SM, et al.: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 34:203, 2003.

9.5 Blepharophimosis Definition

Blepharophimosis is a general diminution of the palpebral aperture in all its dimensions. The lids usually show ptosis, dystopia canthorum, lateral displacement of the lacrimal puncti, or abnormalities of the lashes such as distichiasis or misdirected and stiff lashes (Fig. 9-5). Diagnosis

The criteria for the diagnosis of blepharophimosis include: (1) a palpebral fissure length of 10 to 15 mm and a width of 2 to 4 mm, with measurements remaining almost constant throughout life; (2) a flat nasal bridge; (3) aplasia or hypoplasia of the levator palpebrae and tarsal plates with resultant ptosis, tautness, and transparency of the lid skin, immobility of the lids, and absence of the lid fold; (4) underdevelopment of the eyelashes that grow irregularly from the palpebral margin, a feature especially prominent in the upper lid; (5) lateral displacement of the lacrimal puncti and an elongation of the canthal ligaments and lacrimal canaliculi, resulting in a boat-shaped outline of the palpebral aperture; and (6) lack of contact between the globe and the lids, especially nasally, resulting in epiphora.1

Fig. 9-5. Blepharophimosis syndrome with ptosis, synophrys, and epicanthus inversus.

Patients use the frontalis muscle to elevate their lids; they also assume a chin-up head position to uncover their pupils, allowing them to see. The face appears expressionless, and there may be synophrys of thick eyebrows. The caruncle and semilunar folds are usually hypoplastic. The medial and lateral canthal ligaments are elongated, and there is excessive soft tissue at the bridge of the nose with resultant telecanthus. Eye defects associated with blepharophimosis include strabismus, nystagmus, amblyopia, colobomatous microphthalmia,2 anophthalmia, ptosis, epicanthus, epicanthus inversus, optic nerve hypoplasia,3 and microcornea. The blepharophimosis syndrome, also known as the blepharophimosis-epicanthus inversus-ptosis syndrome or Kohn syndrome, is an autosomal dominant condition characterized by blepharophimosis, ptosis, telecanthus (increased distance between the inner canthi), and epicanthus inversus (a fold of skin running upward from the inner aspect of the lower lid into the medial canthus). Two types have been described associated (type I) or not associated (type II) with premature ovarian failure (POF).4,5 About 50% of cases are due to new mutations. Blepharophimosis is a prominent feature of the SchwartzJampel syndrome.6 This syndrome is characterized by a small muscle mass, peculiar whistling facies, and skeletal abnormalities. Blepharophimosis is also present in the dominantly inherited Freeman-Sheldon syndrome (whistling face syndrome, craniocarpo-tarsal dysplasia).7 Patients with this syndrome have masklike ‘‘whistling’’ facies, hypoplastic alae nasi, and a number of joint and skeletal abnormalities, the most prominent of which is talipes equinovarus. Short palpebral fissures are present in Dubowitz syndrome, which combines growth deficiency, microcephaly, peculiar facies with a broad and flat nasal bridge, infantile eczema, and a number of occasionally present malformations.8 This syndrome is inherited in an autosomal recessive fashion. Blepharophimosis can also occur in Miller-Dieker syndrome and in Ohdo syndrome with mental retardation, congenital heart defect, blepharophimosis, and hypoplastic teeth.9,10 Etiology and Distribution

In a series of 153 cases of ptosis of genetic origin, Edmund found 12 cases with blepharophimosis.1 The blepharophimosis syndrome gene FOXL2 maps to 3q23.11,12 The gene codes for a transcription factor and belongs to the forkhead family of genes.13 The type and location of mutations in FOXL2 correlate partially with the phenotype. In a study of 43 patients, De Baere et al. found that for predicted proteins with a truncation before the poly-Ala tract, the

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risk for development of primary ovarian failure is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation.14,15 It is postulated that dominant negative mutations of FOXL2 could increase expression of follicle differentiation genes in small and medium follicles to accelerate follicle development, resulting in increased initial recruitment of dormant follicles and thus the premature ovarian failure phenotype.16

16. Pisarska MD, Bae J, Klein C, et al.: Forkhead L2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology 145:3424, 2004. 17. Beckingsale PS, Sullivan TJ, Wong VA, et al.: Blepharophimosis: a recommendation for early surgery in patients with severe ptosis. Clin Experiment Ophthalmol 31:138, 2003. 18. Callahan A: Surgical correction of the blepharophimosis syndromes. Trans Am Acad Ophthalmol Otolaryngol 77:OP687, 1973. 19. Nowinski TS: Correction of telecanthus in the blepharophimosis syndrome. Int Ophthalmol Clin 32:157, 1992. 20. Karacaoglan N, Sahin U, Ercan U, et al.: One-stage repair of blepharophimosis: a new method. Plast Reconstr Surg 93:1406, 1994. 21. Nakajima T, Yoshimura Y, Onishi K, et al.: One-stage repair of blepharophimosis. Plast Reconstr Surg 87:24, 1991.

Prognosis, Prevention, Treatment

Visual prognosis is good unless there are major associated ocular abnormalities such as colobomatous microphthalmia or there is occlusion or strabismic amblyopia. Surgical repair of the ptosis should be delayed until age 4 to 5 years unless the lids occlude the pupil and the child cannot compensate by assuming a chin-up posture.17,18 Repair of the telecanthus and epicanthus is generally performed before repair of the ptosis,19 but both can be repaired at the same time.20,21 References (Blepharophimosis) 1. Edmund J: Blepharophimosis congenita. Acta Genet 7:279, 1957. 2. Lee LR, Sullivan TJ: Blepharophimosis syndrome: association with colobomatous microphthalmos. Aust N Z J Ophthalmol 23:145, 1995. 3. Chismire KJ, Witkop GS: Optic nerve hypoplasia and angle dysgenesis in a patient with blepharophimosis syndrome. Am J Ophthalmol 117:676, 1994. 4. Jones CA, Collin JR: Blepharophimosis and its association with female infertility. Br J Ophthalmol 68:533, 1984. 5. Zlotogora J, Sagi M, Cohen T: The blepharophimosis, ptosis, and epicanthus inversus syndrome: delineation of two types. Am J Hum Genet 35:1020, 1983. 6. Edwards WC, Root AW: Chondrodystrophic myotonia (SchwartzJampel syndrome): report of a new case and follow-up of patients initially reported in 1969. Am J Med Genet 13:51, 1982. 7. Freeman EA, Sheldon JH: Craniocarpotarsal dystrophy. An undescribed congenital malformation. Arch Dis Child Fetal Neonatal Ed 13:277, 1938. 8. Moller KT, Gorlin RJ: The Dubowitz syndrome: a retrospective. J Craniofac Genet Dev Biol Suppl 1:283, 1985. 9. Mhanni AA, Dawson AJ, Chudley AE: Vertical transmission of the Ohdo blepharophimosis syndrome. Am J Med Genet 77:144, 1998. 10. Ohdo S, Madokoro H, Sonoda T, et al.: Mental retardation associated with congenital heart disease, blepharophimosis, blepharoptosis, and hypoplastic teeth. J Med Genet 23:242, 1986. 11. Amati P, Chomel JC, Nivelon-Chevalier A, et al.: A gene for blepharophimosis-ptosis-epicanthus inversus syndrome maps to chromosome 3q23. Hum Genet 96:213, 1995. 12. Costa T, Pashby R, Huggins M, et al.: Deletion 3q in two patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). J Pediatr Ophthalmol Strabismus 35:271, 1998. 13. Crisponi L, Deiana M, Loi A, et al.: The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159, 2001. 14. Fokstuen S, Antonarakis SE, Blouin JL: FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients. Am J Med Genet 117A:143, 2003. 15. De Baere E, Beysen D, Oley C, et al.: FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotypephenotype correlation. Am J Hum Genet 72:478, 2003.

9.6 Other Anomalies of the Eyelids Eyelid Coloboma

Eyelid coloboma is a full-thickness notch defect of the lid margin. The colobomas may be triangular or quadrilateral in shape. Upper eyelid defects (the majority of colobomatous lid defects) are usually nasal, whereas lower eyelid colobomas are temporal. Colobomas of the eyelids occur in about 10–20% of patients with Goldenhar syndrome, a variant of the oculo-auriculo-vertebral spectrum (Fig. 9-6);1 the coloboma is usually present in conjunction with epibulbar dermoids and preauricular skin tags. Lower eyelid colobomas are seen in Treacher Collins syndrome (Fig. 9-7).2 Upper and lower eyelid defects may also be seen in the amniotic band syndrome.3,4 Distichiasis

Distichiasis refers to the growth of true cilia in ectopic locations, in extra rows along the lid margin, and out of the orifices of Meibomian glands. The accessory row(s) of lashes are usually seen on all four lids and run on the inner part of the intermarginal strip. The cilia may be soft and depigmented or fully developed and pigmented and may rub against the globe, resulting in corneal damage. Several families with autosomal dominant distichiasis have been reported in the world literature.5,6 The distichiasislymphedema syndrome is inherited in an autosomal dominant fashion and combines distichiasis with lymphedema of the limbs, most often affecting the lower limbs below the knees. It results from mutations in the transcription factor FOXC2.7–9 Orbital Hypertelorism

In hypertelorism there is an increased distance between the two orbits. Hypertelorism is present in a large number of malformation syndromes (Table 9-2). Telecanthus

Telecanthus refers to an increased distance between the inner canthi (Fig. 9-8). The ratio between the inner canthal measurement and the outer canthal measurement is approximately 1:3. Telecanthus is a nondiagnostic abnormality in a number of multisystem malformation syndromes. Epibulbar Choristomas

Epibulbar choristomas are tumorous growths on the exterior of the eye derived from tissue not normally present at that location.10 Epibulbar and orbital choristomas are the most common epibulbar

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Fig. 9-7. Temporal colobomas of the lower lids, downslanting palpebral fissures, malar hypoplasia, microtia, and micrognathia in a 10-year-old girl with Treacher Collins syndrome. (Courtesy of Dr. Charles I. Scott Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

Fig. 9-8. Schematic showing normal interpupillary and inner canthal measurement (top), telecanthus with normal interpupillary but increased inner canthal measurement (middle), and hypertelorism with increased interpupillary and inner canthal measurement (bottom).

Fig. 9-6. Dermoids. Top: orbital dermoid in upper outer quadrant, the most common location. Middle: computed tomography demonstrates cystic nature of lesion. (Courtesy of Dr. John F. Gillis.) Bottom: epibulbar dermoid of the left eye associated with a coloboma of the left upper eyelid in the Goldenhar syndrome.

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and orbital tumors in children. Four histopathologic types are recognized: (1) dermoids, which are made of collagenous connective tissue covered with epidermis; (2) lipodermoids, which, in addition, contain adipose tissue; (3) single tissue choristomas that consist either of dermislike tissue or of ectopic mesectodermal tissue of one origin; and (4) complex choristomas that contain tissues of different origins. Clinically, dermoid cysts contain one or more dermal adnexal structures and are lined by keratinizing epithelium; epidermoid cysts have no adnexal structures; teratomas contain tissues derived from all three germinal layers; and teratoid tumors are derived from only two germinal layers. Epibulbar choristomas are solid tumors of the ocular surface that occur in one to three per 10,000 live births. They may be whitish, yellowish, or pinkish in color and vary from small, flat lesions at the limbus to large masses that cover most of the interpalpebral area. Lesions may be unilateral or bilateral, and multiple tumors have also been reported. Of 82 epibulbar choristomas reported by Ash, 52% were in the bulbar conjunctiva, 29% at the limbus, 6% in the cornea, 4% in the caruncle, 4% in the canthal area, 2.5% in the fornix, and 2.5% in the palpebral conjunctiva.11 Associated ocular and facial abnormalities include scleral and corneal staphyloma, aniridia, congenital aphakia, cataract, miliary aneurysms of the retina, microphthalmia, osseous choristoma of the choroid, dermoid cyst of the orbit or eyelid, choristomatous malformations of the face and scalp, and preauricular tags. Epibulbar choristomas that involve the cornea may induce astigmatism, necessitating their surgical excision, the optical correction of the astigmatism, and the prevention of amblyopia.12 Epibulbar choristomas are associated with Goldenhar syndrome in the facio-auriculo-vertebral spectrum of anomalies.13 They can also be associated with the epidermal nevus syndrome, which includes skeletal, neurologic, vascular, and dermatologic abnormalities.14,15 The choristomas in the epidermal nevus syndrome are usually of the complex variety and may involve the whole ocular surface. Epibulbar choristomas may be inherited, usually in an autosomal dominant fashion16 but also in an X-linked recessive or autosomal recessive manner. Episcleral osseous choristomas are rare whitish, pea-sized, raised lesions that occur 5 to 10 mm posterior to the limbus and are composed of compact bone vested by periosteum. These tumors are freely movable but may adhere to sclera or to extraocular muscles. Posterior episcleral choristomas have been described in patients with the organoid nevus syndrome. They are located close or around the optic nerve head and appear as pale irregular lesions. They are highly reflective on ultrasonography and are also visualized on computed tomographic studies.17 Microblepharon

In microblepharon there is a vertical shortening of the lids. An extreme form of microblepharon is seen in the ablepharonmacrostomia syndrome characterized by absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear anomalies, redundant skin, and abnormal genitalia. Patients with this condition may have visual problems, often related to early corneal exposure. Hearing loss, poor hair growth, finger contractures, and growth retardation are also chronic problems. Mild developmental delay is present in two-thirds of patients.18,19 Ablepharon (no lids) should not be synonymous with cryptophthalmia. Epicanthus

Epicanthus refers to a fold of skin that covers the inner canthus of the palpebral fissure. There are four distinct types: (1) epicanthus supraciliaris, in which epicanthal folds arise from the region of the

eyebrow and run toward the tear sac or the nostril; (2) epicanthus palpebralis, in which the fold arises in the upper lid above the tarsal fold and extends to the lower margin of the orbit; (3) epicanthus tarsalis, in which the fold arises laterally above the tarsal fold and loses itself in the skin next to the inner canthus; and (4) epicanthus inversus, in which a small fold arises in the lower lid and extends upward, partially covering the inner canthus. Epicanthus inversus is usually seen in the blepharophimosis syndrome, along with ptosis and telecanthus. Epicanthus tarsalis is seen in Asians, and epicanthus tarsalis and epicanthus palpebralis are both seen in children of all races. Epiblepharon is probably an exaggerated form of epicanthus tarsalis (Fig. 9-9). Epicanthus supraciliaris is common to a large number of syndromes, for example, Down syndrome, that will not be discussed here. All types of epicanthal folds tend to improve with age, and any cosmetic surgery should be withheld until after full facial growth. Congenital Entropion

Congenital entropion is an infolding of the margins of the eyelids, placing the eyelashes in contact with the optic globe.20 Congenital entropion of the upper eyelid is a very rare abnormality that affects mostly females and has been reported in fewer than 20 patients.21 It is considered an ocular emergency, because corneal ulceration and permanent scarring can result from the associated trichiasis if surgical management is not promptly instituted. Congenital entropion may be due to congenital levator aponeurosis disinsertion or to extreme kinking of the tarsus (congenital tarsal kink). Systemic abnormalities, including agenesis of the corpus callosum, have been reported in patients with entropion of the upper eyelid. Congenital entropion of the upper or lower eyelid should be suspected in infants with atypical or persistent corneal ulceration.22 An examination under sedation or anesthesia would prevent squeezing of the eyelids and would allow correct diagnosis. The presence of distichiasis or other congenital eyelid anomalies are helpful diagnostic clues.23 Autosomal dominant inheritance has been reported.24 Congenital Ectropion

Congenital ectropion is the outfolding of the eyelid margin, exposing the conjunctival surface of the eyelid. Also called congenital eversion of the upper eyelids, this condition is more common in black infants and in patients with Down syndrome.25 It may also be seen in patients with lamellar ichthyosis (Fig. 9-10).26,27 Fig. 9-9. Bilateral epiblepharon in a non-Asian girl.

Eye

Fig. 9-10. Ectropion associated with ichthyosis (harlequin fetus). (Courtesy of Dr. Sami Elhassani, Spartanburg, SC.)

Congenital ectropion is generally a self-limited disease that is best managed with eye lubrication, with or without taping the lids together intermittently or during sleep. Persistent eversion is rare and may require surgical intervention. Congenital upper eyelid eversion is thought to be due to impaired venous return from the upper lids, resulting in eyelid swelling, chemosis, and eversion. Orbicularis spasm may also be a contributory factor. Congenital Eyelid Retraction

Eyelid retraction is an exaggerated elevation of the upper eyelid and lowering of the lower eyelid, exposing the sclera around the cornea. This is a static condition that affects the upper or lower eyelids, or both. It is diagnosed after the exclusion of other causes of lid retraction, such as hyperthyroidism, trauma, proptosis, seventh nerve palsy, and Marcus-Gunn jaw-winking. Patients usually present because of an abnormal staring appearance; corneal exposure is a rare complication. No treatment is required except for lubrication in patients with exposure keratitis. Extensive investigation is not required if the history and clinical course are suggestive of the diagnosis. Some degree of upper eyelid retraction is normal in newborns and young infants. In severe cases, eyelid retractor lengthening procedures may be performed but may be unpredictable, resulting in secondary ptosis. References (Other Anomalies of the Eyelids) 1. Shokeir MH: The Goldenhar syndrome: a natural history. Birth Defects Orig Artic Ser XIII(3C):67, 1977. 2. Fuente del Campo A, Martinez Elizondo M, Arnaud E: Treacher Collins syndrome (mandibulofacial dysostosis). Clin Plast Surg 21:613, 1994. 3. Bagatin M, Der Sarkissian R, Larrabee WF Jr: Craniofacial manifestations of the amniotic band syndrome. Otolaryngol Head Neck Surg 116:525, 1997. 4. Orioli IM, Ribeiro MG, Castilla EE: Clinical and epidemiological studies of amniotic deformity, adhesion, and mutilation (ADAM) sequence in a South American (ECLAMC) population. Am J Med Genet 118A: 135, 2003.

309 5. Robinow M, Johnson GF, Verhagen AD: Distichiasis-lymphedema. A hereditary syndrome of multiple congenital defects. Am J Dis Child 119:343, 1970. 6. Pap Z, Biro T, Szabo L, et al.: Syndrome of lymphoedema and distichiasis. Hum Genet 53:309, 1980. 7. Fang J, Dagenais SL, Erickson RP, et al.: Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67:1382, 2000. 8. Traboulsi EI, Al-Khayer K, Matsumoto M, et al.: Lymphedemadistichiasis syndrome and FOXC2 gene mutation. Am J Ophthalmol 134:592, 2002. 9. Erickson RP, Dagenais SL, Caulder MS, et al.: Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations. J Med Genet 38:761, 2001. 10. Mansour AM, Barber JC, Reinecke RD, et al.: Ocular choristomas. Surv Ophthalmol 33:339, 1989. 11. Ash JE: Epibulbar tumors. Am J Ophthalmol 33:1203, 1950. 12. Gayre GS, Proia AD, Dutton JJ: Epibulbar osseous choristoma: case report and review of the literature. Ophthalmic Surg Lasers Imaging 33:410, 2002. 13. Mansour AM, Wang F, Henkind P, et al.: Ocular findings in the facioauriculovertebral sequence (Goldenhar-Gorlin syndrome). Am J Ophthalmol 100:555, 1985. 14. Mullaney PB, Weatherhead RG: Epidermal nevus syndrome associated with a complex choristoma and a bilateral choroidal osteoma. Arch Ophthalmol 114:1292, 1996. 15. Shields JA, Shields CL, Eagle RC Jr, et al.: Ocular manifestations of the organoid nevus syndrome. Ophthalmology 104:549, 1997. 16. Mattos J, Contreras F, O’Donell FE Jr: Ring dermoid syndrome: a new syndrome of autosomal-dominantly inherited, bilateral, annular limbal dermoids with corneal and conjunctival extension. Arch Ophthalmol 98:1059, 1980. 17. Traboulsi EI, Zin A, Massicotte SJ, et al.: Posterior scleral choristoma in the organoid nevus syndrome (linear nevus sebaceus of Jadassohn). Ophthalmology 106:2126, 1999. 18. Hornblass A, Reifler DM: Ablepharon macrostomia syndrome. Am J Ophthalmol 99:552, 1985. 19. Stevens CA, Sargent LA: Ablepharon-macrostomia syndrome. Am J Med Genet 107:30, 2002. 20. Fox SA: Primary congenital entropion. Ama Arch Opthalmol 56:839, 1956. 21. Barsky D: Congenital entropion of the upper eyelids. J Mich State Med Soc 62:581, 1963. 22. Salour H, Owji N, Razavi ME, et al.: Tarsal kink syndrome associated with congenital corneal ulcer. Ophthal Plast Reconstr Surg 19:81, 2003. 23. Johnson CC: Developmental abnormalities of the eyelids. The 1985 Wendell Hughes lecture. Ophthal Plast Reconstr Surg 2:219, 1986. 24. Amacher AG, 3rd, Mazzoli RA, Gilbert BN, et al.: Dominant familial congenital entropion with tarsal hypoplasia and atrichosis. Ophthal Plast Reconstr Surg 18:381, 2002. 25. Sellar PW, Bryars JH, Archer DB: Late presentation of congenital ectropion of the eyelids in a child with Down syndrome: a case report and review of the literature. J Pediatr Ophthalmol Strabismus 29:64, 1992. 26. Cruz AA, Menezes FA, Chaves R, et al.: Eyelid abnormalities in lamellar ichthyoses. Ophthalmology 107:1895, 2000. 27. Oestreicher JH, Nelson CC: Lamellar ichthyosis and congenital ectropion. Arch Ophthalmol 108:1772, 1990.

9.7 Congenital Corneal Anomalies Cornea Plana

In cornea plana the corneal curvature is flatter than normal. The anterior chamber is shallow, and there is significant hyperopia and astigmatism.1,2 Late development of glaucoma can occur. Autosomal dominant and recessive inheritance have been reported.3

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The more severe recessive form (CNA2) results from mutations in KERA (encoding keratocan) on chromosome 12q.4 Forty-six Finnish patients were found to be homozygous for a founder missense mutation, leading to the substitution of a highly conserved amino acid.4 Management consists of correction of associated errors of refraction and the detection and treatment of glaucoma. Megalocornea

In megalocornea the cornea measures more than 12 mm in diameter at birth but is otherwise normal in curvature, thickness, and endothelial cell density.5 This contrasts with the enlarged corneal diameter in congenital glaucoma in which the cornea is hazy and thick and has a decreased endothelial cell density.6 Megalocornea is generally inherited in an X-linked recessive fashion. Mackey and coworkers mapped the gene for megalocornea to Xq12-q26.7 Patients may have presenile cataracts and with age develop a corneal arcus and a crocodile shagreen pattern of opacification of their corneas (Fig. 9-11). Carrier females do not show any changes. Megalocornea is occasionally seen in Marfan syndrome, Down syndrome, and Rieger syndrome. Megalocornea is associated with mental and neurologic impairment, minor anomalies in Neuhauser syndrome (megalocornea-mental retardation syndrome), and other related conditions.8 Management of megalocornea consists of the recognition of associated systemic disease when it is present. Older patients may require cataract extraction. Microcornea

In microcornea the corneal diameter is less than 9 to 10 mm at birth. Ocular size as determined by ultrasonography is normal in isolated microcornea and decreased in microphthalmia. Microcornea may be inherited in a dominant or in a recessive fashion. Microcornea with cataracts (Nance-Horan syndrome) is X-linked recessive.9 Nance-Horan syndrome is characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. It was mapped to Xp22.13. Burdon et al. identified the NHS gene and found that the gene plays key functions in the regulation of eye, tooth, brain, and craniofacial development.10 Other associated ocular anomalies with microcornea include aniridia, cataracts, subluxated lenses,11 and glaucoma.

Fig. 9-11. X-linked megalocornea with characteristic posterior crocodile shagreen or mosaic corneal dystrophy. (Courtesy of Dr. David Mackey.)

Fig. 9-12. Sclerocornea with blunting of limbal transition most prominent superiorly.

Management of microcornea includes treatment of the associated glaucoma and cataract if they are present. Sclerocornea

In sclerocornea there is congenital, nonprogressive corneal opacification that may be peripheral, sectorial, or central in location (Fig. 9-12). The cornea has a flat curvature. The great majority of cases are bilateral and may be inherited in an autosomal dominant or recessive fashion.12 Histopathologically, corneal collagen is larger than normal in diameter, and the collagen fibers and lamellae are irregularly arranged, resulting in corneal opacification.13 Descemet membrane and the endothelium may also be absent or abnormal. A number of associated ocular anomalies have been reported, and sclerocornea has occurred in a number of well-defined malformation syndromes14–17 and with mutations in the RAX homeobox gene.18 Corneal transplantation may be required in some patients with sclerocornea and central corneal involvement.19,20 References (Congenital Corneal Anomalies) 1. Sigler-Villanueva A, Tahvanainen E, Lindh S, et al.: Autosomal dominant cornea plana: clinical findings in a Cuban family and a review of the literature. Ophthalmic Genet 18:55, 1997. 2. Eriksson AW, Lehmann W, Forsius J: Congenital cornea plana in Finland. Clin Genet 4:301, 1973. 3. Tahvanainen E, Villanueva AS, Forsius H, et al.: Dominantly and recessively inherited cornea plana congenita map to the same small region of chromosome 12. Genome Res 6:249, 1996. 4. Pellegata NS, Dieguez-Lucena JL, Joensuu T, et al.: Mutations in KERA, encoding keratocan, cause cornea plana. Nat Genet 25:91, 2000. 5. Meire FM: Megalocornea. Clinical and genetic aspects. Doc Ophthalmol 87:1, 1994. 6. Ho CL, Walton DS: Primary megalocornea: clinical features for differentiation from infantile glaucoma. J Pediatr Ophthalmol Strabismus 41:11, 2004, quiz 46-7. 7. Mackey DA, Buttery RG, Wise GM, et al.: Description of X-linked megalocornea with identification of the gene locus. Arch Ophthalmol 109:829, 1991. 8. Verloes A, Journel H, Elmer C, et al.: Heterogeneity versus variability in megalocornea-mental retardation (MMR) syndromes: report of new cases and delineation of 4 probable types. Am J Med Genet 46: 132, 1993. 9. Bixler D, Higgins M, Hartsfield J Jr: The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females. Clin Genet 26:30, 1984.

Eye 10. Burdon KP, McKay JD, Sale MM, et al.: Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet 73:1120, 2003. 11. David R, MacBeath L, Jenkins T: Aniridia associated with microcornea and subluxated lenses. Br J Ophthalmol 62:118, 1978. 12. Elliott JH, Feman SS, O’Day DM, et al.: Hereditary sclerocornea. Arch Ophthalmol 103:676, 1985. 13. Kanai A, Wood TC, Polack FM, et al.: The fine structure of sclerocornea. Invest Ophthalmol Vis Sci 10:687, 1971. 14. Perry LD, Edwards WC, Bramson RT: Melnick-Needles syndrome. J Pediatr Ophthalmol Strabismus 15:226, 1978. 15. Harbin RL, Katz JI, Frias JL, et al.: Sclerocornea associated with the Smith-Lemli-Opitz syndrome. Am J Ophthalmol 84:72, 1977. 16. Happle R, Daniels O, Koopman RJ: MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome. Am J Med Genet 47:710, 1993. 17. Schanzlin DJ, Goldberg DB, Brown SI: Hallermann-Streiff syndrome associated with sclerocornea, aniridia, and a chromosomal abnormality. Am J Ophthalmol 90:411, 1980. 18. Voronina VA, Kozhemyakina EA, O’Kernick CM, et al.: Mutations in the human RAX homeobox gene in a patient with anophthalmia and sclerocornea. Hum Mol Genet 13:315, 2004. 19. Frueh BE, Brown SI: Transplantation of congenitally opaque corneas. Br J Ophthalmol 81:1064, 1997. 20. Waring GO 3rd, Rodrigues MM: Ultrastructure and successful keratoplasty of sclerocornea in Mietens’ syndrome. Am J Ophthalmol 90:469, 1980.

9.8 Anterior Segment Dysgenesis Definition

Anterior segment dysgenesis is a spectrum of ocular malformations characterized by abnormal development of the anterior chamber angle and iris.1,2 Terms that have been used to describe the various configurations of the anterior segment abnormalities in this context are anterior chamber cleavage syndrome, mesodermal dysgenesis of the cornea and iris, primary dysgenesis mesodermalis of the iris, and Axenfeld-Rieger syndrome. Included in anterior segment dysgenesis are (1) Axenfeld anomaly or posterior embryotoxon, in which there is a prominent and anteriorly displaced line of Schwalbe (the most peripheral portion of the Descemet membrane) in the cornea with strands of iris tissue attached to it, and (2) Rieger anomaly, in which, in addition to an Axenfeld anomaly, there exists clinical evidence of iris stromal atrophy with hole or pseudohole formation and corectopia. Rieger syndrome is a distinct autosomal dominant condition in which anterior segment dysgenesis is accompanied by facial, dental, umbilical, and skeletal abnormalities.3 Investigators in the last decade have identified the major genes that cause the Axenfeld-Rieger spectrum of malformations, all of which to date have been homeobox transcription factor genes.4,5 Diagnosis

Anterior segment dysgenesis, or the Axenfeld-Rieger spectrum of malformation, is a bilateral, often symmetric condition that affects males and females equally and that shows a wide spectrum of variability in clinical expression within families in which it is inherited as an autosomal dominant trait. Severe cases are recognized in infancy or childhood because of the abnormal appearance of the anterior segment. Some infants are discovered because of signs and symptoms of associated infantile glaucoma such as tearing,

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photophobia, and corneal clouding. Other patients are discovered in adolescence or early childhood when they present with visual loss and are found to have advanced childhood glaucoma. Glaucoma, the only vision-threatening complication, occurs in about 50% of patients with anterior segment dysgenesis by age 20 years and in 10–15% of patients per decade thereafter. Other cases are discovered during routine examinations within or outside the context of a positive family history of the disease. Nonocular abnormalities suggesting a diagnosis of Rieger syndrome may prompt an ocular examination. The appearance of the iris in the Rieger spectrum of abnormalities is highly variable (Fig. 9-13). The iris stroma is thin, and there may be extensive defects of the iris with polycoria (multiple pupils) or pseudopolycoria. The pupil may be ectopic (corectopia), in which case iris hypoplasia is most severe in the sector of iris away from the direction of corectopia. Megalocornea is a frequent association. Rarely, Rieger anomaly is associated with other ocular abnormalities, including aniridia, blue sclera, cornea plana, dislocated lenses, hypoplasia of the optic nerve head, macular degeneration, medullated nerve fibers, and retinal detachment. Ectropion uveae or proliferation of the neuroectodermally derived pigmented posterior layer of the iris onto the anterior surface of the iris in the region of the pupil may be seen. Congenital Fig. 9-13. Rieger anomaly of the anterior segment with prominent Schwalbe line, corectopia, and extensive iris atrophy with pseudopolycoria (top). Prominent Schwalbe line in a patient with Rieger anomaly (bottom).

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ectropion uveae, or congenital iris ectropion (ME Wilson, personal communication), is classified by some with the goniodysgenesis syndromes and may indeed be a separate well-defined abnormality of neural crest development and differentiation. Other authors have also included primary infantile glaucoma in the goniodysgenetic disorders because of the well-documented defect in anterior chamber angle and trabecular meshwork abnormality. Primary infantile glaucoma is inherited in an autosomal recessive fashion in the majority of cases and may be of multifactorial etiology in others. Infantile glaucoma can be the presenting sign of the Axenfeld-Rieger spectrum of abnormalities. Etiology and Distribution

Prominence of the peripheral edge of Descemet membrane or posterior embryotoxon is present in about 15% of the general adult population and is accompanied by bridging iris strands (Axenfeld anomaly) in 6% of otherwise normal individuals. The incidence of Rieger anomaly is not known. Rieger syndrome is estimated to occur in one per 200,000 of the population. The Axenfeld-Rieger spectrum of anomalies results from an abnormality of neural crest development and/or resorption. Shields et al. have postulated that, late in gestation, a developmental arrest leads to retention of the primordial endothelium over portions of the iris and anterior chamber angle.2 Incomplete posterior recession of the peripheral uvea produces a high insertion of the iris. This arrest also causes the zone of differentiation between the corneal and anterior angle endothelium to be abnormally located and associated with prominence and anterior displacement of the Schwalbe line. The retained endothelial cells may bridge the angle along with a few iris strands and contract, pulling the iris strands toward the center. Contraction of the primordial endothelium also leads to corectopia and ectropion uveae. Endothelial cells will later disappear, leaving the abnormal iris configuration. In Rieger syndrome, associated systemic anomalies are also due to abnormal neural crest differentiation. Neural crest-derived structures such as facial bones and cartilage, dental papillae, and the primitive periumbilical ring are affected, resulting in facial dysmorphism with maxillary hypoplasia and a receding chin, hypodontia, peg-shaped teeth, and redundant periumbilical skin. Rare findings include hypospadias, empty or enlarged sella turcica,6 and growth hormone deficiency.7 The genes for the Axenfeld-Rieger syndrome (ARS) are autosomal dominant, fully penetrant, and variable in expressivity. In 1996, Semina et al. reported mutations in PITX2(RIEG1), a gene on 4q25-q26 that codes for a homeobox transcription factor, in subjects with ARS.8 Additional mutations throughout the PITX2 sequence have been observed in subjects with various forms of anterior segment dysgenesis (ARS, iris hypoplasia, iridogoniodysgenesis, and Peters anomaly).9–15 ARS can also be due to mutations in the FOXC1 gene on 6p25, a member of the forkhead family of transcription factors.11,16–22 As with subjects with PITX2 mutations, subjects with FOXC1 mutations have a great deal of phenotypical variability. At least two other ARS loci on 13q14 and 16q24 await cloning. A few multisystem disorders feature anterior segment dysgenesis, and a careful ophthalmologic evaluation should be part of the routine work-up of patients with Alagille syndrome or arteriohepatic dysplasia,23 the Wolf-Hirschhorn syndrome (4p- syndrome),24,25 and the Abruzzo-Erikson syndrome.26 An association with oculocutaneous albinism has also been reported. Additionally, Rieger syndrome has been associated with a number of chromosomal abnormalities that have been reviewed by Stathacopoulos et al., who reported a patient with Rieger syndrome and an interstitial deletion of chromosome 13(q14q31).27

Prognosis, Treatment, and Prevention

The major complication of the Axenfeld-Rieger spectrum of ocular anomalies is the development of glaucoma and glaucomatous visual loss. When glaucoma occurs in infancy, it is detected early because of the associated signs and symptoms of photophobia, tearing, corneal clouding, and corneal enlargement. Early surgical intervention and postoperative visual rehabilitation result in a fair prognosis for good vision. Patients who develop glaucoma in early adulthood may not come to medical attention until field defects impinge on central vision, indicating an advanced disease process. Such patients are usually given topical antiglaucoma medications but often come to filtering surgery with relatively poor eventual visual outcome. The best scenario involves a sib or offspring of a patient with Axenfeld-Rieger anomaly who is followed closely for the development of glaucoma, which is then treated as soon as it is detected and before the development of visual field loss. Frequent ocular examinations (every 4–6 months) are recommended for patients with this spectrum of ocular disorders and for their affected relatives. All available family members should be examined for anterior segment malformations and should be counseled about the genetic risk in this dominant group of disorders and about the variability of clinical presentation. When anterior segment dysgenesis is associated with a multisystem malformation syndrome, prognosis depends on the severity of the associated congenital abnormalities and on their impact on the patient’s general health. References (Anterior Segment Dysgenesis) 1. Waring GO 3rd, Rodrigues MM, Laibson PR: Anterior chamber cleavage syndrome. A stepladder classification. Surv Ophthalmol 20:3, 1975. 2. Shields MB, Buckley E, Klintworth GK, et al.: Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 29: 387, 1985. 3. Rieger H: Beitrage zur Kenntnis seltener Missbildungen der Iris. Graefes Arch Clin Exp Ophthalmol 133:602, 1935. 4. Alward WL: Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 130:107, 2000. 5. Lines MA, Kozlowski K, Walter MA: Molecular genetics of AxenfeldRieger malformations. Hum Mol Genet 11:1177, 2002. 6. Kleinmann RE, Kazarian EL, Raptopoulos V, et al.: Primary empty sella and Rieger’s anomaly of the anterior chamber of the eye: a familial syndrome. N Engl J Med 304:90, 1981. 7. Sadeghi-Nejad A, Senior B: Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger’s syndrome). J Pediatr 85:644, 1974. 8. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996. 9. Alward WL, Semina EV, Kalenak JW, et al.: Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger syndrome (RIEG/ PITX2) gene. Am J Ophthalmol 125:98, 1998. 10. Amendt BA, Sutherland LB, Semina EV, et al.: The molecular basis of Rieger syndrome. Analysis of Pitx2 homeodomain protein activities. J Biol Chem 273:20066, 1998. 11. Borges AS, Susanna R Jr, Carani JC, et al.: Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil. J Glaucoma 11:51, 2002. 12. Kozlowski K, Walter MA: Variation in residual PITX2 activity underlies the phenotypic spectrum of anterior segment developmental disorders. Hum Mol Genet 9:2131, 2000. 13. Perveen R, Lloyd IC, Clayton-Smith J, et al.: Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Invest Ophthalmol Vis Sci 41:2456, 2000.

Eye 14. Phillips JC: Four novel mutations in the PITX2 gene in patients with Axenfeld-Rieger syndrome. Ophthalmic Res 34:324, 2002. 15. Priston M, Kozlowski K, Gill D, et al.: Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome. Hum Mol Genet 10:1631, 2001. 16. Nishimura DY, Swiderski RE, Alward WL, et al.: The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet 19:140, 1998. 17. Honkanen RA, Nishimura DY, Swiderski RE, et al.: A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene. Am J Ophthalmol 135:368, 2003. 18. Kawase C, Kawase K, Taniguchi T, et al.: Screening for mutations of Axenfeld-Rieger syndrome caused by FOXC1 gene in Japanese patients. J Glaucoma 10:477, 2001. 19. Nishimura DY, Searby CC, Alward WL, et al.: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 68:364, 2001. 20. Panicker SG, Sampath S, Mandal AK, et al.: Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly. Invest Ophthalmol Vis Sci 43:3613, 2002. 21. Saleem RA, Banerjee-Basu S, Berry FB, et al.: Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1. Am J Hum Genet 68:627, 2001. 22. Saleem RA, Murphy TC, Liebmann JM, et al.: Identification and analysis of a novel mutation in the FOXC1 forkhead domain. Invest Ophthalmol Vis Sci 44:4608, 2003. 23. Ozeki H, Shirai S, Ikeda K, et al.: Anomalies associated with AxenfeldRieger syndrome. Graefes Arch Clin Exp Ophthalmol 237:730, 1999. 24. Wilcox LM Jr, Bercovitch L, Howard RO: Ophthalmic features of chromosome deletion 4p- (Wolf-Hirschhorn syndrome). Am J Ophthalmol 86:834, 1978. 25. Mayer UM, Bialasiewicz AA: Ocular findings in a 4 p- deletion syndrome (Wolf-Hirschhorn). Ophthalmic Paediatr Genet 10:69, 1989. 26. Verloes A, Dodinval P: Rieger anomaly and uveal coloboma with associated anomalies. Third observation of a rare oculo-palato-osseous syndrome—the Abruzzo-Erikson syndrome. Ophthalmic Paediatr Genet 11:41, 1990. 27. Stathacopoulos RA, Bateman JB, Sparkes RS, et al.: The Rieger syndrome and a chromosome 13 deletion. J Pediatr Ophthalmol Strabismus 24:198, 1987.

9.9 Peters Anomaly Definition

Peters anomaly is a variable anomaly consisting of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and variable amounts of iris and lenticular attachments to the central aspect of the posterior cornea. Diagnosis

The spectrum of the morphology of Peters anomaly is very wide. The anomaly can take the form of a faint corneal leukoma with a small strand of iris attached to the posterior surface of the cornea and a clear lens to severe corneal opacification, extensive iridocorneal adhesions, and cataract formation (Fig. 9-14). Some cases of sclerocornea are also included in this spectrum because of the absence of the Descemet membrane in many cases of sclerocornea and the co-existence of sclerocornea and Peters anomaly in some patients. Associated ocular defects with Peters anomaly include microcornea, anterior polar cataracts, glaucoma with or

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Fig. 9-14. Peters anomaly with central opacification of the cornea. There were iridocorneal adhesions behind the opacity.

without buphthalmos, spontaneous corneal perforation, aniridia, persistence of the hyaloid system, and total posterior coloboma of the retina and choroid.1 Associated systemic congenital anomalies include short stature, short limbs, abnormal ears, cleft lip/palate abnormalities, malformation of the genitourinary system, cardiovascular anomalies, defects of the limbs, and mental retardation.1–3 Familial cases of Peters anomaly are recessively inherited in some cases4,5; however, pedigrees with autosomal dominant transmission have been published.6 The syndrome of Peters anomaly with short limbs (Kivlin-Krause syndrome) appears to be a distinct recessive condition.7–9 In the Peters-plus syndrome, Peters anomaly occurs in association with clefting, mental retardation, and abnormal ears. Traboulsi and Maumenee have found the spectrum of malformation in Peters-plus syndrome to include midline defects, cardiovascular and urogenital anomalies, and the previously described craniofacial anomalies and mental retardation.1 The most common associated ocular abnormality was coloboma/ microphthalmia in about 25% of cases. Peters anomaly with multiple congenital malformations has been reported in a number of patients with chromosomal abnormalities, such as an interstitial deletion of the long arm of chromosome 11,10 partial deletion of the short arm of chromosome 4,11 ring chromosome 21,12 partial trisomy 5p,13 and a balanced translocation between chromosomes 2 and 15. Mutations in PAX6,14,15 CYP1B1,16 and FOXC1 have also been associated with Peters anomaly.17,18 Etiology and Distribution

Peters anomaly probably results from an abnormality in separation of the lens vesicle from the surface ectoderm with interference in the formation of the central cornea and the formation of oflenticulo-irido-corneal adhesions. Cook and Sulik have developed a mouse model of Peters anomaly by exposing the developing mouse fetuses to high doses of alcohol or isotretinoin.19 Miller et al. reported a number of patients with Peters anomaly and the fetal alcohol syndrome.20 Prognosis, Prevention, and Treatment

The visual prognosis depends on the degree of corneal opacification and on the severity of associated ocular malformations. Combined penetrating keratoplasty and cataract extraction is needed in severe cases, whereas simple separation of iridocorneal

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adhesions suffices in mild cases and results in significant clearing of the corneal opacification.21–24 Unilateral cases are usually associated with deep amblyopia, and the risk to benefit ratio of surgery in such cases is probably very high. Congenital or postsurgical glaucoma is a major cause of visual loss in many cases. More than 50% of eyes with Peters anomaly end up with no light perception because of glaucoma. Chromosomal studies should be obtained in those patients with multiple congenital malformations and Peters anomaly. Families with a child who has isolated Peters anomaly should be counseled as to the probable recessive mode of inheritance of this condition.

21. Yang LL, Lambert SR, Lynn MJ, et al.: Long-term results of corneal graft survival in infants and children with peters anomaly. Ophthalmology 106:833, 1999. 22. Yang LL, Lambert SR: Peters’ anomaly. A synopsis of surgical management and visual outcome. Ophthalmol Clin North Am 14:467, 2001. 23. Dana MR, Schaumberg DA, Moyes AL, et al.: Corneal transplantation in children with Peters anomaly and mesenchymal dysgenesis. Multicenter Pediatric Keratoplasty Study. Ophthalmology 104:1580, 1997. 24. Miller MM, Butrus S, Hidayat A, et al.: Corneoscleral transplantation in congenital corneal staphyloma and Peters’ anomaly. Ophthalmic Genet 24:59, 2003.

References (Peters Anomaly) 1. Traboulsi EI, Maumenee IH: Peters’ anomaly and associated congenital malformations. Arch Ophthalmol 110:1739, 1992. 2. Mayer UM: Peters’ anomaly and combination with other malformations (series of 16 patients). Ophthalmic Paediatr Genet 13:131, 1992. 3. Heon E, Barsoum-Homsy M, Cevrette L, et al.: Peters’ anomaly. The spectrum of associated ocular and systemic malformations. Ophthalmic Paediatr Genet 13:137, 1992. 4. Tabuchi A, Matsuura M, Hirokawa M: Three siblings with Peters’ anomaly. Ophthalmic Paediatr Genet 5:205, 1985. 5. Boel M, Timmermans J, Emmery L, et al.: Primary mesodermal dysgenesis of the cornea (Peters’ anomaly) in two brothers. Hum Genet 51:237, 1979. 6. DeRespinis PA, Wagner RS: Peters’ anomaly in a father and son. Am J Ophthalmol 104:545, 1987. 7. Thompson EM, Winter RM, Baraitser M: Kivlin syndrome and Peters’Plus syndrome: are they the same disorder? Clin Dysmorphol 2:301, 1993. 8. Kivlin JD, Carey JC, Richey MA: Brachymesomelia and Peters anomaly: a new syndrome. Am J Med Genet 45:416, 1993. 9. De Almeida JC, Reis DF, Llerena J Jr, et al.: Short stature, brachydactyly, and Peters’ anomaly (Peters’-plus syndrome): confirmation of autosomal recessive inheritance. J Med Genet 28:277, 1991. 10. Bateman JB, Maumenee IH, Sparkes RS: Peters’ anomaly associated with partial deletion of the long arm of chromosome 11. Am J Ophthalmol 97:11, 1984. 11. Mayer UM, Bialasiewicz AA: Ocular findings in a 4 p- deletion syndrome (Wolf-Hirschhorn). Ophthalmic Paediatr Genet 10:69, 1989. 12. Cibis GW, Waeltermann J, Harris DJ: Peters’ anomaly in association with ring 21 chromosomal abnormality. Am J Ophthalmol 100:733, 1985. 13. Dichtl A, Jonas JB, Naumann GO: Atypical Peters’ anomaly associated with partial trisomy 5p. Am J Ophthalmol 120:541, 1995. 14. Hanson IM, Fletcher JM, Jordan T, et al.: Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet 6:168, 1994. 15. Sonoda S, Isashiki Y, Tabata Y, et al.: A novel PAX6 gene mutation (P118R) in a family with congenital nystagmus associated with a variant form of aniridia. Graefes Arch Clin Exp Ophthalmol 238:552, 2000. 16. Vincent A, Billingsley G, Priston M, et al.: Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters’ anomaly. J Med Genet 38:324, 2001. 17. Doward W, Perveen R, Lloyd IC, et al.: A mutation in the RIEG1 gene associated with Peters’ anomaly. J Med Genet 36:152, 1999. 18. Honkanen RA, Nishimura DY, Swiderski RE, et al.: A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene. Am J Ophthalmol 135:368, 2003. 19. Cook CS, Sulik KK: Keratolenticular dysgenesis (Peters’ anomaly) as a result of acute embryonic insult during gastrulation. J Pediatr Ophthalmol Strabismus 25:60, 1988. 20. Miller M, Israel J, Cuttone J: Fetal alcohol syndrome. J Pediatr Ophthalmol Strabismus 18:6, 1981.

9.10 Hypoplasia of the Iris (Aniridia) Definition

Hypoplasia of the iris (aniridia) is a bilateral malformation of the eye in which the most prominent abnormality is variable to neartotal absence of the iris.1,2 Aniridia is a misnomer since the iris is not totally absent. Diagnosis

In hypoplasia of the iris (aniridia), a stump of tissue is invariably present at the base of the iris, and gonioscopy may be required for its adequate visualization (Fig. 9-15). Aniridia occurs in one per 50,000 live births. Ocular abnormalities associated with aniridia include persistent pupillary membrane, congenital cataracts, ectopia lentis, developmental glaucoma, corneal pannus, keratopathy, persistence of the retina over pars plana, and foveal hypoplasia leading to decreased visual acuity and nystagmus.3 Congenital poor visual function in aniridia is due to macular, foveal, and optic nerve hypoplasia. Acquired causes of visual loss in aniridia include cataract, glaucoma, and anisometropic or strabismic amblyopia.4,5 At least two families have been described in which some members have classical aniridia and other members have atypical iris defects, ranging from radial clefts or atypical colobomas and relatively good vision to more extensive absence of iris tissue.6,7 The keratopathy/corneal pannus of aniridia appears late in the 1st decade of life and is presumably due to insufficient/ absent limbal stem cells that depend on the presence of normal PAX6 complement for their development and maintenance. Nystagmus develops in aniridic patients, presumably due to congenital poor visual acuity. Iris vascular anomalies and leakage have been diagnosed on fluorescein angiography of the anterior segment.7 Etiology and Distribution

Shaw et al. estimated the prevalence of aniridia in the lower peninsula of Michigan in 1960 to be about one in 64,000.1 Approximately two-thirds of patients have at least one other affected family member; the remaining one-third are sporadic. Aniridia is caused in almost all cases by mutations in PAX6, a homeobox transcription factor on 11p13.8,9 In some families, mutations in PAX6 cause a predominant keratopathy phenotype.10 In others, the iris is so well-preserved that the phenotype is predominated by isolated foveal hypoplasia.11 In the well-defined contiguous gene syndrome of Wilms tumor-aniridia-genitourinary abnormalities-retardation, or Miller syndrome, aniridia is of the noninherited variety and is always associated with a deletion of band 13 on the short arm of chromosome 11.12,13 Aniridia with

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Fig. 9-15. Left: aniridia with minimal remnants of the iris. Note circular reflex from edge of the lens. Right: aniridia with significant remnants of the iris (undilated pupil). The patient did not have nystagmus.

cerebellar ataxia and mental retardation is a very rare condition inherited in an autosomal recessive fashion and known as the Gillespie syndrome.14,15 Gillespie syndrome is not due to mutations in PAX6.16 Aniridia can also occur in association with malformations of the globe, such as Peters anomaly or congenital anterior staphyloma, or with microcornea and subluxated lenses. Aniridia can also occur in the context of multisystem malformation syndromes and chromosomal abnormalities such as ring chromosome 6;17 the syndrome of multiple ocular malformations and mental retardation described by Walker and Dyson18 and Hamming et al.;19 and the syndrome of aniridia and absence of the patella.20 When iris hypoplasia is not severe, as in aniridia type II, aniridia may be confused with conditions such as Rieger anomaly, ectopia lentis et pupillae, atypical coloboma of the iris, or essential iris atrophy (Chandler syndrome). Prognosis, Prevention, and Treatment

The management of patients with aniridia includes examination of other family members for the presence of mild degrees of iris hypoplasia. In any patient with aniridia and a negative family history, the risk of developing Wilms tumor is 20%; hence, careful, repeated examination and imaging of the renal system should be performed. Ultrasound examination of the kidneys is done at 6-month intervals supplemented with intravenous pyelography, computed tomography, or magnetic resonance imaging to further evaluate any suspicious finding. About one in 70 patients with Wilms tumor will have aniridia. A karyotype should be obtained in patients in whom mental retardation and genitourinary abnormalities are present to look for an interstitial deletion of the short arm of chromosome 11. There is no consensus as to whether a karyotype should be obtained in all sporadic cases; however, it is our recommendation to obtain one. The management of ocular problems in patients with aniridia can be very challenging. Visual acuity is usually less than 20/200 in most patients but may be as good as 20/20 in patients with

aniridia and preserved ocular function. The main cause of acquired visual loss in aniridia is glaucoma, and patients are screened for its presence at regular intervals. The glaucoma in aniridia typically develops in late childhood or in adulthood; however, it may be present in the 1st year of life. Aniridic glaucoma may be due to trabeculodysgenesis but has been observed to follow occlusion of the filtering angle by an up-pulling of the iris stump. Goniotomy or trabeculotomy may be successful in controlling infantile aniridic glaucoma; however, filtering surgery or cyclocryotherapy may be required. Medical therapy should be tried in older individuals with aniridic glaucoma. Cataracts, which develop in most aniridic patients, are extracted if they produce significant further decrease in visual acuity. Some patients have congenital anterior polar cataracts while others have acquired cataracts that usually develop in early adulthood. Ectopia lentis is occasionally found in aniridic eyes and should be looked for before a lensectomy is performed. Finally, penetrating keratoplasty may be required in some instances if progressive keratopathy leads to corneal opacification and to further loss of vision. References (Hypoplasia of the Iris) 1. Shaw MW, Falls HF, Neel JV: Congenital aniridia. Am J Hum Genet 12:389, 1960. 2. Nelson LB, Spaeth GL, Nowinski TS, et al.: Aniridia. A review. Surv Ophthalmol 28:621, 1984. 3. Layman PR, Anderson DR, Flynn JT: Frequent occurrence of hypoplastic optic disks in patients with aniridia. Am J Ophthalmol 77:513, 1974. 4. Walton DS: Aniridic glaucoma: the results of gonio-surgery to prevent and treat this problem. Trans Am Ophthalmol Soc 84:59, 1986. 5. Grant WM, Walton DS: Progressive changes in the angle in congenital aniridia, with development of glaucoma. Am J Ophthalmol 78:842, 1974. 6. Elsas FJ, Maumenee IH, Kenyon KR, et al.: Familial aniridia with preserved ocular function. Am J Ophthalmol 83:718, 1977. 7. Hittner HM, Riccardi VM, Ferrell RE, et al.: Variable expressivity in autosomal dominant aniridia by clinical, electrophysiologic, and angiographic criteria. Am J Ophthalmol 89:531, 1980.

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8. Ton CC, Hirvonen H, Miwa H, et al.: Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell 67:1059, 1991. 9. Glaser T, Walton DS, Maas RL: Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet 2:232, 1992. 10. Mirzayans F, Pearce WG, MacDonald IM, et al.: Mutation of the PAX6 gene in patients with autosomal dominant keratitis. Am J Hum Genet 57:539, 1995. 11. Azuma N, Nishina S, Yanagisawa H, et al.: PAX6 missense mutation in isolated foveal hypoplasia. Nat Genet 13:141, 1996. 12. Miller RW, Fraumeni JF Jr, Manning MD: Association of Wilms’s tumor with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med 270:922, 1964. 13. Turleau C, de Grouchy J, Tournade MF, et al.: Del 11p/aniridia complex. Report of three patients and review of 37 observations from the literature. Clin Genet 26:356, 1984. 14. Gillespie FD: Aniridia, cerebellar ataxia, and oligophrenia in siblings. Arch Ophthalmol 73:338, 1965. 15. Nelson J, Flaherty M, Grattan-Smith P: Gillespie syndrome: a report of two further cases. Am J Med Genet 71:134, 1997. 16. Glaser T, Ton CC, Mueller R, et al.: Absence of PAX6 gene mutations in Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation). Genomics 19:145, 1994. 17. Levin H, Ritch R, Barathur R, et al.: Aniridia, congenital glaucoma, and hydrocephalus in a male infant with ring chromosome 6. Am J Med Genet 25:281, 1986. 18. Walker FA, Dyson C: Dominantly inherited aniridia associated with mental retardation and other eye abnormalities. Birth Defects Orig Artic Ser X(7):147, 1974. 19. Hamming NA, Miller MT, Rabb M: Unusual variant of familial aniridia. J Pediatr Ophthalmol Strabismus 23:195, 1986. 20. Mirkinson AE, Mirkinson NK: A familial syndrome of aniridia and absence of the patella. Birth Defects Orig Artic Ser XI(5):129, 1975.

9.11 Congenital Cataracts Cataracts are opacities of the crystalline lens. They can be congenital or acquired, partial or total, inherited or isolated. Cataracts can occur in otherwise normal eyes or may be seen in microphthalmic or otherwise malformed eyes such as in persistent hyperplastic primary vitreous (PHPV). Congenital cataracts can be classified according to their morphology or to the part or sector of the crystalline lens that they occupy or involve (Table 9-4). A large number of genes have been mapped or cloned that cause inherited congenital or developmental cataracts (Table 9-4). Cataracts are amblyogenic if they occlude the pupillary axis with the pupil in the undilated resting position. In this case surgery is indicated and should be performed as early as the first few weeks of life, and contact lens and amblyopia therapy should be instituted promptly. Infantile and developmental cataracts occur in a number of hereditary patterns and as part of metabolic diseases, malformation syndromes, chromosomal aberrations, or may be secondary to infections or trauma. Table 9-5 gives an etiologic classification of infantile and developmental cataracts. Cataracts may have a number of different morphologic appearances (Table 9-4). The major types are discussed below. Anterior polar cataract is an axial lenticular opacity and varies from 1 to 3.5 mm in size. It may take a pyramidal shape and may be associated with duplicated opacities under the anterior lens capsule. This type of cataract seldom interferes with vision, but

Table 9-4. Inherited cataracts and the responsible genes or gene loci Type of Cataracts

Causation Gene/Locus

Volkmann

(115665) 1p36

Posterior polar or zonular

(116600) 1pter-p36.1

Zonular

(600897) Connexin 50

Nuclear

(607304) 2q12

Nuclear

(123660) CRYG, 2q33-35

Non-nuclear polymorphic

(601286) CRYG1 (123680) CRYGC (123690) CRYGD (603212) BFSP2, 3q21-22

Congenital cataracts

(602669) PITX3, 10q25

Aniridia/cataracts

(607108) PAX6, 11p13

Nuclear

(154050) MIP, 12q13

Zonular

(121015) Connexin 46, 13q11

Anterior polar

(115650) 14q24-qter

Central pouchlike

(605728) 15q21-q22

Zonular

(116800) HSF4, 16q22

Anterior polar

(601202) 17q12-13

Zonular

(600881) CRYBA1, 17q11-12

Cerulean

(115660) 17q24

Hyperferritinemia/cataracts

(600886) FTL, 19q13.3-13.4

Posterior polar

(603307) BFSP1, 20p12-q12

Zonular

(123580) CRYAA, 21q22.3

Cerulean

(123620) CRYBB2, 22q11-12

cases that have progressed to significant opacification have been reported. Anterior polar cataracts may be inherited and are usually found in eyes that are slightly smaller than normal. Nuclear cataract involves the embryonic and fetal nuclear areas of the lens and is usually nonprogressive (Fig. 9-16). Onethird of cases are unilateral and two-thirds are bilateral. Some nuclear cataracts are formed of numerous fine dots between the anterior and posterior ‘‘y’’ sutures, and others are dense enough to be amblyogenic. Some are accompanied by riders in the surrounding

Table 9-5. Etiologic classification of infantile and developmental cataracts INHERITED WITHOUT SYSTEMIC ABNORMALITIES

Craniofacial syndromes

Autosomal dominant

Hallermann-Streiff syndrome (AR-234100)

Autosomal recessive

Crouzon disease (AD-123500)

X-linked

Apert syndrome (AD-101200) Engelmann syndrome (AD-131300)

INHERITED AS PART OF MULTISYSTEM DISORDERS Metabolic disorders

Galactosemia (AR-230400) Galactokinase deficiency (AR-230200) Fabry disease (XLR-301500) Mannosidosis (AR-248500) Refsum disease (AR-266500) Wilson disease (AR-277900)

Lanzieri syndrome Rubinstein-Taybi syndrome (uncertain-268600) Ellis-van Creveld syndrome (AR-225500) Smith-Lemli-Opitz syndrome (AR-214150) Cerebro-oculo-facio-skeletal syndrome (AR-214150) Nance-Horan syndrome (XLR-302350)

Diabetes mellitus Hypocalcemia Hypoglycemia Multiple sulfatase deficiency (AR-272200) Renal diseases

Lowe disease (XLR-309000) Alport syndrome (AD-301050)

ASSOCIATED WITH CHROMOSOMAL ABNORMALITIES

Trisomy 21 Trisomy 13 Trisomy 18 Deletion 5p Deletion 11p

Musculoskeletal disorders

Chondrodysplasia punctata (AD-118650, AR-215100, XLD-302960) Myotonic dystrophy (AD-160900)

Ring 4 10qþ

Marfan syndrome (AD-154700)

ASSOCIATED WITH OCULAR DISEASE

Osteopetrosis (AR-259700)

Leber congenital amaurosis

Weill-Marchesani syndrome (AR-277600)

Aniridia

Stickler syndrome (AD-108300)

Retinitis pigmentosa

Kniest syndrome (AD-156550)

Persistent hyperplastic primary vitreous

Osteogenesis imperfecta (heterogeneous, AR-259410)

Peters anomaly

Albright hereditary osteodystrophy (AD-103580, XLD-300800)

INTRAUTERINE INFECTION

Central nervous system syndrome

Rubella

Zellweger syndrome (AR-214100)

Varicella

Meckel-Gruber syndrome (AR-249000)

Toxoplasmosis

Sjogren-Larsson syndrome (AR-270200)

UVEITIS OR ACQUIRED INFECTION

Marinesco-Sjogren syndrome (AR-248800) Norrie disease (XLR-310600)

Juvenile rheumatoid arthritis Pars planitis

Dermatologic diseases

Toxocara canis

Cockayne syndrome (AR-216400) Goltz syndrome (XL-305600)

DRUG-INDUCED

Rothmund-Thompson syndrome (AR-268400)

Corticosteroids

Atopic dermatitis

Others

Incontinentia pigmenti (XL-308300) Progeria (AD-176670) Werner syndrome (AR-277700)

TRAUMA RADIATION EXPOSURE

Ichthyosis (Heterogeneous) Marshall ectodermal dysplasia

317

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Craniofacial Structures

cortex like rings around the planet Saturn. In unilateral cases, the eye is conspicuously smaller than normal, with a normal-appearing posterior segment. Lamellar or zonular cataracts are formed of opacified shells of cortex around a clear nucleus and are surrounded by normal cortex with or without riders. Most cases are bilateral and inherited in an autosomal dominant fashion, as are most other cataracts. Such cataracts may go unnoticed for years until the pupil is pharmacologically dilated and the opacity appears. They can be misdiagnosed as microspherophakia (small round lens) because one may think that the opacified cortex is the edge of the lens. These cataracts may progress to become total, necessitating surgery in the 1st or 2nd decade of life. Because of the relative clarity of the lens early in life, visual prognosis is excellent following surgery for lamellar cataracts. Posterior lentiglobus is the most common type of unilateral cataract in normal-sized eyes. In these cases, of which more than 90% are unilateral, there is a circumscribed round or oval posterior bowing of the posterior lens capsule, measuring 1 to 5 mm, usually in the area where the hyaloid system of blood vessels originally met with the tunica vasculosa lentis. The cortical lamellae that occupy the bulging part of the lens become progressively disorganized and opaque, possibly because of fluid imbibition through ruptures in the weakened capsule. Some cases have been observed to progress extremely rapidly to total opacification, possibly secondary to blowout of the lentiglobus into the vitreous cavity. If posterior lentiglobus is eccentric and small, it is best observed until progression to a significant opacity involving the

Fig. 9-16. Nuclear cataract.

central visual axis occurs. The presence of central and large defects may be an indication for surgery if associated with high myopic errors of refraction or significant opacification. 9.12 Persistent Hyperplastic Primary Vitreous or Persistence of the Fetal Vasculature Definition

Persistent hyperplastic primary vitreous (PHPV) or persistence of the fetal vasculature (PFV) is a complex malformation of the eye characterized by the presence of remnants of the hyaloid system of blood vessels along with a plaque of fibrovascular tissue behind the lens. PHPV, also referred to as PFV,1 affects the vitreous primarily but also involves the retina, ciliary body, iris, and lens. Elongated ciliary processes converge to and are pulled toward the retrolental fibrovascular tissue. The eye is variably reduced in size, and a cataract may be present. Anterior and posterior varieties of PHPV have been described. Both appear to be on the same continuum of malformations. Congenital falciform fold of the retina may be a manifestation of a posterior form of PHPV but may also be seen in dominant exudative vitreoretinopathy, toxocara canis infection of the eye, and retinal dysplasia such as is seen in the Warburg-Walker syndrome and Norrie disease.1 Diagnosis

PHPV is unilateral in about 90% of cases. The size of the globe varies from normal to moderately decreased, being slightly smaller than normal in the majority of cases (Fig. 9-17). The cornea is clear. The anterior chamber is shallow in smaller eyes because of anterior displacement of the iris/lens diaphragm; this predisposes patients with PHPV to angle-closure glaucoma, which usually develops later in adulthood. Some authors advocate lens extraction to prevent secondary angle-closure glaucoma. The iris may be normal but frequently shows small notches at the pupillary margins, where iridohyaloidal vessels coursed in the developing eye and failed to regress with maturation of iris structures and resorption of the tunica vasculosa lentis. Patent iridohyaloidal vessels may be seen coursing over the anterior iris surface, over the pupillary margin, and over the posterior iris surface to anastomose with vessels in the retrolental membrane. It is thought that such iridohyaloidal vessels are extremely suggestive of PHPV; their presence in a small eye with a white pupillary reflex is diagnostic of this condition.1 The lens may be completely clear or may be cataractous. The fibrovascular plaque may adhere to the posterior lens capsule, and vessels can invade the lens, giving a clinical picture very characteristic of PHPV. The retrolental membrane may contain adipose tissue, cartilage, and smooth muscle tissue. This is thought to be the result of metaplastic changes in tissue of mesenchymal origin. Haddad et al. reported on the clinicopathologic findings in 62 cases of PHPV. The cases were divided into two main groups. Group 1 consisted of 55 unilateral cases not associated with any systemic abnormalities, including 36 eyes (58%) that were considered ‘‘pure cases’’ (Group 1A) and 19 (31%) that disclosed other ocular abnormalities in addition to PHPV (Group 1B). Group 2 consisted of seven (11%) bilateral cases of PHPV accompanied by other ocular and systemic malformations. The most common presenting clinical signs were leukocoria, microphthalmia, and cataract. The main histopathologic features of this condition were outlined, including those responsible for the disastrous results to

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Fig 9-17. Microcornea and microphthalmia in a patient with persistent hyperplastic primary vitreous (PHPV).

the eye (retinal detachment, glaucoma, phthisis bulbi). Several clinical entities were usually mistaken for or associated with PHPV, such as retinoblastoma, congenital cataract, retinal dysplasia, trisomy 13 syndrome, and falciform retinal folds.2 Patients with PHPV present with one of three findings: (1) a small eye since birth, (2) a white pupillary reflex because of the associated cataract or retrolental membrane, or (3) strabismus because of poor vision. Ultrasonography and computed tomography are helpful in the differentiation between PHPV and retinoblastoma in eyes with leukocoria. There is no intraocular calcification in PHPV, and the retrolental mass and/or retinal detachment can be visualized by ultrasonography and by computed tomography with contrast enhancement.3 Retinoblastoma generally occurs in eyes of normal size but has been reported in microphthalmic eyes. Additionally, PHPV and retinoblastoma have rarely coexisted in a microphthalmic eye.4

and appropriate aphakic correction and amblyopia therapy should be instituted. Early surgery may result in relatively good visual results in selected patients.9–11 If the pathology is localized to the anterior segment of the eye, the lens and retrolental membrane are removed through a limbal approach. If significant midvitreal or posterior vitreal components to the PHPV are present, then a combined lensectomy-vitrectomy using a pars-plana surgical approach may be considered.12 Lensectomy probably prevents the development of secondary angle closure glaucoma, which is a source of visual loss and discomfort in these patients with limited visual capabilities and potential. Tractional and rhegmatogenous retinal detachments have been reported in patients with PHPV and are treated surgically as needed. Myopia seems to predict a better visual outcome in patients with PHPV.13 Very rarely, the anterior or posterior lens capsule ruptures in PHPV, and an inflammatory ocular response may be induced.

Etiology and Distribution

References (Persistent Hyperplastic Primary Vitreous)

The incidence of PHPV is unknown, but it is not a very rare condition. PHPV is generally isolated and unilateral without associated congenital malformations. It has, however, been reported in two patients with oculo-dento-osseous dysplasia,5 in one patient with protein C deficiency,6 and in the oculo-palato-cerebral syndrome.7 There is also one report of a family with Rieger anomaly and PHPV in two generations.8 PHPV may be due to a defect in the formation of the secondary vitreous, which is derived from the inner retinal cells starting in the 9th week of gestation. The secondary vitreous fills the developing fetal eye starting from the ocular wall region and progressing centrally. It compresses the regressing primary vitreous, which is probably derived from mesenchyme and contains the hyaloid system of blood vessels that anastomose with the tunica vasculosa lentis anteriorly. A defect in the formation of the secondary vitreous or in the regression of the primary vitreous and of the tunica vasculosa lentis, or a combination of both, may lead to the clinical picture of PHPV. The globe remains small because its growth depends partly on the expansion of the secondary vitreous. Precipitating factors and etiologic agents leading to PHPV have not been identified yet. Familial occurrences of PHPV have been reported in dizygotic twins, in two brothers, and in a mother and son. Prognosis, Prevention, and Treatment

Visual prognosis in eyes with PHPV is generally guarded. Associated cataracts should be extracted in the first few weeks of life,

1. Goldberg MF: Persistent fetal vasculature (PFV): an integrated interpretation of signs and symptoms associated with persistent hyperplastic primary vitreous (PHPV). LIV Edward Jackson Memorial Lecture. Am J Ophthalmol 124:587, 1997. 2. Haddad R, Font RL, Reeser F: Persistent hyperplastic primary vitreous. A clinicopathologic study of 62 cases and review of the literature. Surv Ophthalmol 23:123, 1978. 3. Mafee MF, Goldberg MF: Persistent hyperplastic primary vitreous (PHPV): role of computed tomography and magnetic resonance. Radiol Clin North Am 25:683, 1987. 4. Irvine AR, Albert DM, Sang DN: Retinal neoplasia and dysplasia. II. Retinoblastoma occurring with persistence and hyperplasia of the primary vitreous. Invest Ophthalmol Vis Sci 16:403, 1977. 5. Traboulsi EI, Faris BM, Der Kaloustian VM: Persistent hyperplastic primary vitreous and recessive oculo-dento-osseous dysplasia. Am J Med Genet 24:95, 1986. 6. Hermsen VM, Conahan JB, Koops BL, et al.: Persistent hyperplastic primary vitreous associated with protein C deficiency. Am J Ophthalmol 109:608, 1990. 7. Frydman M, Weinstock AL, Cohen HA, et al.: Autosomal recessive Peters anomaly, typical facial appearance, failure to thrive, hydrocephalus, and other anomalies: further delineation of the Krause-Kivlin syndrome. Am J Med Genet 40:34, 1991. 8. Storimans CW, Van Schooneveld MJ: Rieger’s eye anomaly and persistent hyperplastic primary vitreous. Ophthalmic Paediatr Genet 10:257, 1989. 9. Anteby I, Cohen E, Karshai I, et al.: Unilateral persistent hyperplastic primary vitreous: course and outcome. J AAPOS 6:92, 2002. 10. Stark WJ, Fagadau W, Lindsey PS, et al.: Management of persistent hyperplastic primary vitreous. Aust J Ophthalmol 11:195, 1983.

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Craniofacial Structures

11. Pollard ZF: Persistent hyperplastic primary vitreous: diagnosis, treatment and results. Trans Am Ophthalmol Soc 95:487, 1997. 12. Dass AB, Trese MT: Surgical results of persistent hyperplastic primary vitreous. Ophthalmology 106:280, 1999. 13. Cheung JC, Summers CG, Young TL: Myopia predicts better outcome in persistent hyperplastic primary vitreous. J Pediatr Ophthalmol Strabismus 34:170, 1997.

9.13 Optic Nerve Hypoplasia Definition

Optic nerve hypoplasia is a nonprogressive, segmental, or diffuse congenital abnormality of one or both optic nerves characterized by a decreased number of axons in the involved nerve, which otherwise has normal glial and supportive mesodermal tissue.1,2 Diagnosis

Optic nerve hypoplasia should be suspected in infants with poor vision and nystagmus, especially those with other neurologic deficits; in older individuals with long-standing, nonprogressive visual impairment of unclear etiology; and in patients with midfacial abnormalities. Males are affected as frequently as females, and bilateral disease is more common than unilateral disease.3,4 Patients with unilateral or asymmetric disease may present with strabismus. Patients with bilateral severe disease usually present with poor vision and nystagmus. Visual acuity may be normal in the presence of visual field defects and mild disease. There is a subset of patients with segmental or sectorial optic nerve hypoplasia.5 In such patients, sometimes born to diabetic mothers,6–9 the superior half of the disc is usually missing, hence the name ‘‘topless’’ optic nerve. Ophthalmoscopically, the nerve head is reduced in size because of the decreased number of axons. There may or may not be a surrounding hypopigmented halo, the so-called double ring sign. The double ring sign indicates that a small optic nerve is present in a wider scleral canal.1 The degree of optic nerve hypoplasia is extremely variable and tends to be more severe in bilateral cases. Mild cases are difficult to diagnose because of problems in measuring optic nerve head diameter and because of the variability in appearance of the optic nerve head in different racial groups and with different degrees of myopia or hyperopia. In cases in which a mild degree of hypoplasia is suspected, fundus photographs can be obtained, and absolute measurements or measurements relative to retinal arterial vessel diameter or to other retinal landmarks such as the distance from the center of the disc to the fovea are made to confirm the diagnosis. Retinal vascular tortuosity is often present, and blunting of the macular and foveal reflexes is due to a decrease in the number of nerve fibers. A variety of visual field defects may be present in patients with optic nerve hypoplasia, depending on the severity of nerve fiber loss. Bitemporal visual field defects and generalized constriction are most commonly seen in severe hypoplasia, whereas inferior altitudinal field defects that spare fixation predominate in segmental hypoplasia.8 Bitemporal field defects may indicate the presence of midline defects in the central nervous system.4,10 Optic nerve hypoplasia should be differentiated from the crowded disc in high hypermetropia; hence, refraction should always be performed. Myopic and astigmatic errors are more often present in patients with ONH than pure hypermetropic errors.11

Also, hypoplastic discs have been incorrectly diagnosed as atrophic discs because of the surrounding pallor of the lamina cribrosa; the nerve tissue itself, however, is pink but smaller than normal. The electroretinogram and electrooculogram are normal and differentiate optic nerve hypoplasia from Leber congenital amaurosis.12 Visual evoked responses are usually reduced in amplitude and correlate with the degree of visual acuity loss. Color vision has not been systematically assessed in patients with optic nerve hypoplasia. Histopathologically, the ganglion cells and optic nerve fibers are reduced in number, but the outer retinal layers are normal. The double ring sign appears to be due to an overgrowth of retinal pigment epithelial cells toward the center of the optic disc.1 The ocular and systemic conditions associated with optic nerve hypoplasia are listed in Table 9-6. Of most interest and significance is the association of optic nerve hypoplasia with structural midline brain abnormalities. Optic nerve hypoplasia is seen in 25% of patients with absence of the septum pellucidum, and 27% of patients with optic nerve hypoplasia have partial or complete absence of the septum pellucidum.4 Septo-optic dysplasia (de Morsier syndrome) is characterized by variable degrees of optic nerve hypoplasia and absence of the septum pellucidum or corpus callosum, mental retardation, spasticity, and impairment of taste and smell13 (Fig. 9-18). Patients with septo-optic dysplasia also have problems learning tasks that require spatial orientation. Pituitary dysfunction and endocrinologic abnormalities may result from hypothalamic maldevelopment.14–16 Hypothyroidism is the most common endocrinologic abnormality in patients with septo-optic dysplasia. Growth hormone deficiency and growth retardation usually become evident in the 3rd or 4th year of life. Diabetes insipidus may also be present. Pituitary dysfunction in patients with septo-optic dysplasia may present as prolonged neonatal hyperbilirubinemia, hypotonia, or infantile hypoglycemia without hyperinsulinemia. In a study of 55 children with optic nerve hypoplasia who underwent magnetic resonance imaging (MRI) of the brain and evaluation of the hypothalamic-pituitary (H-P) axis, 49% of patients had an abnormal septum pellucidum on MRI, and 64% had an H-P axis abnormality. Twenty-seven patients (49%) had endocrine dysfunction, and 23 of these had H-P axis abnormality. The frequency of endocrinopathy was higher in patients with an abnormal septum pellucidum (SP) (56%) than a normal SP (39%). Patients were divided into four groups based on SP and H-P axis appearance: (1) both normal; (2) abnormal SP and normal H-P axis; (3) normal SP and abnormal H-P axis; and (4) both abnormal. The frequency of multiple pituitary hormone deficiency was highest (56%) in Group 4, lower (35%) in Group 3, and even lower (22%) in Group 2. Precocious puberty was most common in Group 2. None of the patients in Group 1 had endocrine dysfunction. Thus, SP and H-P axis appearances on MRI can be used to predict the likely spectrum of endocrinopathy.17 Phillips et al. studied 26 children with optic nerve hypoplasia and pituitary hormone deficiency to determine whether structural abnormalities of the neurohypophysis, as detected by MRI, can be used to diagnose hypopituitarism in children with optic nerve hypoplasia. MRI disclosed posterior pituitary ectopia in 16 of these cases, absence of the pituitary infundibulum and posterior pituitary bright spot in seven, and a normal neurohypophysis in three. Fortyone children with optic nerve hypoplasia and normal endocrinologic function had a normal neurohypophysis. These authors concluded that MRI of the neurohypophysis can predict when congenital hypopituitarism will be associated with optic nerve hypoplasia.18

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Table 9-6. Ocular and systemic conditions associated with optic nerve hypoplasia Syndrome

Prominent somatic features

Causation

Aniridia

None

AD (106200)

Albinism

Absence of skin and hair pigmentation

Heterogeneous

High myopia

None

Unknown

Microphthalmia-uveal coloboma

None

AD (156850)

Aicardi

Infantile spasms, chorioretinal lacunae, retardation

XLD (304050)

Potter

Renal agenesis, pulmonary hypoplasia, oligohydramnios

Unknown

Klippel-Trenaunay-Weber

Asymmetric limb hypertrophy, hemangiomas

Unknown

Facio-auriculo-vertebral spectrum

First and second branchial arch defects

Unknown

Duane retraction

None

Unknown

Meckel

Encephalocele, polydactyly, cystic dysplasia of kidneys, genitourinary abnormalities

AR (249000)

Blepharophimosis

Short palpebral fissures, ptosis, epicanthus inversus, hypogonadism in females

AD (110100)

Chondrodysplasia punctata

Flat facies with low nasal bridge, asymmetric limb shortening, scoliosis, punctate mineralization of epiphyses, follicular atrophoderma

Heterogeneous XLD (302960) AD (118650) AR (215100)

Osteogenesis imperfecta

Fragile bone, blue sclera, joint hyperextensibility, odontogenesis imperfecta

Heterogeneous AR (259410)

13q-

Microcephaly with high nasal bridge, microphthalmia, retinoblastoma, thumb hypoplasia, cardiac defects, genitourinary defects

Chromosomal

Trisomy 18

Prominent occiput, malformed ears, micrognathia, short sternum, cardiac defects, horseshoe kidney, overlapping fingers, intrauterine growth retardation, severe developmental retardation

Chromosomal

Nevus sebaceus of Jadassohn

Midfacial nevus sebaceus, seizures, retardation

Unknown

Midline facial defects

None

Unknown

Etiology and Distribution

Failure of differentiation of the retinal ganglion cell layer between embryonic stages 17 and 19 (12–17 mm in size) has been proposed to explain optic nerve hypoplasia. This necessitates that the ganglion cells be affected selectively, since other cells from the inner neuroblastic retinal layer are normal. This theory also does not account for the associated brain anomalies. Another theory suggests that inadequate target organs, such as in anencephaly or other brain defects associated with optic nerve hypoplasia, prevent the development of ascending pathways such as the optic nerve. Finally, excessive death (apoptosis) of ganglion cells following their overdevelopment may be a plausible pathogenetic mechanism in optic nerve hypoplasia. Possible etiologic factors for the development of optic nerve hypoplasia include maternal diabetes mellitus,19 postmaturity,20 young maternal age,21 and first-born children. Gestational intake of anticonvulsants, quinine, lysergic acid diethylamide, and phencyclidine has been associated with optic nerve hypoplasia. Nearly one-half of patients with fetal alcohol syndrome have optic nerve hypoplasia, and 12.5% of mothers of children with optic nerve hypoplasia admit to alcohol abuse during pregnancy.22 Autosomal dominant inheritance of optic nerve hypoplasia has been reported in five members of one family and in at least one mother-daughter pair.23 Mutations in HESX124–27 and rarely of PAX628 have been associated with optic nerve hypoplasia, and in the former with septo-optic dysplasia. Two patients with partial trisomy 10q24-ter

and optic nerve aplasia have also been reported, indicating the presence of a gene for optic nerve development in that chromosomal region.29 Prognosis, Prevention, and Treatment

Patients with bilateral or unilateral optic nerve hypoplasia should undergo neuroradiologic evaluation for associated brain, pituitary, or other midline cerebral defects. MRI rather than a computed tomography scan should be obtained. Patients with unilateral optic nerve hypoplasia and strabismus should undergo a trial of occlusion therapy for any superimposed amblyopia. Optic nerve hypoplasia is compatible with good visual acuity if the maculopapillary bundle is spared.30 Children with bilateral optic nerve hypoplasia should undergo routine endocrinologic evaluation early in life and periodically thereafter, especially in the presence of suggestive symptomatology. Endocrinologic abnormalities are treated as needed. References (Optic Nerve Hypoplasia) 1. Hotchkiss ML, Green WR: Optic nerve aplasia and hypoplasia. J Pediatr Ophthalmol Strabismus 16:225, 1979. 2. Lambert SR, Hoyt CS, Narahara MH: Optic nerve hypoplasia. Surv Ophthalmol 32:1, 1987. 3. Margalith D, Jan JE, McCormick AQ, et al.: Clinical spectrum of congenital optic nerve hypoplasia: review of 51 patients. Dev Med Child Neurol 26:311, 1984. 4. Acers TE: Optic nerve hypoplasia: septo-optic-pituitary dysplasia syndrome. Trans Am Ophthalmol Soc 79:425, 1981.

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Craniofacial Structures

Fig. 9-18. Septo-optic dysplasia. Top: optic nerve is hypoplastic and shows the ‘‘double ring sign.’’ Bottom: sagittal brain image shows thinning of the corpus collosum with defects in septum pellucidum. 5. Hoyt CS, Billson FA: Optic nerve hypoplasia: changing perspectives. Aust N Z J Ophthalmol 14:325, 1986. 6. Kim RY, Hoyt WF, Lessell S, et al.: Superior segmental optic hypoplasia. A sign of maternal diabetes. Arch Ophthalmol 107:1312, 1989. 7. Landau K, Bajka JD, Kirchschlager BM: Topless optic disks in children of mothers with type I diabetes mellitus. Am J Ophthalmol 125:605, 1998. 8. Petersen RA, Walton DS: Optic nerve hypoplasia with good visual acuity and visual field defects: a study of children of diabetic mothers. Arch Ophthalmol 95:254, 1977. 9. Hashimoto M, Ohtsuka K, Nakagawa T, et al.: Topless optic disk syndrome without maternal diabetes mellitus. Am J Ophthalmol 128:111, 1999. 10. Rush JA, Bajandas FJ: Septo-optic dysplasia (de Morsier syndrome). Am J Ophthalmol 86:202, 1978.

11. Zeki SM: Optic nerve hypoplasia and astigmatism: a new association. Br J Ophthalmol 74:297, 1990. 12. Sprague JB, Wilson WB: Electrophysiologic findings in bilateral optic nerve hypoplasia. Arch Ophthalmol 99:1028, 1981. 13. De Morsier G: Agenesis du septum lucidum avec malformation du tractus optique. Schweiz Arch Neurol Psychiatry 77:267, 1956. 14. Morishima A, Aranoff GS: Syndrome of septo-optic-pituitary dysplasia: the clinical spectrum. Brain Dev 8:233, 1986. 15. Wilson PW, Easley RB, Bolander FF, et al.: Evidence for a hypothalamic defect in septo-optic dysplasia. Arch Intern Med 138:1276, 1978. 16. Brodsky MC, Phillips PH: Optic nerve hypoplasia and congenital hypopituitarism. J Pediatr 136:850, 2000. 17. Birkebaek NH, Patel L, Wright NB, et al.: Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab 88:5281, 2003. 18. Phillips PH, Spear C, Brodsky MC: Magnetic resonance diagnosis of congenital hypopituitarism in children with optic nerve hypoplasia. J AAPOS 5:275, 2001. 19. Nelson M, Lessell S, Sadun AA: Optic nerve hypoplasia and maternal diabetes mellitus. Arch Neurol 43:20, 1986. 20. Jan JE, Robinson GC, Kinnis C, et al.: Blindness due to optic-nerve atrophy and hypoplasia in children: an epidemiological study (1944– 1974). Dev Med Child Neurol 19:353, 1977. 21. Lippe B, Kaplan SA, LaFranchi S: Septo-optic dysplasia and maternal age. Lancet 2:92, 1979. 22. Stromland K, Pinazo-Duran MD: Ophthalmic involvement in the fetal alcohol syndrome: clinical and animal model studies. Alcohol 37:2, 2002. 23. Skarf B, Hoyt CS: Optic nerve hypoplasia in children. Association with anomalies of the endocrine and CNS. Arch Ophthalmol 102:62, 1984. 24. Carvalho LR, Woods KS, Mendonca BB, et al.: A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest 112:1192, 2003. 25. Dattani MT, Martinez-Barbera JP, Thomas PQ, et al.: Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19:125, 1998. 26. Tajima T, Hattorri T, Nakajima T, et al.: Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab 88:45, 2003. 27. Thomas PQ, Dattani MT, Brickman JM, et al.: Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 10:39, 2001. 28. Azuma N, Yamaguchi Y, Handa H, et al.: Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. Am J Hum Genet 72:1565, 2003. 29. Pfeiffer RA, Junemann A, Lorenz B, et al.: Aplasia of the optic nerve in two cases of partial trisomy 10q24-ter. Clin Genet 48:183, 1995. 30. Bjork A, Laurell CG, Laurell U: Bilateral optic nerve hypoplasia with normal visual acuity. Am J Ophthalmol 86:524, 1978.

9.14 Morning Glory Disc Anomaly Definition

The morning glory disc anomaly (MGDA) is an enlarged and excavated optic nerve head, with white glial tissue at its center and a raised annulus of pigmentary chorioretinal changes at its edge.1–3 Diagnosis

The appearance of the nerve head is variable in MGDA, and various degrees of dysplasia may be present. The appearance also depends on the size of the posterior scleral opening, the vascular

Eye

pattern, the amount of gliosis and remnants of the hyaloid system at the center of the disc, and the degree of pigmentation at the edge of the disc (Fig. 9-19).4 The macula is usually dragged nasally to the edge of the disc, and the yellow macular xanthophyll pigment is frequently noticeable at that location. The retinal arterioles and venules emerge in a radial pattern from the enlarged scleral canal and are frequently bridged by vascular arcades close to the optic nerve head.5 Other straight arterioarterial bridging vessels can be seen more peripherally. The majority of cases of MGDA are unilateral with equal involvement of the left and right eyes. Males and females are affected equally. One-half of patients with MGDA present with strabismus. The abnormality is otherwise discovered during routine examination of older children. A large optic nerve head with excessive glial tissue may lead to a

Fig. 9-19. Morning glory disc anomaly. Top: a funnel-shaped excavation at the nerve head with remnants of the hyaloid system at the center of the disc. Bottom: note radiating straight retinal vessels and fibrous tissue in center of disc. The disc diameter is enlarged.

323

white pupillary reflex or leukocoria; hence, MGDA is on the differential list of retinoblastoma and white pupillary reflex. Patients may present with total retinal detachment. Retinal detachment occurs in about 30% of cases.6–8 The detachment is usually nonrhegmatogenous, and its exact etiology is unknown. Communication between the subarachnoid and subretinal spaces with seepage of cerebrospinal fluid under the retina has been postulated as a cause of retinal detachment in MGDA.9,10 There may also be a communication between the vitreous cavity and the subretinal space.11 Spontaneous retinal reattachment has been reported. Rhegmatogenous retinal detachment can also occur.12 Visual impairment is variable in MGDA but is generally substantial, and visual acuity ranges from 20/30 to poor light perception. Poor vision results from retinal and optic nerve dysplasia and hypoplasia but may also be due in part to strabismic or anisometropic amblyopia. Associated ocular anomalies in the same eye include strabismus, retinal detachment, persistence of the hyaloid system, foveal dysplasia, and rarely, pupillary membrane remnants, cataracts, epiretinal membranes, ciliary body cyst, vitreous cyst, microphthalmia, and aniridia.4 Retinal vascular tortuosity, optic pits, microphthalmia, anterior segment dysgenesis, Duane retraction syndrome, and remnants of the pupillary membrane have been reported in the same13 and in the fellow eye. Associated craniofacial abnormalities include hypertelorism, basal encephalocele,14,15 agenesis of the corpus callosum,16 sphenoidal encephalocele,17 and cleft lip and/or palate. Congenital renal abnormalities have also been reported in patients with what has been described as MGDA.18–20 These may have represented cases of the papillorenal syndrome that results from mutations in PAX2.21 This author has noted the MGDA in a boy with preauricular skin tags, patent ductus arteriosus, and unilateral renal agenesis. What has emerged as important associated findings with MGDA are anomalies of the carotid circulation and moyamoya disease.22–27 These progressive vascular malformations can lead to serious central nervous system complications and strokes and are surgically treatable in selected cases. It is of paramount importance to obtain vascular imaging studies such as computed tomography angiography in all patients with MGDA to rule out moyamoya vascular abnormalities. Etiology and Distribution

The morning glory disc anomaly probably results from failure of the posterior sclera and the lamina cribrosa of the optic nerve head to form. This leads to herniation of intraocular contents through the defect and formation of the conical deformity.28 This process interferes with regression of the hyaloid vasculature and derived structures, and remnants of the hyaloid system are hence frequently observed in the center of the malformed optic papilla and sometimes in the vitreous.29,30 It is possible that this process also interferes with closure of the most posterior aspect of the optic fetal fissure leading to a colobomatous component to the MGDA. In some cases it is difficult to distinguish between an optic nerve coloboma resulting from failure of closure of the fetal fissure and MGDA.31,32 Optic pit, MGDA, and peripapillary contractile staphyloma are probably a spectrum of malformations with the same etiology. In peripapillary contractile staphyloma, there probably is myofibroblastic differentiation of some of the mesenchymal tissue at the edge of the disc papilla, leading to contractions that have been observed clinically and recorded by ultrasonography. MGDA is a rare malformation. Many cases are probably misdiagnosed as typical uveal colobomas at the optic disc. Slusher

324

Craniofacial Structures

et al. reported a large kindred in which cavitary optic disc anomalies ranging from optic pits to large, anomalous discs and typical colobomas were inherited in an autosomal dominant fashion.33 The great majority of cases with MGDA or optic pits, however, are isolated, and the recurrence risk in sibs is negligible. Prognosis, Prevention, and Treatment

Visual prognosis is very poor in patients who present with profound visual loss in the affected eye. Careful refraction and treatment of any strabismic or anisometropic amblyopia may result in some regain of vision in rare instances.4 Cryotherapy at the nerve head, scleral buckling, vitrectomy, and retinal tamponade with gas or fluid have been tried for treatment of the retinal detachment that occurs in about 30% of cases; poor visual outcome usually follows, even though retinal reattachment is achieved in some cases.8,10,12,34,35 References (Morning Glory Disc Anomaly) 1. Handman M: Erbliche, vermutlich angeborene zentrale gliose Entartung des Sehnerven mit besonderer Beteiligung der Zentralgefasse. Klin Montasbl Augenheilkd 83:145, 1929. 2. Kindler P: Morning glory syndrome: unusual congenital optic disk anomaly. Am J Ophthalmol 69:376, 1970. 3. Steinkuller PG: The morning glory disk anomaly: case report and literature review. J Pediatr Ophthalmol Strabismus 17:81, 1980. 4. Traboulsi EI, O’Neill JF: The spectrum in the morphology of the socalled ‘‘morning glory disc anomaly.’’ J Pediatr Ophthalmol Strabismus 25:93, 1988. 5. Brodsky MC, Wilson RS: Retinal arteriovenous communications in the morning glory disc anomaly. Arch Ophthalmol 113:410, 1995. 6. Hamada S, Ellsworth RM: Congenital retinal detachment and the optic disk anomaly. Am J Ophthalmol 71:460, 1971. 7. Chang S, Haik BG, Ellsworth RM, et al.: Treatment of total retinal detachment in morning glory syndrome. Am J Ophthalmol 97:596, 1984. 8. Harris MJ, de Bustros S, Michels RG, et al.: Treatment of combined traction-rhegmatogenous retinal detachment in the morning glory syndrome. Retina 4:249, 1984. 9. Irvine AR, Crawford JB, Sullivan JH: The pathogenesis of retinal detachment with morning glory disc and optic pit. Retina 6:146, 1986. 10. Von Fricken MA, Dhungel R: Retinal detachment in the Morning Glory syndrome. Pathogenesis and management. Retina 4:97, 1984. 11. Bartz-Schmidt KU, Heimann K: Pathogenesis of retinal detachment associated with morning glory disc. Int Ophthalmol 19:35, 1995. 12. Ho CL, Wei LC: Rhegmatogenous retinal detachment in morning glory syndrome pathogenesis and treatment. Int Ophthalmol 24:21, 2001. 13. Kawano K, Fujita S: Duane’s retraction syndrome associated with morning glory syndrome. J Pediatr Ophthalmol Strabismus 18:51, 1981. 14. Caprioli J, Lesser RL: Basal encephalocele and morning glory syndrome. Br J Ophthalmol 67:349, 1983. 15. Goldhammer Y, Smith JL: Optic nerve anomalies in basal encephalocele. Arch Ophthalmol 93:115, 1975. 16. Eustis HS, Sanders MR, Zimmerman T: Morning glory syndrome in children. Association with endocrine and central nervous system anomalies. Arch Ophthalmol 112:204, 1994. 17. Koenig SB, Naidich TP, Lissner G: The morning glory syndrome associated with sphenoidal encephalocele. Ophthalmology 89:1368, 1982. 18. Weaver RG, Cashwell LF, Lorentz W, et al.: Optic nerve coloboma associated with renal disease. Am J Med Genet 29:597, 1988. 19. Merlob P, Horev G, Kremer I, et al.: Morning Glory fundus anomaly, coloboma of the optic nerve, porencephaly and hydronephrosis in a newborn infant: MCPH entity. Clin Dysmorphol 4:313, 1995. 20. Torralbo A, Nebro S, Remartinez E, et al.: Morning glory optic disc anomaly associated with chronic renal disease. Nephrol Dial Transplant 10:1762, 1995.

21. Parsa CF, Silva ED, Sundin OH, et al.: Redefining papillorenal syndrome: an underdiagnosed cause of ocular and renal morbidity. Ophthalmology 108:738, 2001. 22. Hanson MR, Price RL, Rothner AD, et al.: Developmental anomalies of the optic disc and carotid circulation. A new association. J Clin Neuroophthalmol 5:3, 1985. 23. Komiyama M, Yasui T, Sakamoto H, et al.: Basal meningoencephalocele, anomaly of optic disc and panhypopituitarism in association with moyamoya disease. Pediatr Neurosurg 33:100, 2000. 24. Krishnan C, Roy A, Traboulsi E: Morning glory disk anomaly, choroidal coloboma, and congenital constrictive malformations of the internal carotid arteries (moyamoya disease). Ophthalmic Genet 21:21, 2000. 25. Bakri SJ, Siker D, Masaryk T, et al.: Ocular malformations, moyamoya disease, and midline cranial defects: a distinct syndrome. Am J Ophthalmol 127:356, 1999. 26. Massaro M, Thorarensen O, Liu GT, et al.: Morning glory disc anomaly and moyamoya vessels. Arch Ophthalmol 116:253, 1998. 27. Taskintuna I, Oz O, Teke MY, et al.: Morning glory syndrome: association with moyamoya disease, midline cranial defects, central nervous system anomalies, and persistent hyaloid artery remnant. Retina 23:400, 2003. 28. Manschot WA: Morning glory syndrome: a histopathological study. Br J Ophthalmol 74:56, 1990. 29. Brown GC, Gonder J, Levin A: Persistence of the primary vitreous in association with the morning glory disc anomaly. J Pediatr Ophthalmol Strabismus 21:5, 1984. 30. Cennamo G, Liguori G, Pezone A, et al.: Morning glory syndrome associated with marked persistent hyperplastic primary vitreous and lens colobomas. Br J Ophthalmol 73:684, 1989. 31. Brodsky MC: Morning glory disc anomaly or optic disc coloboma? Arch Ophthalmol 112:153, 1994. 32. Traboulsi EI: Morning glory disc anomaly or optic disc coloboma? Arch Ophthalmol 112:153, 1994. 33. Slusher MM, Weaver RG Jr, Greven CM, et al.: The spectrum of cavitary optic disc anomalies in a family. Ophthalmology 96:342, 1989. 34. Ridings B, Saracco JB, Escoffier P, et al.: [Treatment of a case of retinal detachment in morning glory syndrome]. J Fr Ophtalmol 11:743, 1988. 35. Matsumoto H, Enaida H, Hisatomi T, et al.: Retinal detachment in morning glory syndrome treated by triamcinolone acetonide-assisted pars plana vitrectomy. Retina 23:569, 2003.

9.15 Optic Pit Definition

Optic pit is an oval, round, triangular, or even slitlike excavation of variable color, depth, and location in the disc substance. Pits may be single or multiple, and the optic nerve head may be normal or increased in size.1–3 Optic pits may be considered as part of a continuum of cavitary malformations of the optic nerve head that includes the different configurations of the morning glory disc anomaly.4 Diagnosis

The diagnosis is made by ophthalmoscopy and may be helped by fluorescein angiography. Pits vary from one-tenth of a disc diameter (0.15 mm) to one-half or more disc diameter in size (Fig. 9-20). They may be white, gray, greenish, or even black and are most often located in the inferotemporal aspect of the disc touching, or distant from, the disc margin. Up to three optic pits have been reported in one disc. Bilateral cases are rare. Serous detachment of the retina in the macular area occurs in more than one-third of patients, usually in the 3rd and 4th decades of life, and is the major cause of visual loss that complicates this congenital malformation that may otherwise go unnoticed.5 The etiology of

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the natural history of optic pits associated with detachment of the macula, Sobol et al. showed that 12 of 15 patients had eventual visual acuity of 20/200 or less.5 The treatment of serous macular detachment from optic pits is difficult. Vitrectomy with gas-fluid exchange has been tried with limited success in reattaching the retina and improving vision.12,13 Laser photocoagulation has been tried in the treatment of both macular detachment and peripapillary neovascularization in this condition.14 There is a macular scleral buckling procedure that consists of fixation of a silastic sponge explant at the posterior pole corresponding to the macula that seems to work well in the majority of patients.15,16 References (Optic Pit)

Fig 9-20. Large central pit of the optic nerve head with tortuosity of retinal vasculature.

the serous detachment is still debated. Lincoff et al. demonstrated that the macular lesion starts as an area of schisis that progresses to a serous macular detachment after the formation of an outer retinal tear.6 Another rare complication is the development of subretinal neovascularization at the disc margin.7 Etiology and Distribution

Gass believes that optic pits are due to anomalous development of the primordial optic nerve papilla and failure of complete resolution of the peripapillary neuroectodermal folds that are part of the normal development of the optic nerve head.8 Other authors have, probably erroneously, attributed the development of pits to failure of closure of the ocular fetal fissure in the region of the nerve head. Although pits and typical chorioretinal colobomas have been reported to coexist, a common etiology for both is highly unlikely. On the other hand, pits have been described in fellow eyes of patients with the morning glory disc anomaly (MGDA);4 and in some members of a family with either pits or optic disc cavitary malformations.9 This author believes that both optic pits and MGDA share a common embryologic etiology. Two families with dominant inheritance of optic pits10,11 and another with cavitary malformations of the optic nerve head have been reported.9 No specific genetic loci have been identified. Prognosis, Prevention, and Treatment

A significant proportion of eyes with optic pits later develop serous macular detachment with loss of visual acuity. In a study of

1. Brown GC, Shields JA, Patty BE, et al.: Congenital pits of the optic nerve head. I. Experimental studies in collie dogs. Arch Ophthalmol 97:1341, 1979. 2. Brown GC, Augsburger JJ: Congenital pits of the optic nerve head and retinochoroidal colobomas. Can J Ophthalmol 15:144, 1980. 3. Brown GC, Shields JA, Goldberg RE: Congenital pits of the optic nerve head. II. Clinical studies in humans. Ophthalmology 87:51, 1980. 4. Traboulsi EI, Jurdi-Nuwayhid F, Torbey NS, et al.: Aniridia, atypical iris defects, optic pit and the morning glory disc anomaly in a family. Ophthalmic Paediatr Genet 7:131, 1986. 5. Sobol WM, Blodi CF, Folk JC, et al.: Long-term visual outcome in patients with optic nerve pit and serous retinal detachment of the macula. Ophthalmology 97:1539, 1990. 6. Lincoff H, Lopez R, Kreissig I, et al.: Retinoschisis associated with optic nerve pits. Arch Ophthalmol 106:61, 1988. 7. Jay WM, Pope J Jr, Riffle JE: Juxtapapillary subretinal neovascularization associated with congenital pit of the optic nerve. Am J Ophthalmol 97:655, 1984. 8. Gass JD: Serous detachment of the macula. Secondary to congenital pit of the optic nervehead. Am J Ophthalmol 67:821, 1969. 9. Slusher MM, Weaver RG Jr, Greven CM, et al.: The spectrum of cavitary optic disc anomalies in a family. Ophthalmology 96:342, 1989. 10. Babel J, Farpour H: [The genetic origin of colobomatous fossae of the optic nerve]. J Genet Hum 16:187, 1967. 11. Stefko ST, Campochiaro P, Wang P, et al.: Dominant inheritance of optic pits. Am J Ophthalmol 124:112, 1997. 12. Schatz H, McDonald HR: Treatment of sensory retinal detachment associated with optic nerve pit or coloboma. Ophthalmology 95:178, 1988. 13. Bartz-Schmidt KU, Heimann K, Esser P: Vitrectomy for macular detachment associated with optic nerve pits. Int Ophthalmol 19:323, 1995. 14. Annesley W, Brown G, Bolling J, et al.: Treatment of retinal detachment with congenital optic pit by krypton laser photocoagulation. Graefes Arch Clin Exp Ophthalmol 225:311, 1987. 15. Georgopoulos GT, Theodossiadis PG, Kollia AC, et al.: Visual field improvement after treatment of optic disk pit maculopathy with the macular buckling procedure. Retina 19:370, 1999. 16. Theodossiadis GP, Theodossiadis PG: The macular buckling technique in the treatment of optic disk pit maculopathy. Semin Ophthalmol 15:108, 2000.

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10 Ear John C. Carey

T

he auditory system is a highly interesting and complex structure. A single integrated anatomic unit serves both hearing and equilibrium. The ear develops as three distinct components: the external ear, the middle ear, and the inner ear. In these introductory comments, the morphogenesis of the three parts of the ear will be summarized in the context of the developmental genes currently known to be vital in ear development. In addition, some of the recently discovered genes, known to be expressed in the inner ear and causative in many syndromic and nonsyndromic forms of deafness in the human, will be tabulated and concisely discussed. This latter set of genetic factors and molecules has amazing homology to the genes causing deafness in the mouse. Moreover, these genes have been identified as a genetic basis of deafness only since 1996. Morphogenesis of the Ear and Crucial Genes

The orchestration of the key events involved in the embryogenesis of the three parts of the ear is remarkable: the embryonic inner ear, eventually going on to form the cochlea and semicircular canals, derives from surface ectoderm and migrates inward. It must connect with the two other distinctive components, the middle ear cavity and the auricle with its meatus, both separate structures and derived from the first and second branchial arch.1,2 The main landmarks that occur in the development of the inner, middle, and outer ear are summarized in Table 10-1. The earliest morphologic evidence of the development of the inner ear occurs at about 22 days as a thickening in the surface ectoderm of both sides of rhombomeres four through six. This is occurring just at the time the neural tube is closing. This thickening, called the otic placode, invaginates and forms the otic vesicle. This placode is a distinct structure and similar to the placodes that form the other sensory organs, the eye and the nose. The signals required to induce the otic placode, the first step in ear development, come from the mesoderm and neural cells. The molecules mediating these events in the mouse and human are still being delineated and are under close investigation. In the chick, FGF-19 is likely the crucial molecule that induces the otic placode. However, what is clear is that in the mouse, Fgfs certainly play a crucial role in otic placode induction, with Fgf-3 from the hindbrain and Fgf-10 from the neural tube adjoining the placode.3,4 The line of evidence that leads to this conclusion comes from knockout experiments in the mouse. Other genes are then required to

maintain differentiation of the placode to the otic vesicle and otocyst. Pax-2, expressed ventromedially, is crucial to the cochlear component of the inner ear, while Nkx-5, expressed dorsolaterally, maintains the semicircular canals. Studies of mice who have knockouts of these two genes show cochlear aplasia and semicircular canal agenesis, respectively.3,4 Other genes expressed in the mouse cochlea in early development are known to be crucial to morphogenesis based on similar types of gene inactivation experiments. These include Six1, Eya1, Bmp4, Tpx1, and Wnt8c.5,6 The integration of these various molecular factors and the morphogenesis of the cochlea and semicircular canals are still being widely investigated. The fact that the fully developed inner ear comprises seven distinct cell types underscores the molecular complexity of its morphogenesis. The middle ear harbors a chain of three ossicles that transmit the vibrations of sound from the environment into the inner ear, where they are then converted to neural impulses. Gene inactivation studies, such as those done in inner ear development, have identified molecular factors needed for the formation of the different components of the middle ear. The signaling molecules, Fgf-8 and endothelin1, likely mediate epithelial-mesenchymal interactions.7 Other genes, including Eya1, Hoxa1, Hoxa2, and Dlx1, are involved in patterning the process of neural crest cells migrating into the region to form the middle ear structures.7 Of note, the tympanic ring (TR), which surrounds the future tympanic membrane, plays a crucial role in directing invagination of the first pharyngeal cleft ectoderm to form the external auditory meatus. Thus, the integration of the connections between the middle ear and the external ear are orchestrated by the TR. The TR needs goosecoid and Prx1 to carry out its pivotal role. Absence of these genes results in an embryo without a TR and, subsequently, the external auditory meatus. This particular malformation, aural atresia, will be discussed in the section on the external ear. Eya1 and Msx1 both are also needed in the middle ear, because gene activation studies of these factors result in significant ossicular chain defects. These two genes are both involved in the causation of human craniofacial syndromes; Eya1 is the causative gene for the brachio-oto-renal syndrome and Msx1 mutations cause dental anomalies. The external ear—the auricle and its connection with the external auditory meatus—develops at approximately 42 days from six proliferations of mesenchyme that occur on both sides of the first pharyngeal cleft. These hillocks arise from the first and second 327

328

Craniofacial Structures Table 10-1. Key landmarks in the development of the ear Time from Conception

Landmarks

21 days

Otic placode invaginates and migrates inward to form the otic vesicle. The vesicle differentiates into three components: the dorsal endolymphatic duct, the expanded central utricle, and the ventral saccule.

28–50 days

The central utricle differentiates to form the three semicircular canals and the ventral saccule increases in size and coils to form the cochlea. These derivatives constitute the membranous labyrinth. The VIII nerve also forms from the otic placode tissue.

9–23 weeks

Condensation of mesenchyme around the membranous labyrinth chondrifies and then ossifies to form the bony labyrinth.

5–8 weeks

The first pharyngeal pouch lengthens and forms the tubotympanic recess, which eventually develops into the tympanic cavity of the middle ear and the eustachian tube. The cartilages of the surrounding first and second pharyngeal arch give rise to the malleus, incus, and stapes. The mandibular process of the first branchial arch is the origin of the malleus, while the cartilage from the maxillary portion of the first branchial arch gives rise to the incus. The stapes derives from cartilage of the second branchial arch. The tympanic ring induces the ectoderm of the first pharyngeal cleft to form the external meatus.

6–8 weeks

The auricle develops from six hillocks, which appear on the adjoining edges of the first and second branchial arch. The cleft in between connects with the external auditory canal from the tympanic ring. The tympanic membrane arises from the tissue that separates the first pharyngeal pouch and the first pharyngeal cleft.

Adapted from Larsen1 and Sadler.2

branchial arch. They proceed to form the auricle and connect with the external auditory meatus, as described above. From knockout experiments, Hoxa1, Hoxa2, and retinoic acid receptors all play a role in external ear morphogenesis.1 As indicated, the processes must be integrated in time and place. The final anatomic unit includes the auricle and its meatus connected to the tympanic membrane (the tympanic ring embeds itself into the temporal bone of the osseous labyrinth), which connects to the three ossicles. This leads to the oval window, which opens into the vestibulocochlear apparatus. Mouse Models for Human Deafness

The sections on the inner ear will discuss the malformations of the vestibular and cochlear organs. Currently, there is an impressive collection of mouse mutants with disorders of hearing and equilibrium that provide models for the study of these genes and

their disordered functional outcome, deafness.8,9 Tables 10-2 and 10-3 summarize a selected group of human deafness conditions, nonsyndromic and syndromic, and tabulates the mouse homologous disorder. The selected group includes many of the conditions that will be discussed in the sections on the inner ear (10.31 and 10.32). Currently, over 80 loci for human deafness have been mapped and over 30 genes for nonsyndromic deafness have been identified, most since 1996. Study of the mouse allows detailed knowledge of the expression of these genes, the interaction of their proteins, and potential clues into pathogenesis. The proteins comprise transcription factors, signaling molecules, signal transduction proteins, and extracellular matrix proteins. One group of proteins that is known to be associated with human deafness is the myosins; three of the myosins have been discovered as causative of human conditions, owing to their corresponding mouse mutants.

Table 10-2. Human nonsyndromic deafness genes and selected corresponding mouse genes and mutations Human Disorder

Human Gene/Locus

Mouse Gene/Locus

Mouse Mutation

DFNB12 (also USH1D)

CDH23, 10q21-q22

Cdh23, 10

Waltzer

DFNA13 (also STL2)

COL11A2, 6p21

Col11a2, 17

Targeted null

DFNA1

DIAPH1, 5q31

Diap1, 18

None

DFNA10

EYA4, 6q23

Eya4, 10

None

DFNA3, DFNB1

GJB2 (CX26), 13q11-q12

Gjb2, 14

Targeted, conditional null

DFNA3, DFNB1

GJB6 (CX30), 13q12

Gjb6, 14

Targeted null

DFNA48

MYO1A, 12q13-q14

Myo1a, 10

None

DFNB3

MYO15, 17p11

Myo15, 11

Shaker 2, sh2

DFNA22, DFNB37

MYO6, 6q13

Myo6, 9

Snell’s waltzer, sv

DFNB2, DFNA11 (also USH1B)

MYO7A, 11q13

Myo7a, 7

Shaker 1, sh1

DFN3

POU3F4, Xq21.1

Pou3f4 (Brn4), X

Targeted null; sexlinked fidget, slf

DFNA8/DFNA12/DFNB21

TECTA, 11q22-q24

Tecta, 9

Targeted null

From Jackson Laboratory.11

Ear

329

Table 10-3. Human syndromic deafness genes and corresponding mouse genes and mutations Human Disorder

Human Gene/Locus

Mouse Gene/Locus

Mouse Mutation

USH1D, Usher, type ID (also DFNB12)

CDH23, 10q21-q22

Cdh23, 10

Waltzer, v

USH1B, Usher, type IB (also DFNB2, DFNA11)

MYO7A, 11q13

Myo7a, 7

Shaker 1, sh1

STL3, Stickler, type III

COL11A1, 1p21

Col11a1, 3

Chondro-dysplasia, cho

Alport

COL4A3, 2q36-q37

Col4a3, 1

Targeted null

WS4, Waardenburg-Shah

EDN3, 20q13

Edn3, 2

Lethal spotting, ls

BOR, branchio-oto-renal

EYA1, 8q13

Eya1, 1

Spontaneous—Eya1bor and targeted null

JLNS2, Jervell and Lange-Nielsen, locus 2

KCNE1 (ISK), 21q22

Kcne1 , 16

Targeted null

JLNS1, Jervell and Lange-Nielsen, locus 1

KCNQ1 (KVLQT1), 11p15

Kcnq1, 7

Targeted null

Renal-coloboma

PAX 2, 10q24-q25

Pax2 , 19

Targeted null

WS1, Waardenburg type I WS3, Klein-Waardenburg

PAX3, 2q37

Pax3, 1

Splotch, Sp

WS2A, Waardenburg, type IIA

MITF, 3p14-p12

Mitf, 6

Microphthalmia, mi

PDS, Pendred (also DFNB4)

SLC26A4, 7q31

Slc26a4 12

Targeted null

DGS, DiGeorge anomaly

TBX1, 22q11

Tbx1, 16

Transgene overexpression targeted null

From Jackson Laboratory.11

Myosins are molecules that move along actin filaments. They are known to be involved in various cell functions, such as movement and signal transduction. Understanding their role could provide insight into human deafness and, perhaps, creative strategies for prevention or even treatment. As summarized by Steel and Kros in their seminal paper in 2001,10 the expression patterns in the stereocilia of the hair cells and in the organ of Corti of the cochlea has allowed for the depiction of the array of genes involved in the auditory mechanism. The web page for the hereditary hearing impairment in mice from the Jackson Laboratory11 and the hereditary hearing loss home page at the University of Iowa12 are both valuable resources and provide current listings of the identified genes and loci involved in mouse mutants and human deafness, respectively. References 1. Larsen WJ: Development of the ears. In: Human Embryology, ed 3. Churchill Livingstone, New York, 2001. 2. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams & Wilkins, Philadelphia, 2004.

3. Pauley S, Wright TJ, Pirvola U, et al.: Expression and function of FGF-10 in mammalian inner ear development. Dev Dyn 227:203, 2003. 4. Wright TJ, Mansour SJ: FGF-3 and FGF-10 are required for mouse otic placode induction. Development 130:3339, 2003. 5. Zheng W, Huang L, Wei ZB, et al.: The role of SIX1 in mammalian auditory system development. Development 130:3989, 2003. 6. Vitelli F, Viola A, Morshima M, et al.: TBX1 is required for inner ear morphogenesis. Hum Mol Genet 12:2041, 2003. 7. Mallo M: Formation of the middle ear: recent progress in development and molecular mechanisms. Dev Biol 231:410, 2001. 8. Ahituv N, Avraham KB: Mouse models for human deafness: current tools for new fashions. Trends Mol Med 8:447, 2002. 9. Avraham KB: Mouse models for deafness: lessons for the human inner ear and hearing loss. Ear Hear 24:332, 2003. 10. Steel KP, Kros CJ: A genetic approach to understanding auditory function. Nat Genet 27:143, 2001. 11. Jacskson Laboratory. Hereditary hearing impairment in mice. http:// www.jax.org/hmr/models.html. 12. University of Iowa. Hereditary hearing loss home page. http://www. uia.ac.be/dnalab.hhh

External Ear John C. Carey, Albert H. Park, and Harlan R. Muntz Structural defects of the external, middle, and inner ear comprise a significant class of congenital anomalies because of their overall frequency and their impact on the people who have them. Most of the recurrent themes that surface in the study of malformations in general will emerge in a discussion of ear malformations: all types of congenital defects from malformations/dysplasias to deformations and disruptions are represented in the study of the ear; state-of-the art developmental biology is typified by the role of neural crest in

branchial arch development and the vast number of genes expressed in cochlear development; the psychological and emotional aspects of coping with congenital disorders, especially the stigma of external ear defects and deafness, emerge as themes in the care of individuals with ear abnormalities. The external ear is an important site for the study of phenotypic variations, mild malformations, and so-called minor anomalies. It was once thought to be an identifier in criminology.1

330

Craniofacial Structures

Fig. 10-1. A. Schematic showing anatomic landmarks of the external ear. B–E. Frontal and lateral views of a male and a female showing level of external ears in relation to the outer canthi of the eyes.

The medically insignificant but helpful morphologic clues that lie in the ear are many. It is of note that all of the common chromosomal syndromes and most of the uncommon ones have a variation or malformation of the ear as a consistent feature. The external ear alterations of Down syndrome and trisomy 18 are examples of this. The evolutionary biology of the external, middle, and inner ear serves as a prototype for the application of this body of knowledge to the study of human malformations. The reader is referred to the papers by Gould2 and Van De Water et al.3 on this theme and to classical works on the anthropology of the external ear.4,5 Sections 10.1 through 10.21 provide a comprehensive listing and review of external ear malformations in humans. Sections 10.22 through 10.33 deal with the middle and inner ear. Figure

10-1 shows the normal anatomy of the external ear and the position of the ear in relation to other facial structures. References 1. Rogers B: Microtic, lop, cup and protruding ears. Plast Reconstr Surg 41:208, 1968. 2. Gould SJ: An earful of jaw. Nat Hist 99(3):12, 1990. 3. Van De Water TR, Maderson PFA, Jaskoll TF: The morphogenesis of the middle and external ear. Birth Defects Orig Artic Ser XVI(4):147, 1980. 4. Martin E, Saller K: Lehrbuch der Anthropologie, vol III. G Fischer Verlag, Stuttgart, 1962, p 2051. 5. Schwarzfischer F: Ohrmuschel. In: Humangenetic, vol 1/2. PE Becker, ed. Georg Thieme Verlag, Stuttgart, 1969, p 163.

Ear

10.1 Microtia/Anotia Definition

Microtia/anotia is a malformation or hypoplasia of the auricle, ranging from a measurably small external ear with minimal structural abnormality, to the ear with major structural alteration, to total absence of the ear (anotia). These anomalies are divided into four types, microtias I to IV. (Lop/cup ear and less significant changes of superior or inferior aspects of the auricle are discussed in Section 10.11.) Diagnosis

The spectrum of microtia represents the most severe malformations of the external ear. The diagnosis is made from physical examination, and most clinicians utilize the classification systems of Meurman1 or Aguillar2 modified from Marks (Fig. 10-2). Type I microtia consists of a generally small pinna that retains most of the overall structure of the normal auricle. Type I blends closely to the lop/cup defect, and clear distinction between it and the lop/cup defect is not made in the otologic literature. In this milder form, the auditory meatus is usually patent, and defects of the ossicular chain are infrequent. Type II microtia is a moderately severe anomaly with a longitudinal mass of cartilage that has some resemblance to the pinna; the rudimentary auricle will be hook-shaped or have an

Fig. 10-2. Microtia I: small ear with usual anatomic components, here with excessive downward folding of superior helix in an infant with Down syndrome (A). Microtia II: vertical mass of cartilage with only superficial resemblance to ear, here with atresia of the external canal and preauricular tag in an infant with Goldenhar syndrome (B). Microtia

331

S or a question mark appearance. Type III microtia represents the prototype of this spectrum and is the most common abnormality in the surgical series, comprising 50–60% of cases (Fig. 10-2C). The ear is usually a rudiment of soft tissue, and the auricle no longer has any resemblance to the normal pinna. It is often called ‘‘peanut’’ shaped. Types II and III microtia are almost always associated with external auditory canal atresia, and about 75% of cases will have some degree of mandibular hypoplasia.3 About 10% of individuals with types II and III microtia will have ipsilateral facial nerve weakness, and about 15% will be labeled as having hemifacial microsomia.4 Type IV microtia consists of anotia, and there is no pinna tissue present at all. In the surgical series of 311 cases reported by Jafek et al.,5 approximately 18% of patients were classified with type I microtia; 20% type II; and 50% type III. Only 3% had anotia (type IV), and the remainder of the series had meatal atresia without external ear defects (see Section 10.3). In larger population series, anotia represents about 10–20% of cases. Microtia types I to III will occasionally be accompanied by a preauricular tag that probably represents the mildest form of the continuum of this defect. The degree of hearing loss in persons with microtia depends on the presence of meatal atresia, middle ear ossicular chain defects, and the occasional occurrence of inner ear dysplasias. In nonsyndromic microtia there is a definite correlation between the degree of external ear defect and the presence of middle ear malformations. Highresolution computed tomography (CT) scanning of the middle and

III: irregular tissue mass without resemblance to external ear, here with atresia of the external canal in a child with Goldenhar syndrome (C). Microtia IV: absence of external ear in a child exposed prenatally to thalidomide (D).

332

Craniofacial Structures

inner ear greatly assists in the diagnosis of these associated defects as well as in the planning of surgery. In infancy and the preschool years, the degree and type of hearing loss can be detected with brainstemevoked response, behavioral testing, and impedance audiometry. Axial and coronal CT scanning are usually deferred until just prior to the planned surgical intervention. The range of associated middle ear ossicular defects is wide and seems not to follow any pattern. Fusion of the malleus to the atresia plate or to the walls of the epitympanic recess is common in individuals with meatal atresia (Section 10.3). About 20–40% of children with microtia/anotia will have an associated defect or an identifiable syndrome pattern.3,6,7 Gorlin et a1.7 and Tewfik and der Kaloustian8 have cataloged the many syndromes that can have microtia as a feature (see also Table 10-4). The most important condition associated with microtia is the oculoauriculo-vertebral (OAV) spectrum. Investigators at the Center for Craniofacial Anomalies at the University of Illinois have meticulously documented the relationship between isolated microtia, ear tags, hemifacial microsomia, Goldenhar syndrome, and the OAV spectrum.9 The range of findings within familial cases of the Goldenhar syndrome and of isolated (apparently nonsyndromic) microtia suggests a continuum; however, it is not clear that all individuals who have isolated microtia always have it as one end of the OAV spectrum. Recently, Llano-Riva et al.10 studied 145 children with microtia, many having features of OAV.12 Because of no difference in the groups of patients, they concluded that microtia is the mild end of expression of the OAV spectrum. Certainly not all of the syndromes in which microtia occurs will exhibit the entire OAV spectrum. Kaye et al.,11 Gorlin et al.,7 and Cohen et al.12 have presented reviews of the OAV spectrum. It is clear from all of this work that this malformation pattern is a condition of etiologic and pathogenetic heterogeneity. Any individual who has apparently isolated microtia (with or without hemifacial microsomia) is a candidate for this diagnosis. In addition to the list of well-delineated syndromes, microtia appears to have other, nonrandom associations. Kaye et al.3 documented a positive association between microtia and cervical spine fusion not necessarily as part of the OAV spectrum. Their data suggest that individuals with isolated microtia should be investigated for the presence of cervical spine abnormalities. One of the most widely discussed associations in pediatrics is the apparent relationship between external ear defects and renal malformations. Other than the occurrence of auricular abnormalities (including microtia) in the many syndromes characterized by both ear and kidney defects, there is no conclusive epidemiologic evidence that an external ear defect is a marker for renal malformation and warrants invasive urologic investigation. This issue is discussed again in detail in connection with low-set ears (see Section 10.9). The most important association with microtia is conductive and sensorineural hearing loss. As pointed out by Jaffe,13 the entire range of microtia as well as other milder ear defects should always bring to mind middle and internal ear abnormalities. Bassila and Goldberg14 found a 16% occurrence of sensorineural hearing loss in individuals with microtia and/or hemifacial microsomia. Naunton and Valvassori15 detected a frequency of 8% of cases, whereas in the Jafek et al.5 cases, none had neural hearing loss. More recently, Calzolari et al.16 found inner ear dysplasia in 10% of cases.16 Certainly inner ear abnormalities and sensorineural hearing loss should be excluded when following individuals with microtia. Etiology and Distribution

A number of epidemiologic investigations worldwide have estimated the birth prevalence of microtia/anotia (Table 10-5). The figures

have usually ranged from one in 3000 to 20,000, with the average estimate at about one to two in 10,000 in the most comprehensive birth defect registries. An investigation in South America reported figures of one in 500 to 3000, depending on the location.17 The frequency in Quito, Ecuador, of one in 500 is the highest recorded figure. Aase and Tegtmeier18 found a one in 2000 birth prevalence among Native Americans. As mentioned earlier, 20–40% of individuals will have microtia associated with other defects. In two recently published large population series, 28–49% of reported cases had microtia associated with other defects, with 6–9% having a welldefined syndrome.19,20 Epidemiologic studies have consistently shown a male to female predominance of about 2:1. In unilateral microtia, the location is right-sided about 60% of the time. In the larger series, about 10% of individuals were affected bilaterally, and about 80% had meatal atresia. The etiology of microtia is heterogeneous. Table 10-4 shows the large number of syndromes, many of which are of single-gene etiology, that consistently include microtia as a component. Microtia types I through IV can also occur as features of chromosome disorders, especially type I microtia in trisomy 21 and types II through IV microtia in trisomy 18 and 13 syndromes. The reader is referred to Tewfik and der Kaloustian8 for an extensive listing of syndromes with external ear defects. Microtia/anotia is a consistent finding in the isotretinoin embryopathy. The discovery that the vitamin A congeners are human teratogens and that they can produce alterations of morphogenesis of the external ear has paralleled a body of work surrounding the role of neural crest in ear development. Microtia and external ear malformations have been produced in various animal models with trypan blue, thalidomide, and the vitamin A congeners. Poswillo21 proposed that the pathogenesis of microtia with associated hemifacial microsomia was due to embryonic hematoma formation in the area of the blood vessels that precede the formation of the stapedial artery stem. It is difficult to explain the entire continuum of the OAV spectrum (lower spinal defects, epibulbar dermoids) as secondary to a vascular disruption. An alteration in cephalic neural crest migration is certainly the most attractive hypothesis to explain the pathogenesis of microtia/anotia currently. Most cases of microtia/anotia are isolated, with no family history, and most large surgical series indicate that less than 10% of the time there is a family history; however, numerous authors have mentioned the occasional occurrence of a positive family history in nonsyndromic microtia. Rollnick and Kaye have documented higher frequencies of first- and second-degree relatives with ear abnormalities in individuals with microtia with or without hemifacial microsomia.9 In their studies, 8% of first-degree relatives had some degree of ear abnormality, including preauricular tags. While most of their patients were classified as having hemifacial microsomia as opposed to isolated microtia, eight of 15 of their cases diagnosed as microtia had a positive family history. Their data suggest that microtia is part of a continuum that extends to hemifacial microsomia and Goldenhar syndrome as mentioned above. These investigators thought that the multifactorial model of causation fits the data best. Looking closer at immediate families in their data set, one can note two kindreds of multiple affected sibs with no other affected relatives, a pattern that might suggest autosomal recessive inheritance. However, there were 19 other pedigrees that showed generation to generation transmission suggestive of dominant inheritance. It is of note that microtia with meatal atresia is listed as an autosomal recessive disorder in the Online Mendelian Inheritance of Man,22 yet a review of familial reports of nonsyndromic microtia

Table 10-4. Syndromes with microtia, types I–IV Syndrome

Prominent Features

Acrofacial dysostosis-cleft lip-triphalangeal thumbs

Mandibular hypoplasia, malar hypoplasia, cleft lip, bifid uvula, hypoplastic thumbs with three phalanges.

Causation Gene/Locus

Unknown

Bixler

Hypertelorism, oral facial clefting

AR (239800)

Branchio-oto-renal

Branchial clefts, ear pits, hearing loss, renal defect

AD EYA1, 8q

CHARGE

Coloboma, Heart defects, Atresia choanae, retarded growth and development, genital anomalies, ear anomalies or deafness

Sporadic (214800) CHD7, 8q12

Coxo auricular

Dislocated hips, abnormal femora

AD (122780)

Diabetic embryopathy

Excessive intrauterine growth; increased risks for CNS, cardiac, spine, and limb defects

Maternal diabetes

Fraser

Cryptophthalmia, syndactyly, Mu¨llerian defects

AR (219000) FRAS1, 4q21

Greig

Macrocephaly, hypertelorism, syndactyly, polydactyly

AD (175700) GLI3, 7p13

Hennekam

Intestinal lymphangiectasia, facial anomalies, developmental delay

AR (235510)

Johnson-McMillen

Alopecia, anosmia, hypogonadism

AD (147770)

Kabuki

Characteristic face, prominent ears, short stature

AD (147920)

Maxillofacial dysostosis

Maxillary hypoplasia, downslanting palpebral fissures, delayed and inarticulate speech

AD (155000)

Meier–Gorlin

Absent patella, short stature, distinctive face

AR (224690)

Mengel

Unusual ear defects, conductive hearing loss, mental retardation, hypogonadism

AR (221300) 16p12

Microtia-congenital heart defect-facial weakness

Microtia, aortic arch anomalies, facial paresis

Uncertain (243440)

Moeschler

Oral cleft, preauricular tags, hemifacial microsomia, thumb/radial defects

AD (141400)

Nager

Mandibular hypoplasia, malar hypoplasia, radial/thumb hypoplasia

AD (154400)

Oculo-auriculo-frontonasal

Frontonasal malformation, hemifacial microsomia

Unknown

Oculo-auriculo-vertebral spectrum

Epibulbar dermoids, vertebral defects, variable heart defects

Heterogeneous AD (164210) AR (257700) 14q

Postaxial acrofacial dysostosis (Miller)

Mandibular hypoplasia, postaxial limb deficiency

Unknown (263750)

Townes–Brock

Ear defects, anorectal malformations, thumb defects

AD (107480) SALL1, 16p12

Treacher Collins

Mandibular hypoplasia, malar hypoplasia, downslanting palpebral fissures, lower lid coloboma, cleft palate

AD (154500) TCOF1, 5q32

Wildervanck

Klippel-Feil anomaly, hearing loss, Duane anomaly

XLD (314600)

Trisomy 21

Flat facies, upslanting palpebral fissures, Brushfield spots, small mouth, short stature, mental retardation

Chromosomal

Trisomy 18

Prenatal growth deficiency, distinctive face/hands, short sternum, heart defect, mental retardation

Chromosomal

Del 4p

Prenatal growth deficiency, hypertelorism, orofacial clefts, mental retardation

Chromosomal

Del 5p

Round face, telecanthus, ear tags, distinctive weak cry, mental retardation

Chromosomal

Del 9p

Characteristic face, hypotonia

Chromosomal

Del 18p

Distinctive face, ptosis

Chromosomal

Del 22q11

Velopharyngeal insufficiency, heart defect, Di-George anomaly

Chromosomal

Prenatal alcohol

Prenatal and postnatal growth deficiency, distinctive face, developmental delay

Prenatal alcohol exposure

Prenatal thalidomide

Preaxial limb defects, internal malformations

Prenatal thalidomide exposure

Prenatal isotretinoin

Anotia, CNS defects, conotruncal malformations

Prenatal isotretinion exposure

333

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Craniofacial Structures

Table 10-5. Selected studies of the birth prevalence of microtia/anotia in various parts of the world Study Group, Location

Year

Per 10,000 Population

Aase, American Indian

1976

5.38

Aase, all New Mexico18

1976

1.34

Castilla and Orioli, Quito, Equador17

1986

17.40

Castilla and Orioli, South America17

1986

3.20

Mastroiacova et al., Italy

1995

1.45

Harris et al., Sweden20

1996

2.35

Harris et al., France20

1996

0.76

Harris et al., California, USA20

1996

2.0

Sanchez et al., Venezuela37

1997

3.80

18

19

(even excluding the data from Chicago) produced a minimum of 11 reports of generation-to-generation transmission of microtia, some with three-generation pedigrees and one with a five-generation pedigree.23–26 There are also a number of other cases that are labeled as familial hemifacial microsomia that cannot be distinguished from isolated microtia. One of the classic pedigrees cited to support the idea of recessive inheritance of microtia with meatal atresia is that studied by Ellwood et al.27 Yet, in this kindred there was consanguinity, the actual defect was called anotia, and two of the children died in the first few months of life, which suggests a more complicated syndrome, perhaps of recessive inheritance. These data taken together suggest that nonsyndromic microtia with meatal atresia is probably not inherited as a simple autosomal recessive disorder, but rather occurs in many families as an autosomal dominant trait with variable expression and incomplete penetrance. In the dominant familial cases, unilateral and bilateral microtia with or without hemifacial microsomia occur in the same family. Occasionally, some family members simply have the presence of tags. The most parsimonious explanation for the genetics of nonsyndromic microtia is to invoke complex multifactorial causation in most cases, with well-established autosomal dominant inheritance representing a small proportion. Regarding the molecular genetics of familial nonsyndromic microtia, it is reasonable to postulate that a gene predisposing to OAV, hemifacial microsomia, or microtia could be on 14q32 because of linkage in two families.28 It is likely that microtia/anotia can be caused by many different genes and that these genes are on numerous chromosomes. The molecular genetics of this heterogeneous malformation will probably be complicated but could provide a paradigm for studying other complex and multifactorial disorders. Table 10-4 includes our current knowledge on the developmental genes that cause syndromic microtia (e.g., BOR syndrome). Prognosis, Prevention, and Treatment

The impact of microtia/anotia is twofold: stigmatization related to the visible craniofacial defect and hearing loss. The child with microtia often suffers from psychosocial issues related to the visible defect. The microtic ear draws attention to the difference between the two ears, and this can be especially problematic during the elementary school years when conformity and sameness are so important. In addition, some children with microtia will have an adverse effect from hearing loss. The hearing threshold is usually at about 60 dB in an affected ear. This, of course, is of greater concern in the child with the bilateral microtia. Even moderate conductive unilateral hearing loss may be an issue in school performance and

social settings. Ear canal reconstruction or bone conduction amplification for improved hearing should be discussed in detail with the family early so that the implications of improved hearing can be weighed against the risks of the surgical intervention. Children with microtia, either isolated or as part of the OAV anomaly, are frequently evaluated and cared for by craniofacial specialists on a team. The surgical management of microtia is complicated, and numerous surgeons have developed creative approaches to reconstruction. While some otolaryngologists argue for meatal atresia being repaired prior to ear reconstruction, more recently most surgeons have approached external ear surgery first. Certainly the surgical repair should be accomplished by plastic surgeons and otolaryngologists who are used to working together and are experienced in reconstruction. There are two approaches: prosthetic management and auricle reconstruction. Though it is important to offer the family a choice of no intervention, most families will want the child to have a more normal facial appearance. Surgical reconstruction of the external ear is a multistaged endeavor and, as with any surgery, there are risks involved. Prosthetic management requires the diligence of a maxillofacial prosthedontist but has not received as much acceptance in the United States. A prosthetic ear can be made to look very lifelike. Because there are few limitations to thickness, coloration, and revision, the child with prosthesis may actually have a more normal appearance than the child with a reconstructed auricle. Families are often concerned about removing the ear prosthesis for physical activities and cleaning. The prosthesis usually is attached with adhesives or tape, which may be a limitation for the active child. The use of titanium implants to anchor the prosthesis has revolutionized the field of maxillofacial prosthetics. These implants have been used for both dental and facial reconstruction. The titanium implants osseointegrate into the bone and are relatively nonreactive. They have a post that comes through the skin or mucosa upon which the prosthesis can be attached. The use of bone-anchored prostheses eliminates many of the concerns noted in other methods of retention.29,30 Similar to auricular reconstruction, this is also a multistaged operation but is not as invasive.31 The classical surgical reconstruction consists of four stages for auricular reconstruction,2,32,33 followed by canal and middle ear reconstruction. Though there is some controversy as to the best timing for reconstruction, many believe the ideal time is before the child enters first grade, at age 5 to 6 years. The auricle is usually more than 90% of its full size by then. One uses the normal ear to develop a template for the reconstruction. In the case of bilateral atresia, the template can be made from one of the parents’ ears. High-resolution CT is required prior to surgery to delineate the commonly associated ossicular chain defects as well as the anatomy of the facial nerve.34 Regardless of philosophy or staged approach, reconstruction involves the placement of the selected framework (usually a sculpted costal cartilage graft), development of a postauricular sulcus and concha, rotation of the lobule, repair of the atresia and its plate, and the final adjustments of the helix and placement of the auricle. The reconstructed auricle is allowed to heal for a number of months before the canal is reconstructed to ensure the health of the cartilage and flaps. In the past, individuals with unilateral microtia with meatal atresia usually did not have repair of the atresia. However, some investigators feel that the benefits of binaural hearing exceed the risk of surgery, even the risk of damage to the facial nerve. Approach to the associated ossicular chain defects is discussed in the sections on middle ear malformations (Sections 10.22–10.31).

Ear

In meatal atresia there is usually a firm bony union of the malleus with the atretic plate. This needs to be repaired to regain hearing. Also, in most cases of types II through IV microtia, malformations of the malleus and incus are present, and there is a high incidence of facial nerve anomalies in these patients. Thus, families need to be counseled about potential facial nerve injury from surgery. Most series indicate an average of a 30 dB increase postoperatively. Patients who have a relatively intact middle ear will obviously have better results postoperatively than those who have major ossicular chain defects. Hearing restoration can be done using a bone anchored hearing aid (BAHA).35 This uses the osseointegration to place an implant into the mastoid bone. The post is coupled to a device that translates the auditory signal to vibration, working much like the bone conduction hearing aids but with far superior fidelity. It has also shown remarkable improvement for children with unilateral hearing loss.8 There has been reluctance for the insurers to cover the cost of this technology, but it can be offered as an alternative to surgical hearing reconstruction. Complete discussion of aural rehabilitation is beyond the scope of this chapter. It is important to note that children with microtia/anotia require meticulous hearing evaluation in infancy and appropriate audiologic management. Conductive hearing aids are crucial in children with meatal atresia or other structural causes of hearing loss. Preschool programs for infants with mild, moderate, and severe hearing loss exist in most areas of North America, and referral to these programs is important as soon as possible. There is at least one instance of prenatal diagnosis of microtia in a fetus with Treacher Collins syndrome.36 The abnormally small ear was recognized at 17 weeks gestation. Mild forms of type I microtia are probably not able to be diagnosed prenatally. The sensitivity of prenatal ultrasound in the severe forms of microtia is unknown. References (Microtia/Anotia) 1. Meurman Y: Congenital microtia and meatal atresia. Arch Otolaryngol 66:443, 1957. 2. Augilar EF: Auricular reconstruction in congenital anomalies of the ear. Facial Plast Surg Clin North Am 9:159, 2001. 3. Kaye C, Rollnick BR, Hauck WW, et al.: Microtia and associated anomalies: statistical analysis. Am J Med Genet 34:574,1989. 4. Bennun RD, Mulliken IB, Kaban LB, et al.: Microtia: a microform of hemifacial microsomia. Plast Reconstr Surg 76:859, 1985. 5. Jafek BW, Nager GT, Strife I, et al.: Congenital aural atresia: an analysis of 311 cases. Trans Am Acad Ophthalmol Otol 80:588, 1975. 6. Jahrsdoerfer R: Congenital malformations of the ear: analysis of 94 operations. Ann Otol Rhinol Laryngol 89:348, 1980. 7. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 8. Tewfik TD, der Kaloustian VM: Congenital Anomalies of the Ear, Nose, and Throat. Oxford University Press, New York, 1997. 9. Rollnick BR, Kaye CI: Hemifacial microsomia and variants: pedigree data. Am J Med Genet 15:233, 1983. 10. Llano-Riva I, Gonzalez-del Angel A, del Castillo V, et al.: Microtia: a clinical and genetic study at the National Institute of Pediatrics in Mexico City. Arch Med Res 30:120, 1999. 11. Kaye C, Martin AO, Rollnick BR, et al.: Oculoauriculovertebral anomaly segregation analysis. Am J Med Genet 43:913, 1992. 12. Cohen MM, Rollnick BR, Kaye CI, et al.: Oculoauriculovertebral spectrum: an updated critique. Cleft Palate 126:276, 1989. 13. Jaffe BF: Pinna anomalies associated with congenital conductive hearing loss. Pediatrics 57:332, 1976. 14. Bassila MK, Goldberg R: The association of facial palsy and/or sensorineural hearing loss in patients with hemifacial microsomia. Cleft Palate 126:287, 1989.

335 15. Naunton RF, Valvassori GE: Inner ear anomalies: their association with atresia. Laryngoscope 78:1041, 1968. 16. Calzolari F, Garani G, Sensi A, et al.: Clinical and radiological evaluation on children with microtia. Br J Audiol 33:303, 1999. 17. Castilla EE, Orioli IM: Prevalence rates of microtia in South America. Int J Epidemiol 15:364, 1986. 18. Aase LM, Tegtmeier RE: Microtia in New Mexico: evidence for multifactorial causation. Birth Defects Orig Artic Ser XIII(3A):113, 1977. 19. Mastroiacova P, Corchia C, Bott LD, et al.: Epidemiology and genetics of microtia-anotia: a registry-based study on over one million births. J Med Genet 32:453, 1995. 20. Harris J, Kallen B, Robert E: The epidemiology of anotia and microtia. J Med Genet 33:809, 1996. 21. Poswillo D: The pathogenesis of the first and second branchial arch syndrome. Oral Surg 35:302, 1973. 22. Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov. 23. Zankl M, Zang KD: Inheritance of microtia and aural atresia in a family with five affected members. Clin Genet 16:331, 979. 24. Orstavik KH, Medbo S, Mair IWS: Right-sided microtia and conductive hearing loss with variable expressivity in three generations. Clin Genet 38: 117, 1990. 25. Oliveria CA, Pinheiro LC, Gomes MR, et al.: External and middle ear malformations: autosomal dominant genetic transmission. Ann Otol Rhinol Laryngol 98:772, 1989. 26. Gupta A, Patton MA: Familial microtia with meatal atresia and conductive deafness in five generations. Am J Med Genet 59:238, 1995. 27. Ellwood LC, Winter ST, Dar H: Familial microtia with meatal atresia in two sibships. J Med Genet 5:289, 1968. 28. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress of understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 29. Rotenberg BW, James AL, Fisher D, et al.: Establishment of a boneanchored auricular prosthesis (BAAP) program. Int J Pediatr Otorhinolaryngol 66:273, 2002. 30. Westin T, Tjellstrom A, Hammerlid E, et al.: Long-term study of quality and safety of osseointegration for the retention of auricular prostheses. Otolaryngol Head Neck Surg 121:133, 1999. 31. Tietze L, Papsin B: Utilization of bone-anchored hearing aids in children. Int J Pediatr Otorhinolaryngol 58:75, 2001. 32. Brent B: Microtia repair with rib cartilage grafts: a review of personal experience with one thousand cases. Clin Plast Surg 29:257, 2002. 33. Beahm EK, Walton RL: Auricular reconstruction for microtia: part I. Anatomy, embryology, and clinical evaluation. Plast Reconst Surg 109: 2473, 2002. 34. Yeakley JW, Jahrsdoerfer RA: CT evaluation of congenital aural atresia: what the radiologist and surgeon need to know. J Comput Assist Tomogr 20:724, 1996. 35. Snik AF, Mylanus EZ, Cremers CW: The bone-anchored hearing aid in patients with a unilateral air-bone gap. Otol Neurotol 23:61, 2002. 36. Crane IP, Beaver HA: Midtrimester sonographic diagnosis of manbulofacial dysostosis. Am J Med Genet 25:251, 1986. 37. Sanchez O, Mendez JR, Gomez E, et al.: [Clinico-epidemiologic study of microtia]. Invest Clin 38:203, 1997.

10.2 Small Ear The external ear that has normal anatomy or only a minor abnormality of configuration but has a length of 2 standard deviation (SD) or more below the mean is considered small. Ear length is determined by measuring the ear from the superior helix to the lobe. Normal ear length is greater than 30 mm in the full-term baby. There are standards for plotting ear length at birth and in older infants and children (Fig. 10-3).1–5 Small but structurally normal ears are a sign of Down syndrome. Most babies with Down syndrome have mild ear variations,

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Craniofacial Structures

Fig. 10-3. Curves for normal ear length. Left curve shows growth percentiles from birth to age 14 years. (From Feingold M, Bossert WH: Normal values for selected physical parameters: an aid to syndrome delineations. BDOAS X(13):1, 1974.) Right curve shows mean ear length for males (solid line) and females (dashed line) from birth to age 70 years. (From Goodman RM, Gorlin RJ: The Malformed Infant and Child. Oxford University Press, New York, 1983.)

including defects in the lop/cup ear continuum. However, some simply have a normal-appearing auricle that is small. Only rarely will a newborn with Down syndrome have an ear measuring over 3.1 cm. The external ear, especially the small ear, attains most of its childhood growth by age 5 or 6 years. The etiology and pathogenesis of the small, nonmalformed, nonmicrotic ear are unknown. The physical stigma associated with a small ear is minimal. References (Small Ear) 1. Hall JG, Froster-Iskenius UG, Allanson JE, et al: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 2. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 3. Farkas LG: Anthropometry of the Head and Face. Raven Press, New York, 1994.

10.3 External Auditory Canal Stenosis and Atresia Without Microtia Definition

External auditory canal stenosis or atresia without microtia is narrowing or absence of the external auditory canal without the presence of significant external ear malformations. It is usually called aural atresia by the otologist. Diagnosis

Congenital external auditory canal atresia or stenosis without an external ear malformation or microtia is uncommon. Few reports of this malformation were published before the 1980s. The series of 311 patients with aural atresia reported by Jafek et al. showed that only 24, or about 6%, had atresia without a concomitant microtia.1 Grundfast and Camilon2 reviewed 10 cases and the world literature. The absence of an obvious external malformation hampers early detection, and the average age of diagnosis in their series was 2.5 years, with a range of 2 months to 7 years. Often the practitioner assumes that the narrow or missing ear canal is due to some debris in the canal and

therefore misses the diagnosis. Recognition is obviously made by examination of the ear canal with an otoscope. High-resolution computed tomography (CT) scanning is indicated to assess the presence of an atretic bony plate and the status of associated middle ear ossicular defects.3 Cases with unilateral stenosis or atresia are even more difficult to diagnose than bilateral cases. Atresia of the external meatus may be osseous or membranous. In osseous atresia the tympanic bone is replaced by an atretic plate. Aural atresia (AA) has been classified in various ways. Cremers4 divided AA into three types: in type I there is osseous or membranous atresia of the auditory canal but an almost normal medial aspect of the canal and a normal middle ear. Type II, which accounts for most of the cases, involves a partially or totally atretic ear canal with variable involvement of the middle ear. In type III there is a complete bony meatal atresia, with a very small or absent middle ear cavity. Jahrsdoerfer et al.5 proposed a grading system for AA. This system gives points for the presence of normal structures (e.g., stapes present). Higher scores predict better surgical outcome (see below). Atresia of the auditory canal obviously produces a conductive hearing loss, which is usually of about 60 dB. In the rare patient who has a concurrent inner ear abnormality, there may be a mixed type of loss. As was mentioned in the discussion of microtia/anotia (Section 10.1), sensorineural hearing loss occurs more commonly in association with external and middle ear defects than was originally proposed in the early otolaryngology literature. Isolated external auditory canal atresia/stenosis can occur as a marker for and clue to the deletion 18q syndrome (Table 10-6). Any child with this atresia/stenosis who has other mild malformations, phenotypic variations, or developmental delay should be regarded as possibly having this common chromosomal syndrome. Auditory canal stenosis without microtia is also seen in trisomy 18, in the oculo-auriculo-vertebral spectrum, and in the syndrome reported by Rasmussen et al.6 In the latter condition, congenital vertical talus and hypertelorism occur along with atresia of the external auditory canal. None of the kindred had external ear defects. The condition is inherited as a dominant trait and may represent a submicroscopic 18q deletion.

Ear Table 10-6. Syndromes associated with meatal atresia without microtia Causation Gene/Locus

Syndrome

Prominent Features

Deletion 18q

Distinctive face, tapered fingers

Chromosomal

Rasmussen

Hypertelorism, vertical talus

Uncertain

Trisomy 18

Prenatal growth deficiency, distinctive face/hands, short sternum, congenital heart disease

Chromosomal

Oculo-auriculovertebral spectrum

Epibulbar dermoids, vertebral defects, variable heart defects

Heterogeneous, AD (164210), AR (257700) 14q1

Antley-Bixler

Choanal atresia, characteristic face, humeroradial fusion, femoral bowing

AR (207410) POR, q11

SAMS

Humeroscapular synostosis, club feet

Uncertain (602471)

Etiology and Distribution

Isolated external auditory canal stenosis without microtia is an uncommon defect, accounting for fewer than 10% of all individuals who are evaluated by the otologist with meatal atresia, because most have microtia. No prevalence-at-birth studies are available that provide an estimate of this condition. However, in the Spanish Collaborative Project, a prevalence of 0.19 per 10,000 births, or about two per 100,000, was listed for various rare ear malformations, including atretic or stenosed auditory canals with normal auricle (personal communication: Dr. Maria Luisa Martinez-Frias). This figure is a rough estimate, since it included other uncommon ear malformations. However, the estimate must also be considered to be on the low side since some babies with the condition may not be detected in the newborn period. While in microtia with meatal atresia unilaterality is much more common than bilaterality, in aural atresia without microtia there was equal occurrence of bilateral and unilateral defects.2 Males and females were equally affected; the male predominance found in microtia with meatal atresia was not seen. Because the syndromes showing isolated auditory canal atresia/ stenosis are generally different from those showing microtia with meatal atresia, this defect probably reflects a unique alteration in morphogenesis. It is also of note that, in the few familial cases, the degree and frequency of ossicular chain abnormalities are less than what is usually seen in microtia with meatal atresia. As was noted above, the sex ratio and sidedness differ from those in atresia with microtia. These facts support the notion that this anomaly is a different alteration in morphogenesis. Besides the family reported by Rasmussen et al.6 in whom the meatal atresia occurred as part of a syndrome, three other families have exhibited generation-to-generation transmission, suggesting dominant inheritance. The family in the Robinow and Jahrsdoerfer7 study showed male-to-male transmission, indicating autosomal dominant inheritance in that kindred. Thus, atresia of the auditory canal without microtia is inherited in an autosomal dominant fashion in some of the cases. Recently, Veltman et al.

337

defined a critical region of 5 Mb responsible for AA in the 18q deletion syndrome.8 Prognosis, Prevention, and Treatment

When children have bilateral atresia, bone conduction hearing aids can be placed before the child reaches age 6 months.3,9 Surgery is usually planned for about ages 5 to 6 years. Reconstruction is delayed because pneumatization of the mastoid is not complete until that time. Radiographic evaluation of the middle ear with highresolution CT scanning is important to determine the ossicular chain defects as well as the anatomy of the facial nerve and middle ear cleft. Documentation of a sensorineural component to the hearing loss is also important for prognostic planning. Surgical intervention for auditory canal atresia or stenosis is performed by an experienced otolaryngologist.10 The procedure involves creation of a new ear canal, use of the residual ossicular chain or replacement with an ossicular prosthesis, and creation of a new tympanic membrane using temporalis fascia and split thickness skin graft. Extreme care is needed during dissection of the posterior canal because of the abnormal course of the facial nerve. In general, a postoperative hearing level of 30 dB or better can be achieved in 50–75% of patients with aural atresia.3,9 A hearing level of 20 dB or better is possible in 15–50% of these patients. For patients with unfavorable anatomy (e.g., lack of middle ear pneumatization, facial nerve overlying the oral window), one should consider bone-anchored hearing aid implantation (BAHA) (see Section 10.1). Children with unilateral atresia also require regular otologic assessment. The contralateral ‘‘normal’’ side must be monitored closely for otitis media. These patients are adversely affected from even transient hearing loss involving their functionally hearing ear. The contralateral ‘‘normal’’ side must also undergo hearing testing. References (External Auditory Canal Stenosis and Atresia Without Microtia) 1. Jafek BW, Nager GT, Strife J, et al.: Congenital aural atresia: an analysis of 311 cases. Trans Am Acad Ophthalmol Otol 80:588, 1975. 2. Grundfast KM, Camilon F: External auditory canal stenosis and partial atresia without associated anomalies. Ann Otol Rhinol Laryngol 95:505, 1986. 3. Krowiak E, Grundfast KM: Congenital malformations of the ear. In: Pediatric Otolaryngology, Wetmore RF, Muntz HR, McGill TJ, eds. Thiem, New York, 2000. 4. Cremers CWRJ: Meatal atresia and hearing loss. Autosomal dominant and autosomal recessive inheritance. Int J Pediatr Otorhinolaryngol 8:211, 1985. 5. Jahrsdoerfer RA, Yeakley JW, Aguilar EA, et al.: Grading system for the selection of patients with congenital aural atresia. Am J Otolaryngol 13:6, 1992. 6. Rasmussen N, Johnsen NJ, Thomsen J: Inherited congenital bilateral atresia of the external auditory canal, congenital bilateral vertical talus and increased interocular distance. Acta Otolaryngol 88:296, 1979. 7. Robinow M, Jahrsdoerfer RA: Autosomal dominant atresia of the auditory canal and conductive deafness. Am J Med Genet 4:89, 1979. 8. Veltman JA, Jonkers Y, Nuijten I, et al.: Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH. Am J Hum Genet 72:1578, 2003. 9. Declau F, Cremers C, Van de Heyning P: Diagnosis and management strategies in congenital atresia of the external auditory canal. Study Group on Otological Malformations and Hearing Impairment. Br J Audiol 33:313, 1999. 10. Lambert PR, Dodson EE: Congenital malformations of the external auditory canal. Otolaryngol Clin N Am 29:741, 1996.

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Craniofacial Structures

10.5 Large Ear (Macrotia) Definition

Large ear (macrotia) is an alteration in which the length of the auricle is increased above the 97th percentile on standard curves (Fig. 10-5). Diagnosis

Fig. 10-4. Cryptotia. Incomplete separation of the superior and posterior aspects of the pinna from the scalp. (From Aase JM: Diagnostic Dysmorphology. Plenum Press, New York, 1990.)

10.4 Cryptotia Cryptotia is an uncommon defect of the auricle in which there is incomplete separation of the posterior aspect of the superior helix and the adjoining scalp (Fig. 10-4). The diagnosis is made entirely by observation; the examiner simply tugs on the helical fold and discovers the lack of separation. Cryptotia is usually an isolated defect, but it does occasionally occur as part of a syndrome. The Fraser cryptophthalmos syndrome and trisomy 18 are the two most commonly associated entities. Cryptotia is also seen in the Carmi form of epidermolysis bullosa. However, cryptotia usually is nonsyndromic. Unless it is part of a syndrome, this defect is not usually associated with other external, middle, or internal ear changes. Familial cryptotia has been described in one occasion.1 Japanese investigators have emphasized that cryptotia seems to occur much more commonly in Japan than elsewhere in the world.2 The frequency of cryptotia in Japan is one in 400. No other epidemiologic information is available on the nature and determinants of this defect. Plastic surgeons in Japan have developed a number of techniques and approaches for the treatment and repair of cryptotia.2–5 Basically, the repair consists of soft tissue separation and grafts and is usually successful. References (Cryptotia) 1. Hayashi R, Matsuo K, Hirose T: Familial cryptotia. Plast Reconst Surg 91:1337, 1993. 2. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical correction of congenital auricular deformities. Clin Plast Surg 17:383, 1990. 3. Park C: Correction of cryptotia using an external stretching device. Ann Plast Surg 48:534, 2002. 4. Paredes AA Jr, Williams JK, Elsahy NL: Cryptotia. Clin Plast Surg 29:317, 2002. 5. Hirose T, Tomono T, Matsuo K, et al.: Cryptotia: our classification and treatment. Br J Plast Surg 38:352, 1985.

The diagnosis of large ear (macrotia) is made simply by measuring the length of the external auricle. This is accomplished by taking the measurement between the superaurale, which is the highest point of the free margin of the auricle, and the subaurale, which is the lowest portion of the free margin of the ear lobe. This can be done with a standard ruler or tape measure, and the value can be plotted in the available curves, many of which are in standard texts.1,2 At birth, the ear usually measures less than 4.2 cm. The ear grows steadily throughout the first 2 years of life and then slows in growth until age 5 years, when the slowing increases. The large ear is often prominent or protruding. Probably the most important syndrome to consider in individuals with macrotia is the fragile X syndrome. This disorder is rarely noted in infancy and early childhood, so the actual growth curve of the ear in the fragile X syndrome is unknown. However, in the older child, especially in a boy with mental retardation, this is an important marker. There are a number of other syndromes in which macrotia has been recorded, and these have been summarized by Gorlin and coworkers3 and Tewfik and der Kaloustian4 (Table 10-7). Large ears are also found in the oligohydramnios sequence and may be due to external compression.5 Etiology and Distribution

Although no specific prevalence studies have been performed to examine the frequency of large ears, macrotia by definition does occur in 3% of individuals. This, then, is not strictly a malformation but really is an excessive growth phenomenon. However, intrauterine constraint due to oligohydramnios could be a pathogenetic mechanism inducing excessive growth of the ear.5 The large, unfolded, floppy ear is one of the craniofacial features recognized by Potter in the disorder that bears her name, that is, the Potter syndrome (also called oligohydramnios sequence). Prognosis, Prevention, and Treatment

The major impact of macrotia is the stigmatization associated with prominent ears. Surgical reduction of ear size in individuals with macrotia is uncommon. References (Large Ear/Macrotia) 1. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 2. Hall JG, Froster-Iskenius UG, Allanson JE, et al.: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 3. Gorlin RJ, Cohen MM, Hennekan R: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2002. 4. Tewfik TD, der Kaloustian VM: Congenital Anomalies of the Ear, Nose, and Throat. Oxford University Press, New York, 1997. 5. Aase JM: Structural defects as a consequence of late intrauterine constraint, craniotabes, loose skin and asymmetric ear size. Semin Perinatol 7:270, 1983.

Ear

339

Fig. 10-5. Macrotia. Large ear in a 2-month-old infant with microcephaly of unknown cause (A), in a male aged 2 years 9 months with fragile X syndrome (B), and in an adult female carrier of the fragile X chromosome (C). Note the lack of helical folding. Table 10-7. Syndromes that include macrotia Syndrome

Prominent Features

Causation Gene/Locus

Borjeson-Forssman-Lehmann

Coarse face, mental retardation, hypogonadism

XLR (301900) PHF6, Xq26

Fragile X

Long face, large testes, lax joints

XLR (309550) FMR1, Xq27

Langer-Giedion

Microcephaly, exostoses, facial features similar to those in tricho-rhino-phalangeal I

Chromosomal (150230) 8q24

Melnick-Needles

Distinctive face, skeletal changes

XLR (309350) FLNA, Xq28

Pallister-Killian

Pigmentary dysplasia, distinctive face, mental retardation

Chromosomal

Weaver

Distinctive face, macrosomia, camptodactyly

Unknown (277590) Some cases with NSD1 (5q35) mutations

Oligohydramnios

Canthal folds, depressed nasal tip, joint contractures, lung hypoplasia

Heterogeneous

Lamotte

Prenatal growth deficiency, hypertelorism, preaxial polydactyly, distinctive face

AR (245552)

Nance-Horan

Nystagmus, dental anomalies, cataracts, short metacarpal

XLR (302350) NHS, Xp22

10.6 Polyotia True and complete duplication of the external auricle is very rare; many reviewers state that the case of von Bol and de Kleyn1 was the first authentic case of a true duplication defect. In this patient, the infant had a left ear with two external auricles facing each other as a mirror image. Both were fully developed, but a tragus was lacking. Most cases of alleged polyotia are examples of large auricular appendages. The case reported by Gadre et al.2 of an individual with polyotia and the de Lange syndrome is unconvincing in that this

child’s defect appears to be an enlarged accessory appendage. The patient of von Bol and de Kleyn1 had a left-side cleft lip and cleft palate as well as an ocular dermoid, so this individual may have had the oculo-auriculo-vertebral (OAV) spectrum. Recently other cases have been presented.3,4 The birth prevalence of polyotia is obviously low, given only a few widely agreed upon cases. It is of note that the patients of von Bol and de Kleyn1 and Bendor-Samuel et al.3 had no tragus in the duplicated auricles, because some investigators believe that the tragus is the only hillock derived from the first branchial arch.5 This suggests that true polyotia in this case may represent a true duplication of the hillocks that were part of the second branchial arch.

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Craniofacial Structures

The distinction between accessory appendages and true polyotia may be moot if one assumes that auricular appendages are duplicated structures of the auricular hillocks in the first place. Large auricular appendages then would represent duplication of more of the hillocks, with occasional total duplication of the hillocks. Surgical reconstruction has been successful in true polyotia as it is in individuals with auricular appendages.3,4 References (Polyotia) 1. von Bol G, de Kleyn A: Uber einer fall von polyotic. Acta Otolaryngol 1:187, 1918. 2. Gadre AK, Patil DP, Iyer D, et al.: Duplication of the pinna (polyotia) in a case of Brachmann-de Lange syndrome. Br J Plast Surg 40:642, 1987. 3. Bendor-Samuel RL, Tung TC, Chen YR: Polyotia. Ann Plast Surg 34:650, 1995. 4. Ku PK, Tong MC, Yue V: Polyotia—a rare external ear anomaly. Int J Pediatr Otorhinolaryngol 46:117, 1998. 5. Black FO, Myers EN, Rorke LB: Aplasia of the first and second branchial arches. Arch Otolarynol 98:124, 1973.

10.7 Duplication of the External Auditory Meatus Definition

Duplication of the external auditory meatus is a cyst and/or sinus tract located in the preauricular area in close proximity to the external auditory canal, believed to be duplication of the first branchial cleft. Diagnosis

Cysts or sinus tracts representing duplication defects of the first branchial cleft or groove are found in the region of the external auricle and external auditory canal.1,2 Earlier work has classified these defects as either type I or type II.1 Type I defects involve the membranous canal and are histologically epidermoid cysts; these sacs have no cartilage or adnexal structures and course medially, inferiorly, and posteriorly to the pinna. Drainage can occur from the cystic structure, but there is no external pit nor any association with auricular tags. These first branchial cleft sinuses/cysts are internal, and these defects usually present as a mass or abscess. Type II lesions, which are more common than type I, involve apparent duplication of the membranous and cartilaginous portions of the external auditory canal. These cysts/sinuses contain skin with adnexal structures and cartilage and often connect with the auditory canal and extend into the neck. The drainage site is occasionally below the angle of the mandible. Both type I and type II cysts often originate in the external auditory canal. Recurrence of the cyst with secondary infection is common unless the entire sac is removed. Altmann3 refers to these anomalies as colloaural fistulas. These tracts apparently open into the external auditory meatus but usually not into the middle ear. Altmann3 has reviewed some of the unusual colloaural fistulas, including one associated with microtia in which a second tract was attached to the original fistula tract, which extended into the middle ear. In another frequently mentioned case of Virchow’s, the tract actually began at a preauricular appendage and proceeded into the posterior tonsillar pillar just behind the upper tonsil. Most duplication anomalies of the first branchial cleft are isolated features and are not part of a syndrome. Blevins et al.4 reported a patient with Treacher Collins syndrome in their recent

series of four patients. Most of the case reports of this uncommon defect do not document other abnormalities, but two of the patients reviewed by Altmann3 did have microtia. Etiology and Distribution

The frequency of these duplication defects is unknown. Aronsohn et al.2 were able to collect 11 cases seen over a 40-year period at the University of Michigan. Most were children presenting with a mass in the preauricular region. The pathogenesis of this unusual defect is unknown. The hypothesis that these cystic structures represent a duplication anomaly of the first branchial cleft makes sense embryologically, with the type II defects actually having both ectodermal and mesenchymal (cartilaginous) remnants in the structure. Prognosis, Prevention, and Treatment

Surgical removal of the entire sac is important; without this, recurrence is common. This particular point has been emphasized by Aronsohn et al.2 in their review of the University of Michigan experience. Repeated incisions and drainage will occur unless the diagnosis of these defects is made. As is the case in other external ear defects, careful determination of the location of the facial nerve is crucial. These lesions could be mistaken for a branchial cleft related to the second branchial groove. However, the latter lesions are more commonly found in the carotid triangle, and the external opening usually occurs anterior to the sternocleidomastoid muscle. Histologically, the lesions in the second branchial arch cervical cysts do not keratinize, whereas these duplication anomalies of the first branchial cleft do keratinize. Wittekindt et al.5 detailed their surgical experience and expressed concern about the need for adequate incision and drainage procedures because of the risk of recurrent infection. References (Duplication of the External Auditory Meatus) 1. Work WP: Developments of first branchial cleft defects. Laryngoscope 82:1581, 1972. 2. Aronsohn RS, Batsakis JG, Rice DH, et al.: Anomalies of the first branchial cleft. Arch Otolaryngol 102:737, 1976. 3. Altmann F: Malformations of the auricle and the external auditory meatus. Arch Otolaryngol 54:115, 1951. 4. Blevins NH, Byahatti SV, Karmody CS: External auditory canal duplication anomalies associated with congenital aural atresia. J Laryngol Otol 117:32, 2003. 5. Wittekindt C, Schondorf J, Stennert E, et al.: Duplication of the external auditory canal: a report of three cases. Int J Pediatr Otorhinolaryngol 58:179, 2001.

10.8 Synotia/Otocephaly Definition

Synotia/otocephaly is a malformation involving the mandible and external ears, consisting of marked underdevelopment or almost total absence of the mandible and the presence of the external auricles anteriorly and inferiorly, approaching fusion near the midline. This spectrum of defects includes synotia, agnathia, otocephaly, and agnathia-holoprosencephaly. Diagnosis

This complex early defect in craniofacial development is easily diagnosed by inspection on physical examination (Fig. 10-6). The

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Fig. 10-6. Synotia. Sketches of infants with otocephaly showing variable configuration of the ears and other facial structures. (From Gorlin et al.1)

mandible is either totally missing or very small, with the external ears present near the midline in the usual place of the mandible. A very small or absent oral opening is a consistent feature, and there is often persistence of the buccopharyngeal membrane. Because of the respiratory difficulties and the associated central nervous system defects, all children with this malformation have died in the perinatal period. Gorlin et al.1 recently reviewed the literature on this disorder. The facial defect may occur alone or in association with holoprosencephaly. This particular combination is probably a unique developmental defect. Most individuals who have the agnathia-holoprosencephaly defect have cyclopia as opposed to the other holoprosencephalic facies. Since there are only two known recurrences of otocephaly,2,3 and the sibs both had agnathia and holoprosencephaly as part of the disorder, it is difficult to know whether isolated synotia/otocephaly is part of the agnathiaholoprosencephaly continuum. Over 100 cases have been reported in the medical literature. A number of the individuals have other associated malformations, but, as was mentioned above, the combination of agnathia and holoprosencephaly is probably the most important associated defect. Pauli et al.,4 Stoler and Holmes,5 Ozden et al.,6 and others have described cases of agnathia with situs in versus, vertebral defects, and renal malformations. The latter combination may represent a distinct pattern of malformation of unknown etiology. One important observation of agnathia and one of the only occurrences in sibs was made by Pauli et al.2 This family included two sibs, one who had cebocephaly and agnathia and the other who had a milder craniofacial defect with severe micrognathia and arhinencephaly on autopsy. This particular combination of sibs has been widely cited as one of the few examples of familial agnathia/otocephaly among humans. It has recently been documented that this family had an unbalanced chromosome finding involving 6p and 18p.7 One of the stillborn infants in the original series was rekaryotyped and was found to have a derivative chromosome 18 and to be partially trisomic for the distal part of 6p and monosomic for the distal half of 18p. A number of other congenital defects have been reported in cases of agnathia, but no syndrome pattern has emerged other than those mentioned above. Etiology and Distribution

The precise frequency of otocephaly is unknown. There were two cases among 200,000 births in the Spanish Collaborative Project, giving a birth prevalence of approximately one in 100,0005 (personal communication: Dr. Maria Luisa Martinez-Frias). Gorlin et al.1 cited a prevalence of one in 60,000. Various authors have postulated that the basic defect in the pathogenesis of otocephaly is an alteration in neural crest migration. Juriloff et al.8 have described an autosomal recessive version among

mice, who also have holoprosencephaly. Clarke et al.9 have documented the frequency of agnathia, referred to as aglossia, in C57 and C3H mice, to be approximately one in 200. This defect in C57 mice is sporadic. Holoprosencephaly has not been sought in this mutant, although choanal atresia and aglossia are present. Mice heterozygous for Otx2 have otocephaly or agnathia-holoprosencephaly,10 indicating that this is a candidate gene in the human form. Otocephaly has been produced in experimental models in laboratory rodents using streptonigrin, trypan blue, hyperthermia, and X irradiation.11 The defect also occurs spontaneously in sheep, rabbits, and guinea pigs as well as in mice. Prognosis, Prevention, and Treatment

Otocephaly invariably results in death in newborns. As was mentioned above, this is probably due to marked respiratory deficiency resulting from the persistence of the buccopharyngeal membrane and frequent choanal atresia. The association of holoprosencephaly in many of the reported cases also probably adds a factor of lethality to this complicated developmental defect. Prenatal diagnosis by ultrasound has occurred on several occasions.12 Given the severity of morphologic findings in this disorder and its associated malformations, most cases could likely be detected by 16 to 20 weeks of gestation using high-resolution ultrasound. References (Synotia/Otocephaly) 1. Gorlin RJ, Cohen MM Jr: Syndromes of the Head and Neck, ed 3. Oxford University Press, New York, 1990. 2. Pauli RM, Pettersen JC, Arya S, et al.: Familial agnathia-holoprosencephaly. Am J Med Genet 14:677, 1983. 3. Porteous ME, Wright C, Smith D, et al.: Agnathia-holoprosencephaly: a new recessive syndrome? Clin Dysmorphol 2:161, 1993. 4. Pauli RM, Graham JM, Barr M: Agnathia, situs inversus and associated malformations. Teratology 23:85, 1981. 5. Stoler JM, Holmes LB: A case of agnathia, situs inversus, and a normal central nervous system. Teratology 46:213, 1992. 6. Ozden S, Bilgic R, Delikara N, et al.: The sixth clinical report of a rare association: agnathia-holoprosencephaly-situs inversus. Prenat Diagn 22:840, 2002. 7. Krassikoff N, Sekhon GS: Letter to the editor: familial agnathiaholoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255, 1989. 8. Juriloff DM, Sulik KK, Roderick TH, et al.: Morphogenesis of spontaneously occurring otocephaly in a mouse mutant. Teratology 21:47A, 1980. 9. Clarke L, Hepworth WB, Carey JC, et al.: Chondrodystrophic mice with coincidental agnathia. Teratology 38:565, 1988. 10. Hide T, Hatakeyama J, Kimura-Yoshida C, et al.: Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice. Development 129:4347, 2002.

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Craniofacial Structures

11. Santana SM, Alvarez SM, Alabern C, et al.: Agnathia and associated malformations. Dysmorphol Clin Genet 1:58, 1987. 12. Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathiaholoprosencephaly: three-dimensional imaging by helical computed tomography. Prenat Diagn 21:68, 2001.

10.9 Low-set Ears Definition

Low-set ears are auricles situated low on the lateral face. Diagnosis

The term low-set ears refers to the observation that the auricle or perhaps the meatus is situated low on the individual’s face (Figs. 10-7 and 10-8). This disorder has received much attention in the pediatrics and genetics literature over the last few decades. In fact, the observation of low-set ears is one of the more common observations that the clinician makes when looking at a child who may have a multiple anomalies syndrome. However, the designation of low-set ears is not as useful clinically as is commonly thought. In fact, ‘‘low-set’’ ears are usually due to one of the following four reasons: the ears are small, the ears are posteriorly rotated along their longitudinal axes, the ears are overfolded as in a lop configuration, or the appearance of low-set ears is an illusion due to head tilting or the shape of the cranium. Rarely, an auricle is truly low-set, without posterior rotation. It makes more sense clinically to refer to the more specific observation, that is, small ear, lop ear, or posteriorly rotated ears. However, it is prudent at least to review the different criteria that investigators have used to define this disorder. Farkas1 has indicated that perhaps the best way to look at low-set ears is really to look at the bony meatus and its relationship to the face. He makes a clear and important distinction between ears that are low-set and ears that are posteriorly inclined or posteriorly rotated. Because the ear and its cartilage are a soft tissue structure with many variables, Farkas prefers looking at the relationship of the external meatus to the midface. His criteria for determining low-set ears are as follows: a special profile line is Fig. 10-7. Schematic showing ear placement relative to a horizontal line through the outer canthi of the eyes. Ears are considered low set when the root of the helix is below this line (see also Fig. 10-9). (Courtesy of Dr. Paul R. Dyken, University of South Alabama College of Medicine, Mobile.)

determined (a line connecting the glabella with the most prominent portion of the upper lip), and a perpendicular line is then made from the highest point of the external meatus to this profile line. If this line falls below the upper edge of the alae nasi, the ear canal is low-set. Two other criteria have been suggested in the pediatrics and dysmorphology literature to define low-set ears. The most widely mentioned and cited are those of Feingold and Bossert.2 The technique involves using a piece of radiograph material that is pliable. A series of parallel lines are drawn on the paper, and a line drawn between the inner canthi is extended back to the top of the auricle. The percentage of auricle above the line, or millimeters reached above this line, is recorded, and percentiles are plotted. This measurement obviously depends on the posterior rotation of the auricle as well as the normality of the superior aspect of the pinna. A lop/cup or type I microtia ear would probably fall in the lower percentiles of these curves. Aase3 has suggested that a clinically easy way to measure lowset ears is to take a line that is perpendicular to the lateral aspect of the orbit. This line should cross near the superior attachment of the ear. If it does not, the ear is considered low-set. The syndromes that involve low-set ears obviously overlap with syndromes that produce microtic ears (Table 10-4), lop/cup ear malformation (Table 10-8), and posteriorly rotated ears. As was mentioned in Section 10.1, there is a purported association mentioned in the pediatric and otolaryngology literature of ear and kidney defects. The implication of this association is that, when the clinician sees an ear abnormality, he or she should consider a renal malformation. This particular association is mentioned in most standard pediatrics textbooks and probably has resulted in many children over the last few decades undergoing invasive urologic studies. The question really comes down to the following: is there some special developmental relationship between the external ear and the renal system that is unique and beyond the pleiotropic relationship that exists when ear and kidney malformations are both present as components of heritable syndromes? If there is such a relationship, then one could use an external ear defect as a marker to suggest a kidney malformation. The first mention that the ears and kidneys may be related comes from the concurrence of ear abnormalities and renal malformations in the so-called Potter syndrome. It is now known, of course, that the Potter ‘‘syndrome’’ represents a sequence in which the external, nonrenal defects are secondary to oligohydramnios. This being the case, the ear findings in the Potter syndrome really are secondary to the oligohydramnios, which is secondary to the intrauterine renal oliguria rather than there being some special developmental relationship between the ears and the kidneys. Many of the cases cited suggesting a special developmental relationship between the ears and kidneys were children who had syndromes, often the oculo-auriculo-vertebral spectrum, in which renal malformations sometimes occur.4,5 These papers also reported individuals who would now be considered to have the branchio-oto-renal syndrome. The range of renal defects is usually quite wide, and often they are of minimal medical significance, such as a bifid ureter. Melnick and Myrianthopoulos6 have emphasized the potential relationship between the kidney and the ears. They cite results from the Perinatal Collaborative Project as evidence for such an association; however, it is difficult to conclude from these data that there is any special relationship between the kidneys and the external ear. The odds ratio that is cited involves bifid ureters, and most of the children in the control group would not have undergone a urologic investigation.

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Fig. 10-8. Low-set ears. Measurement of portion of ear (A) and percentage of ear (B) above the level of the eyes. (From Feingold and Bossert.2)

Thus, there is no conclusive epidemiologic evidence of an increased risk of renal malformations associated with ear malformations other than the relationship that exists in known, identifiable syndromes. Recently, Wang et al.7 showed that a renal investigation is only necessary in the patient who has a syndrome in which kidney defects occur. The other problem in this discussion has to do with the issue of what type of ear malformation would suggest a kidney defect in the first place. This could include almost any auricular defect. In the early papers in the otolaryngology literature, there was no distinction between grades of severity that would suggest a kidney problem. Considering simply nonsyndromic microtia, there still appears to be no conclusive evidence warranting routine imaging studies in children with microtia or low-set ears. Etiology and Distribution

Prevalence studies of ear malformations have not recorded low-set ears in particular. Since type I microtia and lop/cup ears fall into this category, one could at least estimate their frequency from those

birth prevalence figures. However, as was mentioned above, the determination of low-set ears is somewhat artificial, so this prevalence figure is not helpful. Posteriorly rotated ears can be defined by percentiles based on data of Farkas.1 References (Low-set Ears) 1. Farkas LG: Anthropometry of the Head and Face in Medicine. Raven Press, New York, 1994. 2. Feingold M, Bossert WH: Normal values for selected physical parameters: an aid to syndrome delineation. Birth Defects Orig Artic Ser X(13):1, 1974. 3. Aase JM: Microtia-clinical observations. Birth Defects Orig Artic Ser XVI(4):289, 1980. 4. Hilson D: Malformations of the ear as a sign of malformation of the genitourinary tract. Br Med J 2:785, 1957. 5. Taylor WC: Deformity of ear and kidney. Can Med Assoc J 93:107, 1965. 6. Melnick M, Myrianthopoulos NC: External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser XV(9): 1, 1979. 7. Wang RY, Earl DL, Ruder RO, et al.: Syndromic ear anomalies and renal ultrasounds. Pediatrics 108E:32, 2001.

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Craniofacial Structures

10.10 Posteriorly Rotated Ears Definition

Posteriorly rotated ears are a variation of the external ear in which the vertical axis of the ear is rotated posteriorly (Fig. 10-9). An extreme degree of this posterior rotation is sometimes called melotia. Description

Posteriorly rotated ears are an important cause of the commonly cited finding of low-set ears. In fact, the majority of infants who are labeled as having low-set ears either have posteriorly rotated ears or the observation of low-set ears represents an illusion. The diagnosis is made on physical examination. Farkas1 has developed criteria and normal angles for rotation of the external ear. Posteriorly rotated ears are defined as an increased posterior rotation of the auricle on its longitudinal-vertical axis. This angulation is measured by establishing the Frankfurt horizontal (FH), dropping a perpendicular line onto the FH at the ear, and measuring the angulation away from the vertical. Range of normal in schoolaged children is usually between 108 and 208. Melotia is a term used in the older literature to refer to a strikingly posteriorly rotated ear where the actual longitudinal axis of the ear is almost parallel to the body of the mandible and the ear may be situated close to the angle of the mandible on the cheek. Posteriorly rotated ears occur as a nonspecific variation in a number of chromosome conditions, but in particular they are seen in Turner syndrome and Noonan syndrome.2 The etiology and pathogenesis of posteriorly rotated ears as a variation and malformation are unknown. Certainly, the disorder could be perceived as a developmental arrest; that is, the external ear, which normally is situated in some degree parallel to the developing Fig. 10-9. Schematic showing posterior rotation of the ear with the angle (arrow) between the facial plane (C,D) and the long axis of the ear (B) exceeding 208. The ear shown here is also low set, with the attachment of the root of the helix below a horizontal line extending from the outer canthus of the eye (A). (Adapted from Aase.3)

mandible, does not rotate properly to the side of the face. The actual frequency of posteriorly rotated ears is unknown, but, if one uses the percentiles in Farkas’1 curve, 2% of people would fall below the curve by definition alone. Mild degrees of posterior angulation are very nonspecific and common and are not particularly useful in the recognition of syndromes. Posteriorly rotated ears are a variation of ear development that is perceived as stigmatizing or of visual significance to the individual. In the person who has an extreme degree, as in Turner syndrome, reconstructive surgery is an option. References (Posteriorly Rotated Ears) 1. Farkas LG: Anthropometry of the Head and Face. Raven Press, New York, 1994. 2. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 3. Aase JM: Diagnostic Dysmorphology. Plenum, New York, 1990.

10.11 Lop/Cup Ear Anomaly Definition

Lop/cup ear anomaly is an anomaly of the auricle involving a downward folding and deficiency of the superior aspect of the helix, often associated with an exaggerated or overdevelopment of the concha. Lop/cup ear represents underdevelopment or hypoplasia of the superior one-third of the auricle. It is sometimes referred to as constricted ear and overlaps with type I microtia. Diagnosis

The lop/cup ear defect represents one of the common and more important alterations of the external ear. The line of separation between the lop/cup ear and microtia type I is hard to draw, and certainly some ears described as showing type I microtia fall into this group. As was pointed out by Rogers,1 a confusing array of terms has been applied to this class of external auricular defect. Many of the terms are derogatory and pejorative but are used in the literature; examples include bat ears, simple ears, satyr ears, and elf ears. This defect probably represents a continuum of alterations of plical folding of the auricle. It could on some occasions be the result of deforming forces and at other times be a true alteration of the morphogenesis (malformation) of intrinsic muscles and/or cartilage folding. There is no standard definition in the plastic surgery and otolaryngology literature for the lop/cup ear defect, and different authors use the term in different ways. Since Rogers so clearly demonstrated a continuum of ear defects, the present author has chosen to refer to this defect as the lop/cup ear anomaly.1 Tanzer2 has labeled this defect constricted ear and has divided it into groups I through III according to the surgical challenges (Fig. 10-10). Group I defects represent the more traditional lop ear and involve an overfolding of the helix along its superior rim, producing some decrease in height and a flattening of the superior helix/ scapha region. Sometimes the folded helix is so closely adherent to the scapha tissue that it appears to be attached. Group II anomalies are more noticeable and involve both the helix and the adjoining scapha. The lack of cartilage folding involves the crura of the anthelix, and the anthelix itself may be flattened. There is a more striking hood, and the length of the ear is reduced. A prominence or protrusion of the ear is usually found, and there is an exaggerated overdevelopment of the cup-shaped, concave concha. The defect is usually what Rogers has

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Fig. 10-10. Lop/cup ear. This anomaly is characterized by underdevelopment of the superior one-third of the pinna and downward folding of the superior helix. It is closely related to microtia (see Fig. 10-2). (From Aase JM: Diagnostic Dysmorphology. Plenum, New York, 1990.)

called the cup ear and has components of both lop ear and protruding ear.1 Group III of the lop/cup ear defect is a severe version of group II, and the auricle is markedly rolled over the inferior portion of the ear, so the ear is always low-set on the cranium. The term cockleshell ear has been used to refer to this group III defect.

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As in microtia, the lop/cup ear raises the question of hearing loss, but the association is not as frequent. The severe end of the spectrum probably represents a malformation and thus is more commonly associated with middle ear defects, as is microtia, while milder degrees of the defect may more often be a deformation and are rarely associated with middle ear changes. Most affected individuals seeking plastic surgery have the lop/cup ear as an isolated defect and not as part of a well-defined syndrome. No studies actually give a frequency figure of associated malformations. However, in the Spanish Collaborative Project, about 25% of the cases listed as ‘‘dysplastic ear’’ had this as part of a syndrome (personal communication: Dr. Maria Luisa Martinez-Frias). This probably represents at least some estimation of the frequency of this problem occurring as part of a syndrome. Most of the syndromes that include microtia/anotia can also involve this milder auricular abnormality. Table 10-8 lists the syndromes that have lop/cup ear anomaly as a component manifestation and rarely have microtia II through IV. It is important to underscore that the line between milder degrees of microtia and the lop/cup ear defect is not easily drawn. Etiology and Distribution

Because of definitional issues, it is difficult to estimate a precise prevalence-at-birth figure for the lop/cup ear defect. In the Melnick and Myrianthopoulos3 review of the Perinatal Collaborative Project, 61 infants, for a rate of 11.45 in 10,000 or just under one in 1000 infants, were labeled as having ‘‘other malformed pinna.’’ The frequency of the ‘‘dysplastic ear’’ in the Spanish Collaborative Project is 5.47 in 10,000 or just under one in 2000. Thus, a figure of

Table 10-8. Syndromes that include lop/cup ear anomaly (occasionally having microtia types II–IV) Causation Gene/Locus

Syndrome

Prominent Features

Branchio-oto-renal

Branchial sinuses, ear and renal anomalies

AD (113650) EYA1, 8q

Familial blepharophimosis

Blepharophimosis, ptosis, epicanthus inversus, subfertility in females

AD (110100) FOXL2, 3q23

Fraser

Cryptophthalmia, syndactyly, Mu¨llerian defects, renal agenesis

AR (219000) FRAS1, 7q

Kabuki

Distinctive face, cleft palate, short stature

AD (147920)

LADD

Lacrimal (nasolacrimal duct obstruction, auricular (hearing loss and cup-shaped pinnae), dental anomalies (small lateral incisors), digital anomalies (variable)

AD (149730)

Lee

Distinctive face, premature aging, short stature

Uncertain

LMC

Micrognathia, conductive hearing loss

AD

Mengel

Unusual ear defects, conductive hearing loss, mental retardation, hypogonadism

AR (221300)

Oto-facio-cervical

Long face, narrow nose, ear pits, web neck, sloping shoulders, cervical fistulas (?same as branchio-oto-renal syndrome)

AD (166780)

Townes-Brocks

Imperforate anus, triphalangeal thumb and other digital anomalies, absence or fusion of foot bones, hearing loss

AD (107480) SALL1, 16q

Tricho-rhinophalangeal

Sparse hair, prominent nose, epiphyseal dysplasia

AD (190350) TRPS1, 8q24

Trisomy 21

Flat facies, upslanting palpebral fissures, small mouth, short stature, brachydactyly, mental retardation

Chromosomal

Del 4q

Cleft palate, nail defect—second digit, mental retardation

Chromosomal

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about one in 1000 to 2000 gives some idea of the birth prevalence. These figures are in contrast to the Japanese experience. Matsuo and colleagues4 indicated that the frequency of the lop ear was 38.1% at birth and 6.1% at age 1 year. These investigators as well as others in Japan have developed strategies of nonsurgical correction of congenital auricular defects. The fact that the frequency of lop ear actually decreased from the newborn period to the age of 1 year suggests that often the mildest form of this defect is in fact due more to intrauterine constraint that resolves during the 1st year of life. The discrepancy in these figures may also result from the recording of very mild degrees of overfolding of the helix in the Japanese series or from true ethnic differences. These points, however, indicate the difficulties in definition of phenotypic variations of the body, especially of the ear. A precise etiology or pathogenesis of the lop/cup ear defect is not determined in most individuals who have the defect. As was mentioned above, the milder degrees of the lop/cup ear defect may truly be a deformation related to intrauterine compression. The fact that many of the cases in Japan of the so-called lop/cup ear defect resolved supports this notion, as does the recent success in tape attachment and other nonsurgical approaches to these defects.4,5 Nonsyndromic lop/cup ear defects have been seen as an autosomal dominant trait in a number of families; however, the proportion of cases due to an autosomal dominant gene is unknown. Smith and Takashima6 and Zerin et al7 have suggested that the lop/cup ear defects as well as the protruding ear may be due to alterations of plical folding of the cartilaginous ear plate that are, in fact, secondary to changes in the extrinsic and intrinsic ear muscles. These investigators suggest that the ear muscles and perhaps the nerve that innervates the muscles are crucial in determining the form and position of the cartilage of the ear. Their dissections of fetuses with anencephaly, who often have the lop/cup defects, along with experimental evidence in rodents and rabbits suggest that the intrinsic auricular muscles are important for the complicated relief of the external ear. Experimental evidence also shows the importance of neuromuscular factors in external ear development. Chiu et al.,8 working with the auricle of the rat, produced changes in auricular form following neurectomy of the auricular nerve. Based on this work, Smith and Takashima6 suggested that the protruding ear results from an alteration of the posterior auricular muscle, while the lop ear results from an alteration of the superior auricular muscle. Prognosis, Prevention, and Treatment

The major impact of the lop/cup ear defect is visual, a potential stigma for the individual who exhibits the defect. The natural history of the deformations producing a lop/cup ear appearance is for spontaneous resolution, as was emphasized by Graham9 and in the Japanese series.4 The challenge is that it is not always easy to determine which of the defects will resolve and which will persist. Tanzer2 has summarized the surgical approach to the lop/cup ear defect. In this abnormality, not only does the protruding ear need repair, but also restoration of the normally shaped helix scapha and anthelix is necessary. More severe cases may require multistage reconstruction. More recently, Elsahy10 and Park11 have published their modifications of the surgical approach to lop/cup ears that resulted in good outcomes. In the 1980s, the Japanese introduced the concept of nonsurgical correction of congenital ear defects, including the lop/cup ear defect.4 The abnormal folding is corrected by splinting with dental compound using Aluwax. Surgical tapes are also used when appropriate. Utilizing this approach, investigators have emphasized that early correction is critical for outcome. Results are less successful after age 6 weeks, when ear elasticity and form have become better

established. In the Japanese experience, with the high frequency of the lop ear defect, many babies whose ears are splinted undergo this therapy unnecessarily, since over 80% of cases resolve on their own. More recently, Ullmann et al.12 reported their results using early splinting with PuttySoft; 87% were graded as ‘‘excellent.’’ It may be that these milder degrees of lop ear deformity are third-trimester deformational events related to high levels of circulating estrogen. Since no controlled studies are available, and since there are numerous definitional problems regarding the spectrum of the lop/cup ear defect, it is difficult to conclude at this point that nonsurgical correction is the best approach for the more moderate or the severe end of the continuum. References (Lop/Cup Ears) 1. Rogers B: Microtic, lop, cup and protruding ears. Plast Reconstr Surg 41:208, 1968. 2. Tanzer RC: The constricted (cup and lop) ear. Plast Reconstr Surg 55:406, 1975. 3. Melnick M, Myrianthopoulos NC: External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser XV(9): 1, 1979. 4. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical correction of congenital auricular deformities. Clin Plast Surg 17:383, 1990. 5. Brown FE, Colen LB, Addante RR, et al.: Correction of congenital auricular deformities by splinting in the neonatal period. Pediatrics 78:406, 1986. 6. Smith DW, Takashima H: Ear muscles and ear form. Birth Defects Orig Artic Ser XVI(4):299,1980. 7. Zerin M, Van Allen MI, Smith DW: Intrinsic auricular muscles and auricular form. Pediatrics 69:91, 1982. 8. Chiu DT, Crikelair GF, Moss ML: Epigenetic regulation of the shape and position of the auricle in the rat. Plast Reconstr Surg 63:411, 1979. 9. Graham JM: Smith’s Recognizable Patterns of Human Deformation, ed 2. WB Saunders Company, Philadelphia, 1988. 10. Elsahy NI: Technique for correction of lop/cup ear. Plast Reconstr Surg 85:615, 1990. 11. Park C: Modification of two-flap method and framework construction for reconstruction of atypical congenital auricular deformities. Plast Reconstr Surg 99:1846, 1997. 12. Ullmann Y, Blazer S, Ramon Y, et al.: Early nonsurgical correction of congenital auricular deformities. Plast Reconstr Surg 109:907, 2002.

10.12 Protruding Ear Definition

Protruding ear is a laterally prominent auricle with the usually normally sized ear standing out from the head at an angle of greater than 408. Protruding ear is often considered a variation of the lop/cup ear defect. Diagnosis

This defect is easily recognized by measuring the angle of the posterior aspect of the pinna and the mastoid occipital plane. Farkas has developed standards for this angle of protrusion, and in school-aged children, both male and female, the angle is less than 408. In the protruding ear, the distance from the outer rim of the helix to the mastoid is greater than 2 cm (Fig. 10-11). The prominent ear involves some alteration of plica whereby the angle between the scapha cartilage and the concha cartilage is changed. Usually this relationship is about 908, but in the prominent ear the angle between these cartilages increases to 1308. The anthelix is often flattened, and the protruding ear is usually normal in size but occasionally is larger. It usually appears larger than it is

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Fig. 10-11. Protruding ear. Normal-sized ear, which stands out from the head at an angle of 408 or more. (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.)

because of its lateral prominence. As was mentioned in Section 10.11, the lop/cup ear defect often involves a lateral prominence, and Rogers2 has suggested that the protruding ear is simply the severe end of this continuum. Occasionally, the helical fold is

unraveled in the so-called shell or unraveled ear. As has always been the case in the literature, the definitions of the variations of the external ear are not established, and terminology is often misleading, confusing, and pejorative.

Table 10-9. Syndromes/disorders in which protruding auricle occurs as a feature Causation Gene/Locus

Syndrome

Prominent Features

Aarskog

Hypertelorism, shawl scrotum, short stature

XLR (305400) FGD1, Xp11

Myotonic dystrophy

Long face, myotonia

AD (160900) DMPK, 19q32

Congenital hypotonia phenotype

Hypotonia, ± joint contractures, long face, narrow palate, small jaw

Heterogenous

Anencephaly

As noted

Multifactorial (206500)

Prenatal alcohol

Prenatal and postnatal growth deficiency, distinctive face, developmental delay

Excessive alcohol in utero

Cohen

Distinctive face/teeth, long thin fingers

AR (216550) COH1, 8q22

Tricho-rhino-phalangeal

Sparse hair, prominent nose, brachydactyly, short stature

AD (190350) TRPS1, 8q

Noonan

Distinctive face, webbed neck, pectus excavatum, pulmonic stenosis

AD (163950) PTPN11, 12q

Coffin-Lowry

Coarse face, tapered fingers, pectus carinatum

XL (303600) RSK2, Xp22

Mandibular-facial dysostosis, Toriello type

Mandibular hypoplasia, distinctive face

X-linked

Kabuki

Distinctive face, long palpebral fissures, mental retardation, short stature

Unknown (147920)

Trisomy 21

Distinctive face, brachydactyly, mental retardation

Chromosomal

Trisomy 18

Prenatal growth deficiency, distinctive face/hands, short sternum, congenital heart defects

Chromosomal

Del 4p

Distinctive face, mental retardation, growth deficiency

Chromosomal

45, X

Short stature, distinctive face, webbed neck

Chromosomal

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Most individuals with a protruding ear have it as an isolated anomaly and not as part of a syndrome. Smith and Takashima3 have suggested the laterally prominent ear, like the lop/cup ear, is a sign of alteration of neuromuscular function. Table 10-9 lists a number of syndromes that include a laterally prominent ear. Etiology and Distribution

The birth prevalence of the protruding ear is not available. Most epidemiologic studies examining the frequency of external ear defects have not included this finding, due to the fact that the laterally prominent ear usually becomes more obvious with age. In a Japanese study, protruding ear was recognized to be an acquired defect, and the frequency in the newborn period was less than 1% while it was 5.5% by age 1 year.4 Farkas has also documented the age effect of this ear variation.1 Prognosis, Prevention, and Treatment

As in the lop/cup ear defect, the social stigma of the protruding ear is its major impact. Otoplasty is the standard surgical technique, and a number of strategies to approach the problem have been developed during this century. The basic approach in surgery for protruding ears is to create a prominent anthelix. Various techniques involve the creation of the desired anthelical fold.5 Recently, Brenda et al. presented their approach.6 As in the lop/cup defect, a nonsurgical approach to the correction of this anomaly has also emerged. The basic principle involves the application of surgical tape to the posterior helical rim, affixing it to the temporal region; a headband is often used for reinforcement. A headband alone has also been utilized to correct the prominent ear. Brown et al.7 have placed dental compound in the sulcus between the ear and the scalp to bring about normal anthelical folding. As with the standard technique, the ear is held in position with surgical tape. These nonsurgical approaches are used primarily in the newborn period.

Apparently, this approach has also been effective when utilized as late as age 6 months; however, the later that the strategy is initiated, the longer the period for which taping will be necessary. References (Protruding Ear) 1. Farkas LG: Anthropometry of the Head and Face. Raven Press, New York, 1994. 2. Rogers B: Microtic, lop, cup and protruding ears. Plast Reconstr Surg 41:208, 1968. 3. Smith DW, Takashima H: Protruding auricle: a neuromuscular sign. Lancet 1:747, 1978. 4. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical correction of congenital auricular deformities. Clin Plast Surg 17:383, 1990. 5. Elliott RA: Otoplasty: a combined approach. Clin Plast Surg 17:373, 1990. 6. Brenda E, Marques A, Pereira MD, et al.: Otoplasty and its origins for the correction of prominent ears. J Craniomaxillofac Surg 23:99, 1995. 7. Brown FE, Colen LB, Addante RR, et al.: Correction of congenital auricular deformities by splinting in the neonatal period. Pediatrics 78:406, 1986.

10.13 Stahl Ear Definition

Stahl ear is an abnormal and distinctive extra fold or crus of the anthelix that extends from the superior portion of the anthelix to the upper posterior aspect of the corner of the helix. This extra fold produces a ‘‘crumpled’’ ear appearance. Diagnosis

The diagnosis of the Stahl ear is made simply through an inspection on physical examination. This ear variation is obvious to anyone who has seen the finding (Fig. 10-12). In the literature on the congenital contractural arachnodactyly syndrome, the disorder is

Fig. 10-12. Left: Stahl ear showing a fold extending from the superior portion of the anthelix to the upper posterior corner of the helix. Stahl ear is also called crumpled ear. Right: configuration of the ear after splinting with an Aluwax mold for 1 month. (From Brown et al.4)

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referred to as a ‘‘crumpled ear.’’1 It has also been labeled as the crus antihelicis tertium.2 Apart from its presence in the congenital contractural arachnodactyly syndrome, it is usually an isolated finding and not part of a syndrome. Etiology and Distribution

The Stahl ear was the second most common auricular defect in the Japanese series,3 occurring in 8% of all Japanese newborns, but the finding decreases over time, with a frequency by age 12 months of only 1.3%. It probably represents abnormal plica folding and is another example, like the lop/cup ear defect, of an alteration in intrinsic auricular muscles with secondary effects on ear form. The frequency of Stahl ear is unknown except in the Japanese series. Prognosis, Prevention, and Treatment

The Stahl ear, as with the lop/cup ear, has been of interest to the Japanese investigating the nonsurgical correction of congenital auricular defects. Matsuo et al.3 claim success in most individuals with the Stahl ear when Aluwax and surgical tape are applied in the first few days of life. The abnormal fold is pressed out, and the normal concavite scapha helix is molded. If nonsurgical correction is initiated in the early neonatal period, only 1 week is necessary to change the auricle to its normal shape; the wax is retained for a few weeks to guarantee that the corrected shape remains permanently. Brown and colleagues4 also claim success in the treatment of a Stahl ear using this dental compound and tape. Since in many of the Japanese infants with Stahl ear the defect resolved by itself in the 1st year of life, the exact efficacy of this therapy is unclear. Certainly the experiences of Matsuo et al.3 and Brown et al.4 suggest success, but it is possible that many of these defects would have resolved without the wax and tape. As in the lop/cup ear defect, early intervention is suggested by the authors who use this nonsurgical approach. For individuals who are recognized in later life to have Stahl ears, reconstructive surgery is available. The impact of this variation, however, is minimal. References (Stahl Ear) 1. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 2. Altmann F: Malformations of the auricle and the meatus. Arch Otolaryngol 54:115, 1951. 3. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical congenital auricular deformities. Clin Plast Surg 17:383, 1990. 4. Brown FE, Colen LB, Addante RR, et al.: Correct auricular deformities by splinting in the neonatal. Pediatrics 78:406, 1986.

10.14 Mozart Ear Definition

Mozart ear is a defect of the external auricle consisting of a prominent superior anthelix caused by a fusion of the crura of the anthelix and the crura of the helix. The anomaly is said to have affected Wolfgang Amadeus Mozart and his son. It has also been called the Wildermuth ear. Diagnosis

This variation of the external auricle probably has no medical significance unless it occurs as part of a syndrome. Davies1 and Paton et al.2 have discussed the description and history of this ear defect (Fig. 10-13). It is still unclear whether Mozart had this ear anomaly,

Fig. 10-13. Mozart ear.

but it appears likely that his son, Franz, did. The salient features of the defect include a broad-appearing auricle with a prominent anthelix such that the two crura of the anthelix are fused and are united with the crus of the helix. The concha then is enlarged, and the antitragus is missing or underdeveloped. The ear lobe is underdeveloped or very small. Sometimes the helical fold appears unraveled, altering the relief of the external auricle. Although there is no direct evidence that Mozart himself had the anomaly, the term has taken on such a meaning in the medical literature that it is probably appropriate to retain the eponym, especially since Mozart’s son probably did have the defect. These observations suggest that this ear abnormality is an autosomal dominant trait. Paton and colleagues2 found 13 examples of the Mozart ear in patients about to have reconstructive plastic surgery of the ear. Their work and the work of Davies1 do not cite the occurrence of this finding as part of a generalized syndrome. However, prominence of the anthelix is a consistent finding in the deletion 18q syndrome.3,4 A review of some photographs of children with 18qsuggests that their finding is also part of the continuum of the Mozart ear. The so-called faun ear described in the trisomy 18 syndrome also has components of the Mozart ear. This finding has been noted in the CHARGE syndrome, as well. Etiology and Distribution

Paton and colleagues2 carried out two surveys, one involving 1185 consecutive individuals and the other involving 1092 patients in a medical clinic. They found one case in each group, or about one in 1100 adults with this defect. Although there is no evidence regarding the pathogenesis in this finding, it may be one of the abnormalities of intrinsic auricular muscle development, as in the lop/cup ear defect. It is of note that the three specific syndromes in which the Mozart ear has been noted, trisomy 18, deletion 18q, and CHARGE syndrome, all have narrowed ear canals. There may be some developmental relationship between the Mozart ear and the development of the external ear auditory meatus. Garcia-Cruz et al.4 described a boy with multiple anomalies and the Mozart ear. Prognosis, Prevention, and Treatment

Reconstructive plastic surgery is available for individuals with the Mozart ear. Correction of this defect through a nonsurgical

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approach, that is, splinting or molding using Aluwax, may be an option in the future, although there has been no documented application as yet.

Reference (Darwinian Tubercle)

References (Mozart Ear)

10.16 Prominent Crus of the Helix

1. Davies PJ: Mozart’s left ear, nephropathy and death. Med J Aust 147:581, 1987. 2. Paton A, Pahor AI, Graham GR, et al.: Looking for Mozart ears. Br Med J 293:1622, 1986. 3. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 4. Garcia-Cruz D, Sanchez-Corona J, Ruenes R, et al.: A syndrome with mixed deafness, Mozart ear, middle and inner ear dysplasias. J Laryngol Otol 94:773, 1980.

10.15 Darwinian Tubercle Definition

Darwinian tubercle is a small protrusion on the helix of the auricle just below the margin where the superior helix curves down to the inferior helix, usually at the level of the superior crus of the anthelix (Fig. 10-14).1 Description

This medically insignificant phenotypic variation is easily recognized by the examiner who searches for it. It is documented simply for historic reasons; it is not a marker for any particular syndrome, and it is not known to be associated with middle or internal ear defects. The frequency of the Darwinian tubercle is approximately 1% in population studies. Females are said to show the protrusion more often than males. The tubercle is usually present in fetal life up to about 7 weeks and then disappears. Thus, in infancy and childhood it is a persistence of a pointlike structure that usually resolves. Some evolutionary biologists have suggested that the tubercle of Darwin is at the place where other mammalian ears are pointed. Since a Darwinian tubercle has no visual or cosmetic significance, no treatment is necessary. Prognosis is not an issue, since it is not a marker for other malformations. Fig. 10-14. Darwinian tubercle (arrow), an insignificant feature of external ear anatomy.

1. Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov.

Definition

Prominent crus of the helix is an unusual prominence or posterior flaring of the crus of the helix. Description

The crus of the helix usually extends around inferiorly and posteriorly just into the concha and above the auditory meatus. Usually, this fold ends gradually as it moves above the auditory meatus. Occasionally, there is a striking prominence of this fold, so that it extends back to the anthelix. This disorder produces an unusual-appearing ear configuration; it was described by Aase1 as a ‘‘railroad track ear’’ (Fig. 10-15). The superior aspect of the anthelix and this unusually prominent crus of the helix parallel each other, producing a more prominent cymbal concha. Unusual prominence of the helix has been described in fetal alcohol syndrome and in the Sathre-Chotzen syndrome.1,2 Jaffe3 described an 11-year-old Navajo boy with an unusual flared end of the prominent crus of the helix and an absent external meatus. This individual also had auricular skin tags and conductive hearing loss. Surgical creation of an external meatus improved hearing significantly. The frequency of variations of the crus of the helix is unknown. This finding is probably a variation of plica folding and perhaps alteration of intrinsic auricular muscles, producing this secondary change in form. This particular variation has no stigmatizing impact; its only significance is as a clue to the above-mentioned syndromes. References (Prominent Crus of the Helix) 1. Aase JM: Microtia-clinical observations. Birth Defects Orig Artic Ser XVI(4):289, 1980. 2. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 3. Jaffe BF: Pinna anomalies associated with congenital conductive hearing loss. Pediatrics 57:332, 1976.

10.17 Lobular Defects Definition

Lobular defects are alterations of the form or contour of the ear lobe, including bifid and notched ear lobe (Fig. 10-16), uplifted lobules, antitragus base tag, and thickened ear lobes. Diagnosis

The diagnosis of any of the ear lobe variations described herein is made with visualization on physical examination of the auricular lobule. A notched ear lobe was recorded in one in 300 newborns in Holmes’ unpublished data of minor anomaly prevalence in newborns (personal communication: Dr. Lewis Holmes). A true bifid ear lobe, with two separate lobes, is less common, occurring in only one in 3000 to 4000 infants. These ear lobe findings are usually unilateral and rarely syndromic. The defects usually occur by themselves and are not clues to a malformation syndrome. A tag at the base of the antitragus was described as a dominant trait by Ramirez and Cantu.1 This has also been described in the

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Fig. 10-15. Crumpled ear, with ‘‘railroad track’’ horizontal folding of the anthelix, in two children with contractual arachnodactyly. Ear in B is also retroverted. (Courtesy of Dr. Charles I. Scott, Jr., A.I. DuPont Institute, Wilmington, DE.)

Goldberg-Pashayan syndrome of abnormal ear lobes and ulnar polydactyly.2 Thickened ear lobes are of note in that they were described as an external marker associated with conductive hearing loss and discontinuity between the incus and the stapes. This latter finding has been described in two families and has been referred to as the Escher-Hirt syndrome (see Section 10.24).3

and pathogenesis of these variations of ear lobe development are also unknown. An uplifted ear lobule could be secondary to intrauterine constraint and the shoulder pushing up on the ear lobe. Uplifted ear lobules are also seen as part of the Turner syndrome and perhaps are related to the intrauterine cystic hygroma of that syndrome. Prognosis, Prevention, and Treatment

Etiology and Distribution

The frequency of ear lobe variations has not been determined. As was mentioned above, bifid and notched ear lobes were recorded in the unpublished Boston data on minor anomalies.1 The frequencies of thickened ear lobes or tags of the ear lobes are unknown. The etiology

The significance of these findings is primarily as a clue to syndromes, and rarely are they associated with a need for reconstruction, the exception being extreme alteration of the ear lobes, such as a true bifid lobe or absence of the ear lobe. Park summarized the approach to lower auricular defects.4 References (Lobular Defects)

Fig. 10-16. Cleft ear lobe.

1. Ramirez M, Cantu JM: Two distinct autosomal dominant traits in the pinna. Birth Defects Orig Artic Ser XVIII(3B):243, 1982. 2. Goldberg MJ, Pashayan HM: Hallux syndactyly-ulnar polydactyly abnormal ear lobes: a new syndrome. Birth Defects Orig Artic Ser XII(5): 255, 1976. 3. Escher F, Hirt H: Dominant hereditary conductive deafness through lack of incus stapes junction. Acta Otolaryngol 65:25, 1966. 4. Park C: Modification of two-flap method and framework construction for reconstruction of atypical congenital auricular deformities. Plast Reconstr Surg 99:1846, 1997.

10.18 Auricular Tags Definition

Auricular tags are skin-colored, fleshy appendages represented as nodules or skin protrusions located usually just in front of the tragus of the ear. Diagnosis

Auricular appendages or tags are rather common, mild malformations located usually just in front of the auricle near the tragus (Fig. 10-17).1 These defects vary in size from 1 or 2 mm to several centimeters; they can be pedunculated on a short stalk or sessile.

352

Craniofacial Structures

Fig. 10-17. Preauricular tags in otherwise normal infant (A) and in infant with hemifacial microsomia (B). Postauricular tag in 32-week fetus with tracheoesophageal and genitourinary anomalies (C, D). Skin tag is covered with hair (ST) and is distinctly separate from microtic ear (RE). (Courtesy of Dr. Will Blackburn and N. Reede Cooley, Jr.)

Diagnosis is straightforward, and the disorder is usually not mistaken for any other congenital anomaly. Auricular tags follow an arc-shaped line of predilection from the temple just above the ear to the crus of the helix, then into the concha of the external auditory meatus, and out again just anterior and below the tragus. This line, according to some authors, is a line of junction between the first and second branchial arches. Occasionally, the preauricular tags will extend down from just anterior to the tragus to the angle of the mouth, that is, the oral-tragal line. This second zone corresponds to the line between the maxillary and mandibular portions of the first branchial arch. Tags or appendages in this latter location are more frequently combined with other malformations, such as microtia, and are commonly seen in the oculo-auriculo-vertebral (OAV) spectrum. Also, auricular tags located on the cheek are often associated with a pit or scarlike lesion. Etiology and Distribution

A number of the studies on the frequency of microtia/anotia have also included this mild malformation. Prevalence figures range

from about one in 300 to 1.5%. The Perinatal Collaborative Project reported a prevalence at birth of 17 in 10,000 or about one in 5002, while Holmes’ study in Boston records a frequency of just under 1% (personal communication: Dr. Lewis Holmes). Over 90% of individuals have the tag as a unilateral finding. Although most individuals have this mild malformation as an isolated problem, it may occur as part of a generalized syndrome (Table 10-10). In the Perinatal Collaborative Study, 89 of the 91 children had it as an isolated defect. In a study of 850 school children in Turkey, a tag was detected in 0.47%.3 In the Spanish Collaborative Study, however, approximately 2% of individuals with a preauricular tag had it as part of a syndrome (personal communication: Dr. Maria Luisa Martinez-Frias). Kankkunen and Thiringer4 found a prevalence of five in 1000 live births, and among their 188 cases with auricular tags, 5% had other malformations of the face and ear. Among the neonates in whom the tag was the only defect, 13% were found to have some degree of sensorineural hearing impairment, usually mild to moderate. The authors suggest an association between isolated ear

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Table 10-10. Syndromes that include auricular pits and/or tags Syndrome

Prominent Features

Causation

Branchi-oto-renal (pits)

Brachial sinuses, ear and renal defects

AD (113650) EYA1, 8q

Oculo-auriculo-vertebral spectrum (both)

Epibulbar dermoids, vertebral defects, variable heart defects

Heterogeneous; AD (164210) AD (257700) 14q

Michels syndrome

Oral face clefts, corneal opacities, growth delay

AD (257920)

Oto-facio-cervical (pits)

Ear pits, webbed neck, sloping shoulders

AD (166780)

Moeschler (both)

Thumb/radial defects

AD (141400)

Townes-Brocks (tags)

Anorectal defects, thumb and ear defects

AD (107480) SALL1, 16p12

Autosomal dominant microtia with meatal atresia (tags)

Microtia, atresia of external auditory canal

AD (251800)

Wildervank

Klippl-Feil anomaly, hearing loss, Duane anomaly

X (314600)

Cat eye (both)

Distinctive face, coloboma, anorectal defects

Chromosomal

Del 4p (both)

Distinctive face, mental retardation, growth deficiency

Chromosomal

Del 5p (both)

Round face, telecanthus, ear tags

Chromosomal

Dup 11q and many other chromosomal conditions

Growth delay, mental retardation

Chromosomal

tags and sensorineural hearing loss and recommend routine hearing assessment in all children with preauricular tags. Kugelman et al.5 recently performed renal ultrasound on 108 infants with tags (or pits) and found no increase in renal defects compared to controls. Early anatomists suggested that the auricular appendages resulted from excessive growth of the auricular hillock in the developing ear, perhaps representing a form of duplication of the original six hillocks (see Section 10.6). Occasionally, there is enlargement of the appendages, and they may group together to form a structure that almost resembles an extra auricle. However, as was mentioned in Section 10.6, a true accessory auricle is extremely uncommon, though the term accessory is sometimes used with regard to these mild malformations. As was mentioned in Section 10.1, auricular tags can be the mildest form of familial microtia. They are one of the more common findings in the family studies of microtia and hemifacial microsomia by the Chicago group. In a number of the kindreds with autosomal dominant-appearing microtia with meatal atresia, a preauricular tag is present in a person presumed to have the autosomal dominant gene for microtia. Thus, it is thought to represent the mildest form of variable expression in the dominant trait in those families. In the majority of infants who have no other obvious defect, preauricular tags are isolated, without a positive family history. Kankkunen and Thiringer4 also documented autosomal dominant kindreds showing isolated nonsyndromic ear tags. Prognosis and Treatment

The auricular tag can be removed through an incision around the base. The tag often contains a delicate rod of elastic cartilage, which can extend deeply. Care must be taken not to damage any fibers of the facial nerve that may be running beneath the tag. Removal should be made by a reconstructive surgeon or otolaryngologist who has experience with this malformation.

References (Auricular Tags) 1. Altmann F: Malformations of the auricle and the external auditory meatus. Arch Otolaryngol 54:115, 1951. 2. Melnick M, Myrianthopoulos NC: External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser XV(9):1, 1979. 3. Beder LB, Kemaloglu YK, Maral I, et al.: A study on the prevalence of accessory auricle anomaly in Turkey. Int J Pediatr Otorhinolaryngol 63:25, 2002. 4. Kankkunen A, Thiringer K: Hearing impairment in connection with preauricular tags. Acta Paediatr Scand 76:143, 1987. 5. Kugelman A, Tubi A, Bader D, et al.: Pre-auricular tags and pits in the newborn: the role of renal ultrasonography. J Pediatr 141:388, 2002.

10.19 Auricular Pits Definition

Auricular pits are pitlike depressions, dimples, or fossae usually just at the anterior margin of the ascending limb of the helix (Fig. 10-18). Pits are also referred to as auricular fistulas. Diagnosis

Altmann1 and Congdon et al.2 have reviewed the anatomy and potential embryogenesis of this common ear defect. The sinuses, fossae, or pits are usually depressions not more than 1 to 3 mm in greatest diameter. Although there are a number of uncommon locations, in over 90% of cases reviewed by Congdon et al.,2 the pits were situated at the anterior margin of the ascending limb of the helix (Fig. 10-18). While most are rather shallow, some can be as deep as 15 mm. A small pigmented mole is sometimes seen near the opening of the dimple. The second most common location is the preauricular region. One of the characteristics of the preauricular pit is that it is sometimes associated with auricular appendages or even with what

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Craniofacial Structures

Fig. 10-18. Preauricular pit (top arrow) associated with retroverted pinna and branchial fistula (bottom arrow) in adult with branchio-oto syndrome (A). Preauricular pits and tag in a 7-month-old infant (B). Preauricular pit and microtia in a 13-month-old infant with Treacher Collins syndrome (C). (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.)

appears to be a congenital scar. The preauricular pits are located in the area from the tragus to the corner of the mouth, the area between the maxillary and mandibular portions of the first branchial arch. Other locations include the posterior helicine region (along the rim of the outer helix), the helicolobular region, and within the center aspect of the lobule. An even rarer type is the postauricular pit, which occurs just behind the attachment of the auricle to the temporal region. Altmann1 reviewed the concept of a ‘‘line of predilection’’ and suggested that pits may very well be remnants of the closure of the mandibular and hyoid arch or the mandibular and maxillary portions of the first branchial arch. Congdon et al.2 have also emphasized that the location of these pits seems to be near where the hillocks of His formed. The idea here is that the sinuses may be derived from grooves that are remnants of the closure of these auricular tubercles. They may be elements of a defective closure of the helix or of the branchial clefts. Most auricular pits are isolated defects and are not part of a broader pattern of anomalies. In the Perinatal Collaborative Study, fewer than 10% of individuals had the pit associated with other malformations.3 On the other hand, in the Spanish Collaborative Project, approximately 30% of infants had an associated defect, but only 1% had a recognizable syndrome (personal communication: Dr. Maria Luisa Martinez-Frias). The high frequency of associated malformations in the Spanish study may be due to the close examination of all the babies, including the recording of minor anomalies. Approximately 20% of these pits are bilateral. Numerous syndromes have been described along with which auricular pits are described (Fig. 10-18). The most important and common of these is the branchial-oto-renal syndrome (see Table 10-10). Pits located on the posterior rim of the helix are characteristic of the Beckwith-Wiedemann syndrome (Fig. 10-19). The preauricular pits seen in the oculo-auriculo-vertebral spectrum are part of what was referred to above as congenital scars and also may relate to the development of accessory appendages. Etiology and Distribution

A number of epidemiologic studies have recorded the frequency of auricular pits and depressions. There does seem to be some racial

predilection. These literature studies have been reviewed by Melnick and Myrianthopoulos3 and usually indicate that the birth prevalence is about 1%, with higher frequencies among black and Asiatic children. The frequency in the Perinatal Collaborative Study was just under 1%, with the frequency among blacks being higher than that among whites. As was mentioned above, the majority of pits are unilateral. Auricular pits of the ascending limb of the helix have been described as an autosomal dominant trait. Zou recently found linkage to 8q11 for ear pits as a trait in a Chinese family.4 Some thoughts on pathogenesis were discussed above. Because of the line of predilection of these depressions, it is tempting to postulate that they represent remnants of closure of the auricular hillocks or the closure of the first and second branchial arches. Preauricular pits on the oral-tragal line are probably a

Fig. 10-19. Pits on posterior ear lobe in Beckwith-Wiedemann syndrome. (Courtesy of Dr. H. Eugene Hoyme, Stanford University School of Medicine, Stanford, CA.)

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different alteration of morphogenesis and most likely are part of the continuum of accessory appendages. Prognosis, Prevention, and Treatment

Except for the rare occurrence of secondary infection, medical complications with these findings are uncommon. Reconstructive surgery is an option for preauricular pits. Mandell summarized the surgical issues recently.5 References (Auricular Pits) 1. Altmann F: Malformations of the auricle and the external auditory meatus. Arch Otolaryngol 54:115, 1951. 2. Congdon ED, Rowhanavongse S, Varamisara P: Human congenital auricular and juxtaauricular fossae, sinuses and scars (including the socalled aural and auricular fistulae) and the bearing of their anatomy upon the theories of their genesis. Am J Anat 51:439, 1932. 3. Melnick M, Myrianthopoulos NC: External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser XV(9):1, 1979. 4. Zou F, Perry Y, et al.: A locus of preauricular fistula arrays to chromosome 8q11. J Hum Genet 48:155, 2003. 5. Mandell DL: Head and neck anomalies related to the branchial apparatus. Otolaryngol Clin N Am 33:1309, 2000.

10.20 Ear Lobe Creases/Pits Definition

Ear lobe creases/pits are transverse linear fissures (creases) or pits in the lobule of the ear. Diagnosis

This alteration of the lobule involves a distinctive linear fissure or crease easily recognized on physical examination (Fig. 10-20). The prenatal onset of congenital ear fissures is most important because of their usefulness in the diagnosis of the Beckwith-Wiedemann syndrome. These ear lobe creases are sometimes called Kerbenohr fissures. They are to be distinguished from the diagonal ear lobe crease that occurs in middle-aged and older adults and that was once thought to be a marker or sign of coronary artery disease. This latter marker will not be reviewed here because it is not a congenital defect, but this topic has been summarized by Jorde et al. Well-defined depressions in the earlobe that resemble pits have been described as an autosomal dominant trait.2 These depressions usually are 3 to 5 cm in diameter and approximately 1 mm in depth. They are sometimes referred to ‘‘natural earring holes.’’ This condition is inherited as an autosomal dominant trait, with variable expressivity and incomplete penetrance. The trait can be both bilateral and unilateral within families. Etiology and Distribution

The frequencies of ear lobe fissures/creases and ear lobe holes/pits are unknown. Ear lobe pits, an autosomal dominant trait, are certainly distinct from autosomal dominant auricular pits, and the two findings are probably mutually exclusive even though they are sometimes discussed together in the otology literature. The frequency of ear lobe creases in the unpublished data from the Boston Minor Anomaly Study is just under 1% for the unilateral finding and approximately one in 300 for the bilateral finding (personal communication: Dr. Lewis Holmes). The deep transverse creases usually seen in Beckwith-Wiedemann syndrome are uncommon as a congenital finding except in that disorder.

Fig. 10-20. Crease on ear lobe associated with macrosomia and macroglossia (Beckwith-Wiedemann syndrome).

The frequency of ear lobe pits or so-called natural earring holes is unknown. The major significance of these findings is as a clue to the Beckwith-Wiedemann syndrome. There is no intrinsic medical significance other than as a diagnostic marker. References (Ear Lobe Creases/Pits) 1. Jorde LB, Williams RR, Hunt SC, et al.: Lack of association of diagonal earlobe crease with other cardiovascular risk factors. West J Med 140:220, 1984. 2. Ramirez M, Cantu JM: Two distinct autosomal dominant traits in the pinna. Birth Defects Orig Artic Ser XVIII(3B):243, 1982.

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Craniofacial Structures

constraint from the longstanding lack of amniotic fluid. It is of note that this particular finding is the primary basis for the so-called ear-kidney association. This alleged association was in fact based on a deformation of the external ear secondary to the oligohydramnios, which was secondary to the intrauterine renal failure, as opposed to an alteration in mesenchymal or cell differentiation (see Section 10.9). Etiology and Distribution

Fig. 10-21. Deformation of the ear. Flattening and crumpling of the ear secondary to intrauterine pressure associated with oligohydramnios. Note the relatively large size of the ear and the interrupted helical fold. (Courtesy of Dr. Will Blackburn and N. Reede Cooley, Jr.)

10.21 Deformation of the Auricle Definition

Deformation of the auricle is an alteration of the form of the external auricle due to unusual mechanical forces on the ear. Diagnosis

The diagnosis of a deformation of the external ear is made by noting an alteration of the form of the auricle in the context of a bona fide history of constraint or intrauterine mechanical forces. The external auricle that is deformed by constraint phenomena in utero can resemble the lop/cup ear defect or can be large and posteriorly rotated (Fig. 10-21). Graham1 has documented a number of examples of alterations of the external ear. Ear variations such as flattening of the ear against the head, overfolding of the helix, and asymmetric growth of the ear should all be considered potential clues to suggest a deformational process. Prolonged oligohydramnios, breech presentation, and uterine malformations are examples of intrauterine phenomena associated with ear deformations. The ear alterations in the Potter syndrome, now recognized as the oligohydramnios sequence, are in fact deformations of the external ear due to the

The exact frequency of deformations of the external ear is unknown. It has been estimated that approximately 2% of liveborn babies will have an extrinsic deformation of late fetal origin. Ear deformations, then, probably occur in a frequency less than that 2% figure. These ear abnormalities can mimic the alterations of intrinsic plical folding, that is, lop/cup ear defect and Stahl ear, but in ear deformations the variation should improve postnatally. Aase2 proposed that prolonged constraint of the external ear actually results in overgrowth, which may be the pathogenetic basis of the ear in the oligohydramnios sequence. Prognosis, Prevention, and Treatment

The natural history of many external ear deformations is postnatal improvement. This applies especially to external ear changes occurring very late in gestation. Perhaps many of the variations of the external ear prevalent among the Japanese (38% for the lop ear and 8% for the Stahl ear) are in fact deformations that mimic alterations of morphogenesis. This may be the reason why many of the external ear defects in the Japanese series improve with time.3 For example, while 38% of infants had a lop ear at birth, only 6% showed this disorder at age 1 year. Ear deformations that involve overfolding lend themselves to the nonsurgical approaches using Aluwax and tape. However, many infants who have reversible ear deformations may be exposed to this taping unnecessarily in that the deformation would have improved on its own. Matsuo et al.3 elect to treat all children, since it is not possible to separate those deformations that will resolve from those that will not resolve. Even in the individual who has a well-documented reason for intrauterine constraint, that is, late oligohydramnios due to leakage or bicornuate uterus, the outcome is not predictable. References (Deformation of the Auricle) 1. Graham JM: Smith’s Recognizable Patterns of Human Deformation, ed 2. WB Saunders Company, Philadelphia, 1988. 2. Aase JM: Structural defects as a consequence of late intrauterine constraint, craniotabs, loose skin and asymmetric ear size. Semin Perinatol 7:270, 1983. 3. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical correction of congenital auricular deformities. Clin Plast Surg 17:383, 1990.

Middle Ear John C. Carey and Albert H. Park Congenital malformations of the middle ear ossicular chain include a wide array of osseous defects of the malleus, incus, and stapes. In this introduction, these defects will be discussed in general. Individual entries for specific middle ear defects and their management will follow.

Interest in these malformations has paralleled developments in the reconstructive surgery of acquired lesions of the middle ear and progress in high-resolution computerized tomography (CT) scanning. Most of the detailed descriptions of the various defects

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have been written in the last 4 decades. Because of the many defects that have been described in all three middle ear bones, one has the impression that there is no pattern to the malformations and that almost any defect can occur in a disorder that involves the middle ear. This notion is not entirely correct, and a few classifications have emerged that are helpful to the clinician. In individuals who have external ear defects, the issue of the potential for a middle ear malformation is always considered. On the other hand, cases involving isolated middle ear defects without an external ear malformation are often not diagnosed or are misdiagnosed as acquired conditions, especially disorders that are unilateral. Funasaka et al.1 have classified ossicular malformations without defects of the external ear into three groups: (1) fixations of the malleus and/or incus, malleoincudal fixations; (2) incudostapedial disconnection; and (3) stapes fixation. While one case can involve all three of these classes of defects, as in Treacher Collins syndrome, most will fall into only one. The Japanese literature abounds with cases of autosomal dominant ossicular defects.2 Cases of this nonsyndromic familial ossicular chain defect are rarely present in the English language literature. In the Japanese literature, individuals in the same family usually have the same type of defect. Familial or autosomal dominantly inherited ossicular defects are usually bilateral, whereas typical ossicular malformations are usually unilateral. Incudostapedial disconnection and/or defects of the incus, either hypoplasia or absence of the long process, appear to be the most common ossicular chain defect in an individual without external ear defects. Congenital fixation of the stapes is probably the most well-known of the three classes of defects, and, because of the dual origin of this important bone, interest in this defect has been high. Stapes ankylosis represents the second most common defect. Fixation of the malleus to either the wall of the tympanic cavity or the incus is commonly seen in meatal atresia. The child with a nonsyndromic ossicular malformation presents with a nonprogressive conductive hearing loss that is present at birth but usually not recognized until later in childhood. The decibel loss is usually in the 40 to 60 range, and the differential diagnosis usually includes acquired hearing loss due to infection and trauma. Audiologic testing, including the tympanogram, will often provide diagnostic clues. The air conduction curve tends to be flat through the midfrequencies while the bone conduction is normal. Impedance audiometry shows changes in the contour of the tympanogram curve, depending on whether there is a defect of discontinuity or fixation. However, the tympanogram is not diagnostic, and further evaluation would be necessary to make a diagnosis. Occasionally, defects of the malleus, especially absence or interruption of the short handle, may be detected on otoscopic examination. High-resolution CT scanning will allow delineation of a number of ossicular chain defects. Swartz et al.3 and more recently Siegert et al.4 have reviewed the radiology of these middle ear defects. Frey5 has also classified middle ear malformations. This categorization includes four groups based on the presence and severity of defects of the external auditory canal. Group 1, the least common form, includes the individual with solitary malformations of the ossicles. The remainder of Frey’s classification (groups 2–4) includes individuals who have middle ear malformations with associated external ear canal defects such as stenosis of the external canal (group 2) and atresia of the external canal (group 3). Group 4 malformations represent the severe end of the spectrum of microtia and meatal atresia with middle ear ossicular chain defects. This classification basically separates individuals with middle ear ossicular defects from those who have the wide range of microtia with

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meatal atresia. Since the overwhelming number of individuals with middle ear malformations are ones who also have external ear malformations, this particular classification is useful to the otologist and radiologist. Teunissen and Cremers6 also proposed a classification of middle ear malformations based on a series of 144 operations. Their classification has four classes: (1) stapes ankylosis; (2) stapes ankylosis with ossicular anomaly; (3) ossicular anomaly with mobile footplate or discontinuity; and (4) aplasia of the round or oval window. In a review on the assessment of individuals with middle ear malformations, Bergstrom7 reported a series of 687 children having congenital hearing loss. Seventeen percent had defects of the conducting mechanism. Only eight of these 117 children had isolated middle ear defects without external ear defects or other malformations. Thus, in this series individuals with nonsyndromic, isolated ossicular chain defects not associated with an external ear malformation were uncommon. Bergstrom, like others, suggests that there are probably many individuals in this group who go undiagnosed. The average age at diagnosis for individuals with congenital conductive hearing loss was 13.4 years, as opposed to 4.2 years in children with associated defects. This figure will clearly become smaller in the future because of universal newborn screening in many areas of the United States and Europe. Nadol8 has separated individuals with middle ear defects into three classes of syndromes: those with progressive hearing loss, including bone dysplasias and connective tissue dysplasias; those with nonprogressive hearing loss, including dysostoses, localized ear defects, and chromosome disorders; and those in which progression of hearing loss is unknown. Nadol8 and Bergstrom7 have compiled the many syndromes associated with ossicular chain defects (see also Table 10-11). As mentioned above, an ascertainment bias probably accounts for the fact that the overwhelming number of individuals in the otology literature have ossicular chain defects as part of a more generalized disorder either of the external and inner ear or as part of an otofacial syndrome. Nadol’s8 classification of disorders that have progressive hearing loss and defects of the middle ear chain includes skeletal dysplasias in which there is postnatal onset of hearing loss. The majority of these conditions fall into the craniotubular dysplasias, including craniometaphyseal dysplasia and frontometaphyseal dysplasia. Autosomal recessive osteopetrosis is the best example of a congenitalonset progressive disorder of conductive hearing loss involving the ossicular chain. This is an intrinsic metabolic disorder of bone. Otosclerosis is the prototypic condition of a postnatal onset disorder of the middle ear bones, while osteogenesis imperfecta is a common example of a syndrome in this grouping. Most of the disorders that fall into the category of nonprogressive hearing loss are congenital malformation syndromes that are in the dysostosis category. These are discussed elsewhere in conjunction with their individual bone defects (see Sections 10.22, 10.23, and 10.24). Other disorders labeled as ‘‘nonprogressive’’ are those that Nadol8 called ‘‘regional defects.’’ These include external, middle, or inner ear malformations; meatal atresia, the X-linked mixed hearing loss with congenital fixation of the stapes; perilymphatic gusher; and Treacher Collins syndrome. Chromosomal disorders are also included. Nadol’s last group consisted of syndromes in which progression was unknown, and these included Apert, otopalatal-digital, and ectrodactyly-ectodermal dysplasia-clefting syndromes. Given that these disorders are all malformation syndromes, it is likely that there is not progression. An accurate prevalence of ossicular chain defects not part of a syndrome cannot be given. If only 7% of individuals with

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congenital hearing loss have isolated, nonsyndromic ossicular defects and the incidence of congenital hearing loss is assumed to be one in 1000, then the incidence could be approximated as one in 14,000. However, this figure has to be an underestimate of the nonsyndromic forms, as mentioned above. The prevalence of individuals with all ossicular malformations is much higher and would approximate the frequency of microtia with meatal atresia because of the high frequency of middle ear defects in microtia. While animal models exist for the study of both external and inner ear defects, middle ear malformations in animals are not as well-described. Altmann9 has reviewed some of the middle ear malformations seen in mammals. Jaskoll10 has conducted investigations of a number of potential teratogens on the development of the chick middle ear. She has listed the teratogens of the middle ear that have been reported in various animal species, including mouse, rat, hamster, monkey, and chick. It is of note that thalidomide induces ossicular chain defects of the middle ear in animal models as it does in the human. Thalidomide is the principal human teratogen recognized to affect the middle ear. A wide range of ossicular chain defects have been reported in infants exposed to thalidomide during the critical period. Vitamin A also alters the middle ear cavity and ossicles in rodents, an important finding since the vitamin A analog, isotretinoin, is a human teratogen. Some authors have proposed that rubella can affect the middle ear as well as the inner ear, but there is little documentation of this. Although maternal diabetes is known to affect external ear development, evidence that it produces middle ear alterations is limited. As mentioned above, there are a number of reports in the Japanese literature of autosomal dominant middle ear ossicular defects. Higashi et al.2 have reviewed a number of the families reported in the Japanese literature. Most defects remain consistent within a single family. There are large Japanese families with autosomal dominant stapes fixation as well as other reports of autosomal dominant incudostapedial disconnection. Higashi et al.2 also reported malleo-incal fixation as a dominant defect. Most of the familial cases have bilateral involvement, although there are a number of exceptions. The genetics of nonsyndromic ossicular malformations have barely been studied. The only citation in the Online Mendelian Inheritance of Man of nonsyndromic middle ear malformations (165680) refers to the above-mentioned report.11 Some of the so-called familial cases of hearing loss may be due to conductive losses in this category. Cases with middle ear defects are often underascertained, and unilateral cases frequently go undetected. With high-resolution CT scanning of the middle ear and newborn screening, the genetic aspects of ossicular chain defects can be better studied in the future. The hearing loss in individuals with middle ear malformation is nonprogressive, of early onset, and conductive in nature. In individuals who have no auditory canal defect or cochlear dysplasia, options for surgical reconstruction of the middle ear are available. Educational intervention for the individual with moderate hearing loss is obviously appropriate. Prior to any surgical intervention and in situations in which surgery is not selected, conductive hearing aids are warranted. Middle ear implantable hearing devices are also a treatment option.12 Individuals with ossicular chain defects have benefited from the many advances in surgery that were developed for otosclerosis, stapes fixation, and acquired defects of the bones secondary to long-standing infection. A number of prosthetic devices and grafting techniques have been developed for reconstruction of the middle ear chain.12 These are discussed in the individual entries for specific defects. Prostheses include the total ossicular replacement

prosthesis and the partial ossicular replacement prosthesis.13,14 Materials used have included titanium, high-density polyethylene sponge, and hydroxyapatite, a dense calcium phosphate ceramic. The House wire is also used in connecting the incus to the oval window. Because of the many advances in the last 3 decades in both the diagnosis and reconstruction of ossicular chain defects, referral to an otologist experienced in this surgery is warranted when evaluating persons with malformations of the auditory conduction system. The following entries on the middle ear discuss the specific defects. References 1. Funasaka A, Abe H, Tozuka G, et al.: Anomalies of the ossicles without malformaton of the external ear. Otol Fukuoka 17:250, 1971. 2. Higashi K, Yamakawa K, Itani O, et al.: Familial ossicular malformations: case report and review of literature. Am J Med Genet 28:655, 1987. 3. Swartz JD, Glazer AU, Faerber EN, et al.: Congenital middle-ear deafness: CT study. Radiology 159:187, 1986. 4. Siegert R, Weerda H, Mayer T, et al.: High resolution computerized tomography of middle ear abnormalities. Laryngorhinootologie 75:187, 1996. 5. Frey K: Malformations of the middle ear. In: Fundamentals of Ear Tomography. J Jensen, H Rovsing, eds. Charles C Thomas, Springfield, IL, 1971, p 77. 6. Teunissen EB, Cremers CWRJ: Classification of congenital middle ear anomalies: report on 144 ears. Ann Otol Rhinol Laryngol 102:606, 1993. 7. Bergstrom L: Assessment and consequence of malformation of the middle ear. Birth Defects Orig Artic Ser XVI(4):217, 1980. 8. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 9. Altmann F: Congenital atresia of the ear in man and animals. Ann Otol Rhinol Laryngol 64:824, 1955. 10. Jaskoll TF: Morphogenesis and teratogenesis of the middle ear in animals. Birth Defects Orig Artic Ser XVI(7):9, 1980. 11. Online Mendelian Inheritance in Man. http://www.nchi.nlm.nih.gov. 12. Spindel JH: Middle ear implantable hearing devices. Am J Audiol 11:104, 2002. 13. Kartush JM: Ossicular chain reconstruction. Otolaryngol Clin N Amer 27:689, 1994. 14. De La Cruz A: Ossiculoplasty in congenital hearing loss. Otolaryngol Clin N Amer 27:799, 1994.

10.22 Hypoplasia/Aplasia/Malformation of the Malleus Malformations of the malleus include underdevelopment or absence of the malleus, shortening of the handle of the malleus, and alterations of the manubrium (Fig. 10-22). Aplasia or hypoplasia of the malleus is recognized by the detection of congenital hearing loss due to the poor mechanical transmission from the ear drum to the incus. Otoscopic examination will sometimes identify this uncommon bony defect. Clues to the diagnosis can come from the pattern on the tympanogram, but the definitive recognition requires high-resolution CT scanning or surgical exploration, often for other reasons. This defect is associated with microtia with meatal atresia, Treacher Collins syndrome, branchio-oto-renal syndrome, and other less common disorders (Table 10-11).1,2 As in all the ossicular chain defects, exact figures for prevalence do not exist. Hypoplasia/aplasia of the malleus represents one of the less frequent of the ossicular middle ear defects. The goal of surgery is to establish a functional connection from the tympanic membrane and direct it to the incus, stapes, or

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Fig. 10-22. Ossicular chain of the middle ear. A. Normal malleus, incus, and stapes. B. Malformed malleus lacking handle; incus lacking long crus and short process; malleus and incus fused. C. Malleus lacking handle; incus lacking long crus and short process; stapes absent; malleus fused to incus and to lateral wall of attic and atresia plate.

oval window, depending on the status of the other bones.3 A partial ossicular replacement prosthesis or a homograph can be used. A thorough description of prostheses or homographs is provided by Kartush.4 References (Hypoplasia/Aplasia/Malformation of the Malleus) 1. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 2. Bergstrom L: Assessment and consequence of malformation of the middle ear. Birth Defects Orig Artic Ser XVI(4):217, 1980. 3. Jaffe BF: Middle ear isolated anomalies. In: Hearing Loss in Children: A Comprehensive Text. University Park Press, Baltimore, 1977, p 286. 4. Kartush JM: Ossicular chain reconstruction. Otolaryngol Clin N Amer 27:689, 1994.

Fig. 10-23. Fusion of head of malleus to the lateral wall of the attic.

10.23 Fusion Defects of the Malleus Malleus head fixation is the most common isolated malleus anomaly. The malleus may be fused to the incus, the atretic plate (in the case of microtia/meatal atresia), or the superior wall of the tympanic cavity (Figs. 10-22 B and C, and 10-23). In the case of a patent external canal, fixation of the malleus could be diagnosed by the astute clinician who notes the movement of the tympanic membrane while the malleus remains immobile. Fixation of the malleus results in nonprogressive conductive hearing loss with a maximum of 60 dB loss when there is total fixation. Malleus fixation is well-known to otologists in association with otosclerosis. Malleal head fixation, however, can also be a congenital defect as described here. The pathogenesis of this defect has been discussed by Goodhill,1 who proposed a number of mechanisms, including excessive air cell formation in the epitympanum, bony fixation of the anterior malleal ligament, and partial failure of the

epitympanic expansion. Fusion defects of the malleus either to the epitympanum or to the incus are relatively uncommon in the major classes of ossicular chain defects. Fusion of the malleus to the atretic plate commonly occurs with meatal atresia. In the review of the Japanese literature on autosomal dominant chain defects by Higashi et al.,2 one of the families had nonsyndromic malleus and/or incus fixation accompanied by stapes fixation. Fixation defects of the malleus have been described in a number of disorders (Table 10-11). Fixation of the malleus requires mobilization and/or use of a prosthesis (tympanic membrane/malleus to incus). Mobilization of the malleus may be challenging even with curette or microdrill instrumentation. If mobilization is unsuccessful, the incudostapedial joint is separated and the malleus head is amputated and repositioned between the malleus handle and stapes suprastructure. As

Table 10-11. Syndromes with middle ear malformations Syndrome

Causation Gene/Locus

Ossicular Defect(s)

Prominent Features

Osteopetrosis, recessive form

Abnormal bone

Increased bone density, bone marrow failure

AR (259700) CLCN7, 16p13

Achondroplasia

Ossicular chain fusion

Disproportionate short stature, macrocephaly

AD (100800) FGFR3, 4p16

Dyschondrosteosis

Hypoplasia/aplasia of malleus and/or incus, stapes fixation

Forearm shortening, short stature, Madelung defect

AD (127300) SHOX, Xp22

Diastrophic dysplasia

Ossicular fusion

Disproportionate short stature, joint contractures

AD (222600) SLC26A2, 5q32

Osteogenesis imperfecta

Stapes ankylosis

Osseous fragility, blue sclera

AD (166210) Multiple loci

Cleidocranial dysostosis

Incudo-malleal fusion, stapes fixation

Clavicular defect, short stature

AD (119600) CBFA1, 6p21

Symphalangism-brachydactyly

Stapes fixation

Distinctive nose, proximal symphalangism, brachydactyly

AD (186500) NOG, 17q22

Teunissen

Stapes fixation, incus hypoplasia

Brachydactyly, brachytelephalangism, broad thumbs

AD (184460) NOG, 17q22

Dominant symphalangismconductive hearing loss

Stapes fixation

Symphalangism, anomalies of hands and feet

AD (185750)

Forney

Stapes fixation

Joint fusion, mitral insufficiency

AD (157800)

Cleft palate-oligodontia

Stapes fixation

Cleft palate, oligodontia

AR (216300)

X-linked hearing loss

Stapes fixation

Mixed hearing loss, perilymphatic gusher at surgery

XLR (304400) POU3F4, Xq21

Escher-Hirt

Abnormal incudo-stapedial joint

Thickened ear lobules, middle ear malformation

AD (128980)

Skeletal Dysplasias

Dysostoses

Otofacial Syndromes

LMC

Stapes fixation

Lop ears, micrognathia

Unknown

Branchio-oto-renal

Stapes fixation, incus hypoplasia/aplasia, malleus hypoplasia/aplasia, absence of the oval window

Branchial fistulas, ear abnormalities, mixed hearing loss, renal defects

AD (113650) EYA1, 8q

Treacher Collins

Hypoplasia and fusion of malleus and incus, absence of stapes and oval window, stapes fixation

Mandibular hypoplasia, malar hypoplasia, Robin sequence, microtia

AD (154500) TCOF1, 5q32

Oculo-auriculovertebral spectrum

Fusion of the incus and malleus, hypoplasia/aplasia of the ossicles

Epibulbar dermoids, hemifacial microsomia, vertebral defects

Heterogeneous; AD (164210) AD (257700) 14q

Wildervanck

Abnormal ossicles, oval window

Duanne anomaly, Klippel-Feil syndrome, mixed hearing loss, ear defects

Unknown, XLR (314600)

Sellars

Hypoplasia of incus, stapes fixation

Microtia

AD (124690)

Kabuki

Multiple ossicular chain defects

Distinctive face, cleft palate, short stature

AD (147920)

Apert

Various ossicular chain defects

Craniosynostosis, hypertelorism, syndactyly

AD (101200) FGFR2, 10q26

Crouzon

Various ossicular chain defects

Craniosynostosis, hypertelorism

AD (123350) FGFR2, 10q26 (continued)

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Table 10-11. Syndromes with middle ear malformations (continued) Syndrome

Ossicular Defect(s)

Prominent Features

Trisomy 18

Wide range of ossicular defects

Neonatal growth deficiency, distinctive face/hands, short sternum, congenital heart disease

Trisomy 13

Stapes aplasia/hypoplasia, many ossicular defects

Cleft lip/palate, scalp defects, polydactyly, eye defects

45,X

Stapes fixation, stapes hypoplasia/aplasia

Short stature, webbed neck, distinctive facies, gonadal dysgenesis

del 22q

Fused and malformed ossicles

Distinctive face, velopharyngeal insufficiency, heart defects

del 18q

Fused and malformed ossicles

Distinctive face, meatal stenosis or atresia, midfacial hypoplasia, tapered fingers, variable developmental retardation

Causation Gene/Locus

Chromosomal Syndromes

mentioned above, numerous prostheses are available to reestablish ossicular continuity. References (Fusion Defects of the Malleus) 1. Goodhill V: The fixed malleus syndrome: surgical and audiological consideration. Trans Acad Ophthalmol Otolaryngol 70:370, 1966. 2. Higashi K, Yamakawa K, Itani O, et al.: Familial ossicular malformations: case report and review of literature. Am J Med Genet 28:655, 1987.

10.24 Hypoplasia/Aplasia/Malformation of the Incus Malformations of the incus include underdevelopment or absence of the incus and abnormalities of the lenticular process and long process (Figs. 10-22B and C, and 10-24). As in defects of the malleus, underdevelopment or absence of the incus is diagnosed by the nonprogressive, conductive hearing loss and by high-resolution CT scanning. Defects can be discovered during reconstruction for the problem or for other defects of the middle ear. The range of defects includes absence of the lenticular process, absence of the long process with persistence of the lenticular process and body, absence of the short process and body, and total absence of the incus (Fig. 10-24). This range comprises the class of malformations called incudostapedial disconnection, which represents the most

common middle ear defects seen in one series.1 A variation of this defect was seen by Higashi et al.2 In this family there was unilateral hypoplasia of the long process of the incus producing a conductive hearing loss. Higashi et al.2 also reviewed three other families with apparent autosomal dominant inheritance of an incudostapedial disconnection. This particular continuum of defects has been seen in a number of syndromes, for example, the common disorders of Treacher Collins syndrome, microtia with meatal atresia, trisomy 18, trisomy 13, and Wildervanck syndrome (Table 10-11).3 In addition to these broader patterns of malformation, reports by Escher and Hirt4 and by Wilmont5 delineated an autosomal dominant condition consisting of conductive hearing loss due to an abnormal incudostapedial joint and thickening of the external ear lobes. Teunissen and Cremers6 reported an uncommon condition of brachydactyly, brachytelephalangy, stapes fixation, and hypoplasia of the incus, now known to be caused by mutations of the NOGGIN gene. The ossicular discontinuity due to abnormalities of the incus can be repaired by a partial ossicular replacement prosthesis. References (Hypoplasia/Aplasia/Malformation of the Incus) 1. Swartz JD, Glazer AU, Faerber EN, et al.: Congenital middle-ear deafness: CT study. Radiology 159:187, 1986.

Fig. 10-24. A. Agenesis of incus except for lenticular process; agenesis of a part of anterior crus. B. Malformed incus with only long crus present; stapes solid. C. Agenesis of long crus of incus and the crural arch of the stapes. D. Agenesis of the long crus of the incus. E. Agenesis of short process of the incus, the stapes, and stapedius muscle.

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Craniofacial Structures

2. Higashi K, Yamakawa K, Itani O, et al.: Familial ossicular malformations: case report and review of literature. Am J Med Genet 28:655, 1987. 3. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 4. Escher F, Hirt H: Dominant hereditary conductive deafness through lack of incus stapes junction. Acta Otolaryngol 65:25, 1966. 5. Wilmont TJ: Hereditary conductive deafness due to incus-stapes abnormalities and associated pinna deformity. J Laryngol 84:469, 1970. 6. Teunissen B, Cremers CWRJ: An autosomal dominant inherited syndrome with congenital stapes ankylosis. Laryngoscope 100:380, 1990.

10.25 Fusion Defects of the Incus The incus may be fused to the malleus, to a portion of the epitympanum and middle ear fossa (Figs. 10-24 B and C), or to the stapes. Making the diagnoses of fusion of the incus to the middle ear cavity or to the malleus is the same as for other ossicular chain defects. The most typical incudostapedial anomalies are fibrous union, absence of the joint or bony fusion. Incudostapedial fusion was the second most common middle ear defect in the Teunissen and Cremer series.1 As mentioned in the above entry, recently Teunissen and Cremers2 described an autosomal dominant condition of stapes fixation, brachydactyly, brachytelephalangy, and, in a few cases, fusion of the short process to the fossa incudis. This fusion defect has also been seen in Winter syndrome, branchio-oto-renal syndrome (incus fused to stapes), and Crouzon syndrome.3 Tympanoplasty may be performed for this and for other forms of bony ossicular fixation.4,5 References (Fusion Defects of the Incus) 1. Teunissen EB, Cremers CWRJ: Classification of congenital middle ear anomalies: report on 144 ears. Ann Otol Rhinol Largyngol 102:606, 1993. 2. Teunissen EB, Cremers CWRJ: An autosomal dominant inherited syndrome with congenital stapes ankylosis. Laryngoscope 100:380, 1990. 3. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 4. Tos M: Tympanoplasty for bony ossicular fixation. Arch Otolaryngol 99:422, 1974.

5. De La Cruz A, Doyle KJ: Ossiculoplasty in congenital hearing loss. Otolaryngol Clin N Am 27:799, 1994.

10.26 Hypoplasia/Aplasia/Malformation of the Stapes Malformations include underdevelopment or absence of the stapes and a wide range of structural alterations of this middle ear ossicle (Figs. 10-22 C, 10-24 A, C, and E, and 10-25). Hypoplasia or aplasia of the stapes are diagnosed using high-resolution computerized tomography. A variety of structural alterations of the shape of the stapes have been described. These include the unicrurate defect, incomplete development of the crura without attachment to the footplate, entire absence of the superstructure of the stapes, and the so-called columella or monopodal stapes.1 The columella type is one of the most common of this group. These defects also can be classified as part of the group of incudostapedial disarticulation defects or disconnection defects. When there are alterations of its superstructure, the stapes is not connected with the incus. The genetics of these malformations are unclear. Most of the information on defects of the stapes involve fixation of the stapes footplate. Sellars and Beighton2 reported a family with an apparently autosomal dominant condition involving type I microtia and absence of the stapes superstructure. In this condition there are varying degrees of hypoplasia of the incus and fixation of the stapes footplate. This particular syndrome is of note, since it seems to comprise a range of findings, including alterations of the long process of the incus, lenticular process of the incus, and stapes superstructure. Variability in the reported family suggests a common denominator in the development in this area of the ossicular chain. The malleus was usually normal. It is of note that the stapes superstructure and perhaps the long process of the incus come from the second branchial arch. Structural alterations of the stapes also occur in Treacher Collins syndrome, oculo-auriculo-vertebral spectrum, Escher-Hirt syndrome, trisomy 13, microtia with meatal atresia, and a number of less common disorders (Table 10-11).3

Fig. 10-25. A. Agenesis of the stapes and stapedius muscle. B. Agenesis of the stapes except for a remnant of the anterior crus; agenesis of stapedius muscle. C. Partial absence of the anterior and posterior crus of the stapes.

Ear

Treatment should center on removing the malformed stapes atraumatically and leaving a mobile footplate. A laser may be helpful in removing an ossified stapedius tendon or abnormal stapes suprastructure. Once accomplished, a prosthesis can be placed from the footplate to either the tympanic membrane, incus (if available), or malleus handle.4,5

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10.27 Congenital Fixation of the Stapes

cular chain. In a series dealing with reconstruction of the middle ear by Scheer,1 16 of 17 patients had a structurally abnormal stapes related to their conductive hearing loss without an abnormal external ear or meatus, and three of these had congenital fixation. In a study of congenital middle ear deafness involving patients with normal external ears, three of 15 had congenital stapes fixation.6 In the series by Teunissen and Cremers, 30% of their 144 cases had congenital stapes ankylosis.7 The etiology of stapes fixation is usually not determined. Most case descriptions in the otology literature provide no family history. However, there are a number of exceptions to this statement, and there has been very little systematic study of the genetic aspects of congenital stapes fixation. The X-linked disorder mentioned above should always be considered, and there are probably more autosomal dominant families than are suspected. There are no studies of parents of individuals with congenital stapes fixation, and unilateral findings could certainly go undetected. Treacher Collins syndrome probably represents the most common of the syndromic disorders in which this defect occurs. Congenital stapes fixation has been seen in individuals with prenatal thalidomide syndrome. None of the other human teratogens has been implicated as a cause of this ossicular defect, but it is plausible that it is a feature of the isotretinoin embryopathy.

Definition

Prognosis, Prevention, and Treatment

Congenital fixation of the stapes is the congenital fusion of the footplate of the stapes to the oval window, thus altering the stapedial-vestibular joint. Congenital stapes footplate fixation is considered in an individual with a nonprogressive conductive hearing loss in which there is no other ossicular chain defect detected on radiography. A definitive diagnosis is made during exploratory tympanotomy. The stapes footplate may be totally or partially fixed on gentle palpation. Absence of the oval window is sometimes associated with stapes ankylosis. When there is total fixation, about 50–100% of the footplate is fixed to the otic capsule. Audiometry will reveal a maximum flat 60 dB conductive loss. About one-fourth of the cases reviewed by Scheer1 had partial fixation with less conductive loss. A historical overview and description of this relatively recently described congenital defect was presented by House2 in 1969. He proposed that congenital fixation of the stapes footplate was due to an abnormality of the differentiation of the annular ligament. The defect is sometimes associated with absence of the oval window, which some otologists feel is the full expression of this morphologic defect of the stapedial-vestibular joint. While the otology literature usually states that family history is negative, there are a number of families reported with an X-linked form associated with the perilymphatic gusher at surgery. In addition, there are a number of autosomal dominant families reported in the Japanese literature.3 Table 10-11 lists a number of syndromes in which congenital stapes fixation occurs. Of special note are the two symphalangism conditions that are due to mutations of NOGGIN and the X-linked disorder of mixed hearing loss with congenital fixation of the stapes footplate and the perilymphatic gusher at the time of surgery. This latter condition has been mapped to the long arm of the X chromosome and is due to mutations of POU4.4,5

Treatment options are dictated by the severity of stapes fixation and the presence of other ossicular anomalies. If stapes fixation is minimal, one can try to mobilize the footplate. House noted good long-term results following stapes mobilization procedures.2 For more extensive stapes fixation, a stapedectomy or stapedotomy procedure is advocated. Proponents have shown good postoperative results with both techniques. Stapedectomy involves complete removal of the footplate; stapedotomy involves creation of a fenestra in the footplate. A prosthesis is then placed for either procedure between the incus and oval window niche. A temporalis fascia graft or trajal perichondrium is typically placed between the prosthesis and oval window niche for stapedectomy procedures to prevent medial migration into the vestibule. The most challenging situation arises when the stapes fixation is associated with incus and malleus abnormalities. In this case, a total ossicular reconstructive prosthesis (TORP) is necessary. It is placed over a temporalis fascia/trajal perichondrium following a stapedectomy procedure. A thin piece of trajal cartilage is then interposed between the TORP and tympanic membrane. Battaglia et al.8 reviewed 21 patients undergoing TORP and stapes footplate removal. Hearing results indicated that 52% have an airbone gap less than 20 dB. House and Teufert9 noted similar results. Awareness of the possibility of the perilymphatic gusher is always necessary prior to surgical intervention. This finding is seen in stapes fixation of various causes, including the X-linked type.

References (Hypoplasia/Aplasia/Malformation of the Stapes) 1. Jaffe BF: Middle ear isolated anomalies. In: Hearing Loss in Children: A Comprehensive Text. BF Jaffe, ed. University Park Press, Baltimore, 1977, p 286. 2. Sellars S, Beighton P: Autosomal dominant inheritance of conductive deafness due to stapedial anomalies, external ear malformations and congenital facial palsy. Clin Genet 23:376, 1983. 3. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 4. Briggs RJS, Luxford WM: Correction of conductive hearing loss in children. Otolaryngol Clin N Am 27:607, 1994. 5. De La Cruz A, Doyle KJ: Ossiculoplasty in congenital hearing loss. Otolaryngol Clin N Am 27:799, 1994.

Etiology and Distribution

The exact frequency of congenital stapes fixation is not known, but it does represent the second most common anomaly of the ossi-

References (Congenital Fixation of the Stapes) 1. Scheer AA: Correction of congenital middle ear deformities. Arch Otolaryngol 85:55, 1967. 2. House HP: Congenital fixation of the stapes footplate. Otolaryngol Clin N Am 2:35, 1969. 3. Higashi K, Yamakawa K, Itani O, et al.: Familial ossicular malformations: case report and review of literature. Am J Med Genet 28:655, 1987.

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Craniofacial Structures

4. Wallis C, Ballo R, Wallis G, et al.: X-linked mixed deafness with stapes fixation in a Mauritian kindred: linkage to Xq probe pDP34. Genomics 3:299, 1988. 5. Brunner HG, van Bennekom A, Lambermon EM, et al.: The gene for X-linked progressive mixed deafness with perilymphatic gusher during stapes surgery (DFN3) is linked to PGK. Hum Genet 80:337, 1988. 6. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 7. Teunissen EB, Cremers CWRJ: Classification of congenital middle ear anomalies: report on 144 ears. Ann Otol Rhinol Laryngol 102:606, 1993. 8. Battaglia A, McGrew BM, Jackson CG: Reconstruction of the entire ossicular conduction mechanism. Laryngoscope 133:654, 2003. 9. House JW, Teufert KB: Extrusion rates and hearing results in ossicular reconstruction. Otolaryngol Head Neck Surg 125:135, 2001.

10.28 Absence of the Oval Window Nondevelopment of the oval window of the middle ear is usually associated with congenital defects of the stapes, including footplate fixation. Congenital absence of the oval window would usually be recognized at the time of surgery in individuals with conductive hearing loss. In the series of Swartz et al.,1 one individual was recognized by computed tomography. Some otologists feel that congenital stapes fixation is a milder degree of maldevelopment of the stapedial-vestibular joint. Abnormalities of the facial nerve canal and lower ossicular chain, especially the long process of the incus, usually accompany this defect. Commonly the long process of the incus is short and more medially positioned. Some individuals have also had accompanying absence of the round window. The stapes is invariably abnormal. In Lambert’s review2 of seven cases, aplasia of the stapes was present in one case, and structurally abnormal stapes were present in the remaining six cases. Family history data on this disorder are not available. Absence of the oval window has occasionally been seen in Treacher Collins syndrome and in the oculo-ariculo-vertebral spectrum. In addition, individuals with Wildervanck syndrome and 22q11 deletion have been reported with absence of the oval window. This defect is also seen with Mondini dysplasia of the inner ear.3 Absence of both the round window and the stapes has been seen as the middle ear defect in a distinctive dominant syndrome involving limb reduction defects, cardiac arrhythmias, abnormal external ears, and conductive hearing loss. Other than the presence of this finding in some Mendelian syndromes, genetic information is unavailable. As is the case of other middle ear defects, especially congenital stapes fixation, little study of family histories has been accomplished. Congenital absence of the oval window has been reported in cases of prenatal thalidomide syndrome. The frequency of this particular finding is unknown. Lambert’s review2 in 1990 included only seven papers from 1958 to 1990 on this topic. Jahrsdoerfer’s series4 of 13 patients represents the largest to date. This investigator suggested that congenital absence of the oval window may in fact be related to abnormal development of the facial nerve. The surgical challenges to this anomaly are significant given the potential risk to the facial nerve and inner ear. Sterkers and Sterkers have described success with drilling a fenestra above the facial nerve and placing a prosthesis to the incus in six cases.5 Lambert reviewed the outcomes of six patients who underwent vestibulotomios and reconstruction with House wires or a total

ossicular reconstruction prosthesis (TORP).2 Hearing initially improved in four of the six patients but was lost over time. Given the poor surgical outcome and potential morbidity of the procedure, use of hearing aids is recommended. References (Absence of the Oval Window) 1. Swartz JD, Glazer AU, Faerber EN, et al.: Congenital middle-ear deafness: CT study. Radiology 159:187, 1986. 2. Lambert PR: Congenital absence of the oval window. Laryngoscope 100:37, 1990. 3. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 4. Jahrsdoerfer R: Congenital malformations of the ear analysis of 94 operations. Ann Otol Rhinol Laryngol 89:348, 1980. 5. Sterkers JM, Sterkers O: Surgical management of absence of the oval window with malposition of the facial nerve. Adv Otorhinolaryngol 40:33, 1988.

10.29 Congenital Cholesteatoma Definition

Congenital cholesteatoma is a cystic epithelial remnant of embryologic origin found medial to an intact tympanic membrane. Diagnosis

While the actual existence of congenital cholesteatoma was once debated in the otology literature, the present consensus is that this disorder does exist. Many children present with conductive hearing loss. An opaque or whitish-appearing mass is typically seen behind the tympanic membrane. Many cases are diagnosed during surgical exploration for the cause of conductive hearing loss. High-resolution computed tomography scanning may detect these lesions as a homogenous mass in the middle ear. The review by McDonald et al.1 indicates that congenital cholesteatomas make up about 2% of all such lesions. Derlacki and Clemis originally established the clinical criteria for diagnosis: (1) no history of otorrhea, perforation, or previous otologic procedures; (2) normal pars tensa and flaccida; and (3) a pearly white mass medial to an intact tympanic membrane. Levenson et al.3 relaxed the criteria by including some children with serious otitis media. The mean age of presentation as reported in more recent reviews is 4.5 years.4,5 There is a male preponderance of nearly 3:1 in recent reports. If allowed to enlarge, these cholesteatomas can erode the ossicles and spread to the attic and antrum. A child with a conductive hearing loss in the absence of serious effusion should be suspected of having a cholesteatoma unless proved otherwise.6 Etiology and Distribution

Von Remak in 1854 (cited in reference 7) suggested that many cholesteatomas may be dermoids originating from epidermal rests formed during embryologic development.7 Michaels in 1988 demonstrated epidermoid tissue in a fetus at 5 to 6 weeks gestation, that apparently involuted by 33 weeks.8 He suggested that this epidermoid tissue, if persistent, could result in primary cholesteatoma located in the anterosuperior portion of the mesotympanum. Other theories such as epithelial implantation, squamous metaplasia from otitis media, or epithelial migration through the tympanic ring have also been considered.9,10 Currently, the epidermal rest theory has been the most widely accepted one.

Ear

Treatment, Prevention, and Prognosis

The treatment of congenital cholesteatoma is surgical removal. The major impact of these lesions, as mentioned above, is ossicular destruction and occasional involvement of the inner ear. The sequence of events is such that they grow, become secondarily infected, and with time produce destruction of the osseous chain and temporal bones. Occasionally, the lesion will recur even after surgery. Surgical strategy depends on the extension of the lesion. Lesions involving the anterosuperior mesotympanum can be removed via an anteriorly based tympanotomy with excellent results. For extensive tumors involving the entire mesotympanic and antrum, a mastoidectomy may need to be performed. In general, the surgeon attempts to preserve as much of the ossicular chain and posterior canal wall as possible without sacrificing the extent of removal. Reexploration is undertaken when the surgeon cannot be certain of residual disease. Ossiculoplasty is usually performed once epithelial removal is complete. References (Congenital Cholesteatoma) 1. McDonald TJ, Cody DT, Ryan RE: Congenital cholesteatoma of the ear. Ann Otol Rhinol Laryngol 93:637, 1984. 2. Derlacki EL, Clemis JD: Congenital cholesteatoma of the middle ear and mastoid. Ann Otol Rhinol Laryngol 74:706, 1965. 3. Levenson MJ, Parisier SC, Chute P, et al.: A review of twenty congenital cholesteatomas of the middle ear in children. Otolaryngol Head Neck Surg 94:560, 1986. 4. Friedberg J: Congenital cholesteatoma. Laryngoscope 104(3 Pt 2):1, 1994. 5. Friedberg J: Congenital cholesteatoma. In: Pediatric Otology and Neurotology. Lalwani AK, Grundfast KM, eds. Lippincott Williams and Wilkins, Philadelphia, 1998, p 284. 6. Chem JM, Schloss MD, Manoukian JJ, et al.: Congenital cholesteatoma of the middle ear in children. J Otolaryngol 18:44, 1989. 7. Curtis AW: Congenital middle ear cholesteatoma: two unusual cases and a review of the literature. Laryngoscope 89:1159, 1979. 8. Michaels L: Origin of congenital cholesteatoma from a normally occurring epidermoid rest in the developing middle ear. Int J Pediatr Otorhinolaryngol 15:51, 1988. 9. Sade J, Babiacki A, Pinkus G: The metaplastic and congenital origin of cholesteatoma. Arch Otolaryngol 96:119, 1983. 10. Aimi K: Role of the tympanic ring on the pathogenesis of congenital cholesteatoma. Laryngoscope 93:1140, 1983.

10.30 Persistence of the Stapedial Artery The stapedial artery is usually present in the early stages of embryonic development of the middle ear and thereafter regresses. Its persistence beyond this point is considered a malformation. Persistence of the stapedial artery is usually diagnosed during middle ear surgery for conductive hearing loss. While there are some radiologic clues on a skull x-ray (absence of the foramen spinosum in the radiograph of the cranial base), it is difficult to diagnose even with carotid angiography. However, recent reports of successful detection with computed tomography scanning have been reported.1 It is also difficult to sort out the various associations with persistence of the stapedial artery, because it is usually found at the time of middle ear surgery and thus, there is clearly an ascertainment bias. It has been seen in individuals with the oculoauriculo-vertebral (OAV) spectrum. In a review by PascualCastroviejo,2 persistence of the stapedial artery was reported in a

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child with an unusual branchial arch abnormality consisting of anotia and trilobulated mass in the area of the pinnae. The persistence of the stapedial artery in this case was demonstrated on arteriography. The frequency of this condition cannot be determined. As of Pascual-Castroviejo’s review,2 there had only been about 20 reported cases. Only a few reports have been published since.1,3 Although the pathogenesis is unclear, the condition does appear to represent the persistence of an artery that usually regresses during embryonic development. The stapedial artery is present in the developing embryo at 35 days as a branch of the hyoid artery. By age 55 to 60 days, the branches of the stapedial artery have become part of the ophthalmic artery, and the arteries originate in the third pharyngeal arch. The trunk of the stapedial artery disappears during the 3rd month of fetal life. It is not clear if the presence of a stapedial artery is developmentally related to the OAV spectrum or to other middle ear defects. It simply may be that this arterial variation occurs in conjunction with other developmental disorders of the external and middle ear. References (Persistence of the Stapedial Artery) 1. Yilmaz T: Persistent stapedial artery; MR angiographic and CT findings. Am J Neuroradiol 24:1133, 2003. 2. Pascual-Castroviejo I: Persistence of the stapedial artery in a first arch anomaly: a case report. Cleft Palate J 20:146, 1983. 3. Pahor AL, Hussain SS: Persistent stapedial artery. J Laryngol Otol 106:254, 1992.

10.31 Highly Placed Jugular Bulb A highly placed jugular bulb is an anomaly of placement of the jugular bulb in which the location of the vascular structure interferes with ossicular chain motion and produces conductive hearing loss. This rare anomaly is sometimes associated with conductive hearing loss.1 A bluish-red mass can be seen in the posterior portion of the middle ear behind the tympanic membrane. A vascular mass is recognized at the time of surgical exploration. A venogram would show distension of the jugular bulb. Because of the rarity and small number of cases of this condition, its association with other malformations or syndromes is unknown. The association of a highly placed jugular bulb with conductive deafness and interference with the osseous chain is uncommon. Moretti1 reviewed the literature on this topic in 1976. The etiology and pathogenesis are unknown. In the case he studied, there was hypoplasia of the contralateral sinuso-jugular system. Other cases can be due to normal variation in the height of the jugular bulb and occasional dehiscence of the floor of the middle ear. Kondoh et al.2 recently documented a case associated with hearing loss. This anomaly is an uncommon cause of unilateral conductive loss due to its involvement with the middle ear chain. Because of the unilateral involvement, vascular surgery would involve decisions about risks versus benefits. References (Highly Placed Jugular Bulb) 1. Moretti JA: Highly placed jugular bulb and conductive deafness. Arch Otolaryngol 102:430, 1976. 2. Kondoh K, Kitahara T, Mishiro Y, et al.: A rare case of the high jugular bulb associated with only hearing ear. (Article in Japanese.) Nippon Jibiinkoka Gakkai Kaiho 105:893, 2002.

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Inner Ear Daryl A. Scott and John C. Carey 10.32 Vestibulocochlear Dysplasias Definition

Vestibulocochlear dysplasias are a continuum of malformations and dysplasias involving the osseous and membranous components of the cochlea, vestibule, and lateral semicircular canals of the inner ear. The normal anatomy of the inner ear is shown in Figure 10-26. Diagnosis

Individuals with vestibulocochlear dysplasias may seek medical attention for hearing loss or vestibular complaints such as dizziness or vertigo. Historically, little could be done to define the anatomy of the inner ear until an individual was deceased and a postmortem examination could be performed. In contrast, modern radiologic techniques can be used to explore the inner ear with relative ease. High resolution computed tomography (CT) in both the axial and coronal views is the standard method of examining the bony labyrinth and internal auditory meatus. Four to five 2 mm axial sections are usually sufficient to exclude congenital dysplasia, with 1 mm sections being obtained if a dysplasia is visualized. Magnetic resonance imaging techniques, including gradient echo, three dimensional Fourrier transformation-constructive interference in the steady state (3-DFT CISS), and fast or turbo-spin echo two-dimensional sequencing heavily weighted with high signal from fluids (T2), are also used for inner ear imaging.1 Dysplasias of the membranous and osseous labyrinth are classified on an anatomic and histologic basis according to schemes that describe a continuum of severity. A classification proposed by Omerod in 1960 is still in common use today.2 This system divides vestibulocochlear dysplasias into four types, each named after the individual who wrote the classical account of that

malformation: (1) Michel aplasia; (2) Mondini-Alexander dysplasia; (3) Bing-Siebenmann dysplasia; and (4) Scheibe dysplasia. Each of these malformations is summarized in Table 10-12 and described in detail below. In 1987, Jackler et al. proposed a second classification system based on the radiographic appearance of various cochlear malformations and the hypothesis that the various morphologic patterns seen in the inner ear result from an arrest of maturation during one the states of inner ear embryogenesis.3 This scheme includes five types: (1) complete labyrinthine aplasia; (2) cochlear aplasia; (3) common cavity; (4) cochlear hypoplasia; and 5) incomplete partition. Each of these malformations is summarized in Table 10-13 and described in detail below. In 1967, Schuknecht proposed a classification system for vestibulocochlear dysplasias similar to Omerod’s.4 In this system Michel and Scheibe types are identical to those proposed by Omerod, but Mondini dysplasia is broadly defined as incomplete development of the bony and membranous labyrinth. Bing-Siebenmann type is deleted, and a milder sembranous cochlear dysplasia (Alexander dysplasia) is added. Michel or Complete Labyrinthine Aplasia

Formation of the inner ear begins during the 3rd week of gestation when a thickening of ectoderm, the otic placode, forms on the lateral surface of the neural tube. Failure of development at this stage results in complete labyrinthine aplasia of the Jackler et al. classification with no development of inner ear structures. Michel aplasia may be bilateral or unilateral and can be seen in conjunction with other abnormalities caused by failure of the otic placode. These include nondifferentiation of the stapes, abnormal course of the facial nerve, hypoplasia of the petrous bone, and abnormal course of the transverses sinus and jugular veins. Michel aplasia is rare and accounted for only about 1% of radiologically apparent cochlear malformations in the report of

Fig. 10-26. Schematics of the bony internal ear (left) and membranous internal ear (right).

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Table 10-12. Omerod’s classification system of vestibulocochlear dysplasias2 Malformation

Description

Associated Disorders

Michel aplasia

Complete lack of inner ear development

Familial autosomal dominant Familial autosomal recessive Anencephaly Klippel-Fiel anomaly Wildervanck Thalidomide embryopathy

Mondini-Alexander dysplasia

Cochlea contains a decreased number of turns and underdevelopment of vestibular structures

Wildervanck Waardenburg Del 22q11 Pendred CHARGE Congenital cytomegalovirus infection Trisomy 18, 13

Bing-Siebenmann dysplasia

Malformation restricted to the membranous labyrinth. Normal bony labyrinth

Jervell and Lange-Nielsen Usher Oculo-auriculo-vertebral spectrum

Scheibe dysplasia

Malformation of the membranous cochlea and saccule. No vestibular involvement and normal bony labyrinth

Waardenburg Congenital rubella infection

Table 10-13. Jackler classification of radiologically apparent vestibulocochlear malformations3 Malformation

Description

Equivalent in Omerod’s Classification

Complete labyrinthine aplasia

Complete lack of inner ear development

Michel aplasia

Cochlear aplasia

Complete lack of cochlear development*

No equivalent

Common cavity

Cochlea and vestibule form a common cavity without internal architecture

Classified by some authors as severe Mondini-Alexander

Cochlear hypoplasia

Small cochlear bud*

Classified by some authors as severe Mondini-Alexander

Incomplete partition

Small cochlea with incomplete or interscalar septum*

Mondini-Alexander

*The vestibule and semicircular canals in cochlear aplasia, cochlear hypoplasia, and incomplete partition may be normal or malformed.

Jackler et al.3 In a recent series by Park et al. of 24 patients with 39 ears involved, four (10%) had the Michel dysplasia.5 Common Cavity Dysplasia

During the 4th week of embryonic development, the otic placode invaginates to form a simple cavity called the otocyst. Arrest at this stage of development results in the persistence of a large cloaca. In the Jackler et al. system, this malformation is designated as the common cavity defect. Common cavity defects represent about 13–25% of vestibulocochlear malformations.3,5 Common cavity dysplasia is associated with increased risk for recurrent otogenic meningitis. Cochlear Aplasia

In the 5th week of embryonic development, three folds form, representing the primordial cochlear, vestibular, and endolymphatic sac appendages. Arrested development of the cochlear bud at this stage would result in cochlear aplasia with complete lack of cochlear development with preservation, but not necessarily normal development, of the semicircular canals and vestibule. Cochlear aplasia is relatively uncommon vestibulocochlear dysplasia and represents only about 3–10% of radiologically apparent cochlear malformations.3,5

Mondini-Alexander Dysplasia or Cochlear Hypoplasia and Incomplete Partition Dysplasia

Between the 5th and 8th weeks of development, the cochlear duct undergoes continuous growth. As the cochlear duct grows the characteristic turns of the cochlear also form. Arrest of development in the 6th week would result in the formation of a rudimentary cochlea, ranging from a small diverticulum to a cochlear bud several millimeters in length. This is classified as cochlear hypoplasia in the Jackler et al. classification scheme.3 Arrest in cochlear development during the 7th week results in a small, flattened cochlea with only 1 to 1.5 turns instead of the 2.5 to 2.75 turns seen at full development. This is referred to as the Mondini-Alexander dysplasia of Omerod’s classification and as incomplete partition in the Jackler et al. classification scheme. The basal turn of the cochlea is usually fully developed, while the upper turns form a common cavity known as the scala communis. Typical findings also include a short cochlear duct, immature auditory and vestibular sense organs and nerves, a large vestibule, a bulbous endolymphatic sac, and malformed semicircular canals that can be wide, small, or missing.6

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Craniofacial Structures

Bing-Siebenmann Dysplasia

In Bing-Siebenmann dysplasia the development of the bony labyrinth is normal, but the membranous portion of the cochlea and semicircular canals are malformed or degenerate. Since the petrous bone and the bony cochlea and vestibule are fully formed, this type of dysplasia cannot be detected radiographically and is not included in the Jackler et al. classification.3 Extensive involvement of the membranous cochlea is typical. The sensory endorgan and tectorial membrane are underdeveloped, and the canal of the cochlea is often collapsed. In cases where the canal of the cochlea is dilated rather than collapsed, the immaturity of the sensory endorgan is attributed to a degenerative process rather than an arrest in development.2 Although Bing-Siebenmann dysplasia is characterized by a greater involvement of the semicircular canals and the vestibular organ than that seen in Scheibe dysplasia, it is likely that BingSiebenmann dysplasia represents a severe form of the more common Scheibe dysplasia. Scheibe or Cochleosaccular Dysplasia

In 1978, Valvassori and Clemis8 described a series of 50 patients, out of 3700 referred for tomographic evaluation, whose vestibular aqueduct was enlarged—1.5 to 8 mm in diameter at the midpoint. Currently a midpoint diameter of greater than 2 mm is typically used for defining large vestibular aqueduct syndrome. Other terms for this abnormality include enlarged—or dilated—vestibular aqueduct and large endolymphatic duct. Individuals with large vestibular aqueducts are at risk for paroxysmal vertigo and progressive sensorineural hearing loss. In one study of 130 children with sensorineural hearing loss, 18 patients had large vestibular aqueducts. Progression of hearing loss was noted in 46% of these patients compared to 35% in the absence of this abnormality.9 Large vestibular aqueducts have been described in association with Pendred and branchio-oto-renal syndrome. In contrast to individuals with large vestibular aqueduct syndrome, about 60% of individuals with Meniere disease have a hypoplastic or narrowed vestibular aqueduct. It is unclear, however, if this abnormality plays a significant role in the disease since it is not present in all affected individuals and is also found in 21% of individuals without Meniere disease.10,11

Scheibe dysplasia represents the mildest end of the spectrum of vestibulocochlear dysplasias and consists of membranous abnormalities primarily of the cochlea with involvement of the saccule. It is also referred to as cochleosaccular dysplasia. In contrast to BingSiebenmann dysplasia, the membranous utricle and semicircular canals are fully formed and functioning. The petrous bone and the bony cochlea and vestibule are fully developed, making radiologic diagnosis impossible. The organ of Corti is often rudimentary with very few sensory cells, and the stria vascularis is degenerate with relatively few vessels. The canal of the cochlea is collapsed and the techtorial membrane is formed but flattened down over the organ of Corti and its supporting cells. In cases where the canal of the cochlea is dilated rather than collapsed, the immaturity of the sensory endorgan is attributed to a degenerative process rather than an arrest in development.2 The degree of development can vary throughout the cochlea, and some areas of the cochlea function sufficiently well to provide some level of hearing.

Internal Auditory Meatus Abnormalities

Semicircular Canal Abnormalities

In retrospective reviews of temporal bone CT scans, between 22% and 31% of children with sensorineural or mixed hearing loss had radiologically detectable vestibulocochlear abnormalities.5,13,14 These abnormalities were more common in children with congenital syndromes than in those with nonsyndromic hearing loss. The true incidence of inner ear malformations in this population is probably higher than given in these series since abnormalities restricted to the membranous labyrinth are not detected on CT scans. Several etiologies have been identified as the cause of inner ear abnormalities: (1) chromosomal abnormalities; (2) single gene disorders; (3) congenital associations; (4) congenital infections; and (5) toxic exposures (see Tables 10-12 and 10-13). Inherited disorders are probably the most common etiology.

During the 6th week of embryonic development, the superior, posterior, and lateral semicircular canals appear as folded invaginations of membrane from the vestibular appendage. Failure of these epithelial folds to form results in complete absence of the involved semicircular canal or semicircular canal aplasia. Over time the central portion of each invagination is resorbed, forming a semicircular duct. Incomplete absorption of the central membrane results in a pocket-shaped semicircular canal that is confluent with the vestibule. Although malformations of the semicircular canals, or semicircular canal dysplasia, can be an isolated defect, they are often associated with cochlear malformations. Semicircular canal abnormalities have been described in a number of hearing loss syndromes, including branchio-oto-renal syndrome, Goldenhar syndrome, Waardenburg syndrome, and CHARGE syndrome. Vestibular Aqueduct Abnormalities

The vestibular aqueduct is a bony canal through which courses the endolymphatic duct. Although most of the membranous labyrinth reaches adult size by the 18th week of fetal life, the vestibular aqueduct continues to grow throughout embryonic life, and the midpoint diameter of the duct is usually between 0.4 and 1.0 mm.7

The cochleovestibular nerve passes through the internal auditory meatus (IAM) along with the facial nerve. Several variations of the internal auditory meatus have been described, including absent, narrowed, widened, ballooned/bulbous, and tapered configurations.12 Absence of the IAM is rare but has been associated with thalidomide embryopathy. Although a narrowed IAM (<2 mm) can be seen in individuals with normal hearing, it is more common in individuals with senorinerural hearing loss and may indicate the hypoplasia or absence of the cochleovestibular nerve. A widened IAM (>8 mm) probably has little significance, except in individuals in whom an acoustic neuroma is suspected. A ballooned/bulbous IAM has been associated with the X-linked deafness perilymphatic gusher. A tapered IAM associated with a common cavity or hypoplastic cochlea has been associated with the formation of spontaneous cerebrospinal fluid fistulae. Etiology and Distribution

Prognosis, Prevention, and Treatment

A reduction in the incidence of inner ear abnormalities caused by congenital infection and toxic exposures may be possible through immunization and patient education programs. A prime example is the dramatic decrease in cases of congenital hearing loss due to rubella infections, which have been associated with Scheibe dysplasia, after the implementation of effective vaccination programs. In the majority of cases, however, prevention is not possible, and medical efforts should be concentrated on preserving residual inner

Ear

ear function, early intervention, timely rehabilitation, and careful monitoring and intervention for potential complications. The majority of individuals with inner ear abnormalities present with hearing loss. Patients with inner ear abnormalities should be discouraged from participating in activities that could result in further damage to the inner ear, such as contact sports, scuba diving, and parachuting. It would also be wise to minimize exposure to ototoxic medications and loud noise. Early diagnosis of hearing loss and appropriate intervention may help to maximize communication potential. Universal newborn screening would detect those patients. Careful monitoring of hearing level throughout life is essential, since individuals with inner ear abnormalities are at an increased risk for progressive hearing loss. Amplification with hearing aids is usually sufficient for auditory rehabilitation in individuals with inner ear abnormalities. In cases where hearing aids prove ineffective, cochlear implantation may provide improved communication outcomes. Multiple case, case series, and literature reviews have been written, which describe the outcomes of cochlear implantation in patients with various inner ear dysplasias. It appears that all degrees of cochlear dysplasia, ranging from incomplete partition to common cavity, can be implanted safely and auditory responses expected.15,16 It should be noted, however, that postoperative speech perception may be highly variable, and intraoperative and postoperative complication may occur. Absolute contraindications to cochlear implantation include Michel aplasia and absence of the auditory nerve. Bony dysplasias of the inner ear are associated with an increased risk of fistulous communication between the subarachnoid space and the middle ear cavity. These communications, called perilymphatic fistulas, can present with cerebrospinal otorhinorrhea or recurrent attacks of meningitis. Parents should be counseled about the early signs and symptoms of meningitis and vaccines against Haemophilus influenzae type B, and invasive pneumococcus should be strongly encouraged. Individuals with inner ear abnormalities are also at risk for perilymphatic fistulas as a result of head trauma or barometric insult. Perilymphatic fistulas are an abnormal connection between the inner and middle ear that allows perilymph fluid to escape into the middle ear compartment. Perilymphatic fistulas usually occur due to tears or ruptures of the oval window annulus, the round window membrane, or both. Symptoms include hearing loss, ranging from mild and fluctuating to sudden and profound; tinnitis; aural fullness; and vestibular symptoms such as vertigo, disequilibrium, lightheadedness, and intolerance to motion. References (Vestibulocochlear Dysplasias) 1. Graham JM, Phelps PD, Mechaels L: Congenital malformations of the inner ear and cochlear implantation in children: review and temporal bone report of common cavity. J Laryngol Otol 114(suppl 25):1, 2000. 2. Omerod FC: The pathology of congenital deafness. J Laryngol Otol 74:919, 1960. 3. Jackler RK, Luxford WM, House WF: Congenital malformations of the inner ear: a classification based on embryonogenesis. Laryngoscope 97(suppl 40):2, 1987. 4. Schuknecht HF: Pathology of sensorineural deafness of genetic origin. In: Deafness in Childhood. McConnell F, Ward PH, eds. Vanderbilt University Press, Nashville, TN, 1967, p 69. 5. Park AH, Kau B, Hutaling A, et al.: Clinical course of pediatric inner ear malformation. Laryngoscope 110:1715, 2000. 6. Schuknecht HF: Mondini dysplasia: a clinical and pathological study. Ann Otol Rhinol Laryngol 89(suppl 65):1, 1980. 7. Pyle GM: Embryological development and large vestibular aqueduct syndrome. Laryngoscope 110:1837, 2000.

369 8. Valvassori GE, Clemis JD: The large vestibular aqueduct syndrome. Laryngoscope 88:723, 1978. 9. Arcand P, Desrosiers M, Dube J, et al.: The large vestibular aqueduct syndrome and sensorineural hearing loss in the pediatric population. J Otolaryngol 20:247, 1991. 10. Sando I, Ikeda M: The vestibular aqueduct in patients with Meniere’s disease. Acta Otolaryngol 97:558, 1984. 11. Sennaroglu L, Yilmazer C, Basaran F, et al.: Relationship of vestibular aqueduct and inner ear pressure in Meniere’s disease and the normal population. Laryngoscope 111:1625, 2001. 12. Phelps PD, Lloyd GAS: Diagnostic Imaging of the Ear, ed 2. SpringerVerlag, London, 1990. 13. Antonelli PJ, Varela AE, Mancuso AA: Diagnostic yield of highresolution computed tomography for pediatric sensorineural hearing loss. Laryngoscope 109:1642, 1999. 14. McClay J, Tandy R, Grundfast K, et al.: Major and minor temporal bone abnormalities in children with and without congenital sensorineural hearing loss. Arch Otolaryngol Head Neck Surg 128:664, 2002. 15. Hoffman RA, Downey LL, Waltzman SB, et al.: Cochlear implantation in children with cochlear malformations. Am J Otol 18:184, 1997. 16. Woolley AL, Jenison V, Stroer BS, et al.: Cochlear implantation in children with inner ear malformations. Ann Otol Rhinol Laryngol 107: 492, 1998.

10.33 Prelingual Hearing Loss Definition

Prelingual hearing loss is a decrease in auditory acuity with onset in infancy or early childhood that produces potential for difficulty in communicating. Diagnosis

Hearing loss is classified as a decrease in auditory acuity and can be classified according to type, severity, and configuration. Types of hearing loss include (1) sensorineural, (2) conductive, and (3) mixed. Sensorineural hearing losses result from disorders of the cochlea or the auditory branch of the VIII cranial nerve. Conductive hearing losses are due to interference with the transmission of sound vibrations to the sensory apparatus. When both sensorineural and conductive hearing loss occur in the same ear, the hearing loss is considered mixed. The severity of hearing loss is divided into four levels: (1) mild, 25 to 40 dB, (2) moderate, 41 to 70 dB, (3) severe, 71 to 90 dB, and (4) profound, greater than 90 dB. Progressive forms of hearing loss are characterized by increasing severity of hearing loss over time in contrast to stable forms where the severity is constant and fluctuation forms where the severity waxes and wanes unpredictably. The extent to which low, middle, and high frequencies are affected determines the configuration of the hearing loss. Concerns of hearing loss in a child may arise from a failed newborn hearing screen, failure to reach developmental milestones, parental concern, or the presence of risk factors for hearing loss. Screening tests based on otoacoustic emission (OAE) or auditory brainstem response (ABR) can help to identify children with hearing loss, but the diagnosis is made by an audiologist after careful administration of a battery of age-appropriate tests to assess the integrity of the auditory system and to estimate the type, degree, and configuration of the hearing loss. Genetic forms of hearing loss can occur in isolation—nonsyndromic—or as a component of a genetic syndrome. Over 300 hearing loss syndromes have been reported. The characteristics

Table 10-14. Common hearing loss syndromes Hearing Loss Syndrome

Clinical Features

Gene or Locus

Alport

Hereditary nephritis (microscopic hematuria and/or proteinuria)

COL4A3 COL4A4 COL4A5

Branchio-oto-renal (BOR)

Preauricular pits, branchial fistulas or cysts, anomalous pinna

EYA1 Second locus at 1q31

Jervell and Lange-Nielsen

Syncopal episodes, prolonged QT interval on electrocardiogram

KVLQT1 KCNE1

Pendred

Thyroid goiter

SLC26A4

Stickler

Cleft palate, Pierre Robin sequence, flat midface, severe myopia, cataracts, marfanoid habitus

COL2A1 COL11A2 COL11A1

Treacher Collins

Downward-slanting palpebral fissures, coloboma of lower eyelid, ear tags, mandibular hypoplasia, anomalous pinna, cleft palate

TCOF1

Usher

Retinitis pigmentosa, vestibular abnormalities (Type 1 and 3)

Type Type Type Type Type Type Type Type Type Type Type

1A 14q32 1B MYO7A 1C USH1C 1D CDH23 1E 21q 1F PCDH15 1G 17q24-25 2A USH2A 2B 3q23-24.2 2C 5q14.3-21.3 3 USH3

Waardenburg

White forelock or premature graying of hair, fused eyebrows, bicolored iris or two eyes of different colors, telecanthus, pigmentary anomalies including partial albinism

Type Type Type Type

I PAX3 II MITF III PAX 3 IV EDNRB, EDN3, SOX10

Table 10-15. Genes responsible for nonsyndromic hearing loss Locus*

Gene

Autosomal Dominant Genes

Locus*

Gene

Autosomal Recessive Genes

DFNA1

DIAPH1, 5q31

DFNA2

GJB3 (Cx31), 1P34

DFNA3

DFNB1

GJB2 (Cx26), 13q11-q12 GJB6 (Cx30), 13q12

GJB2 (Cx26), 13q11-q12 GJB6 (Cx30), 13q12

DFNB2

MYO7A, 11q13.5

DFNB3

MYO15, 17p11.2

DFNA5

DFNA5, 7p15

DFNB4

SLC26A4, 7q31

DFNA6/DFNA14

WFS1, 4p16.1

DFNB6

TMIE, 3p21

DFNA8/DFNA12

TECTA, 11q22-q24

DFNB7/DFNB11

TMC1, 9q13-q21

DFNA9

COCH, 14q12-q13

DFNB8/DFNB10

TMPRSS3, 21q22.3

DFNA10

EYA4, 6q23

DFNB9

OTOF, 2p23-p22

DFNA11

MYO7A, 11q13.5

DFNB12

CDH23, 10q21-q22

DFNA13

COL11A2, 6p21.3

DFNB16

STRC, 15q15

DFNA15

POU4F3, 5q31

DFNB18

USH1C, 11p15.1

DFNA17

MYH9, 22q11.2

DFNB21

TECTA, 11q22-q24

DFNA22

MYO6, 6q13

DFNB22

OTOA, 16p12.2

DFNA28

TFCP2L3

DFNB29

CLDN14, 21q22.3

DFNA36

TMC1, 9q13-q21

DFNB30

MYO3A, 10p11.1

DFNA48

MYO1A, 12q13-q15

DFNB37

MYO6, 6q13

X-Linked DFN3 *As the chromosomal locations—loci—of the various genes responsible for nonsyndromic hearing loss are discovered, they are given specific designators based on their inheritance pattern and their order of discovery. Loci of genes causing autosomal dominant nonsyndromic hearing loss are given the designation DFNA and then numbered sequentially. Autosomal recessive loci have DFNB as their common designator and X-linked loci have DFN as their common designator. As of 2003 there were 51 dominant loci, 39 recessive loci, and eight X-linked loci reported.

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POU3F4, Xq21.1

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of several common syndromes are listed in Table 10-14 and have been thoroughly cataloged by Gorlin et al.1 The genes for many hearing loss syndromes have been identified, and in some cases genetic testing on a research or clinical basis is available. In the past, a diagnosis of nonsyndromic hearing loss was typically made as a diagnosis of exclusion after a careful history, physical exam, and laboratory testing failed to reveal evidence of a hearing loss syndrome or an environmental etiology. The identification of several genes that cause nonsyndromic hearing loss has opened the door for the development of genetic tests for nonsyndromic hearing loss (Table 10-15).2 However, the costeffectiveness of most of these tests, in open populations, is limited by the relatively small percentage of nonsyndromic hearing loss cases that are attributable to a particular gene. A notable exception is genetic testing for mutations in the connexin 26 gene (GJB2), which accounts for about 20–30% of congenital nonsyndromic hearing loss in the United States and is a common cause of nonsyndromic hearing loss worldwide.3,4 Testing for mutation of connexin 26 gene has become routine in the evaluation of infants and children with nonsyndromic hearing loss. Etiology and Distribution

Hearing loss may be caused by a number of environmental and disease-related factors, including viral and bacterial infections, prematurity, hypoxic insults, hyperbilirubinemia, exposure to ototoxic medications, and trauma. However, improvements in health care have resulted in significant reductions in the number of cases attributable to some of these etiologies, and the percentage of hearing loss cases with a genetic etiology continues to rise. In developed nations, at least half of severe childhood hearing loss can be attributed to genetic causes. Seventy percent of hereditary deafness is nonsyndromic. Syndromic forms of hearing loss account for the remaining 30% of inherited cases, or about 15% of the total. Prognosis, Prevention, and Treatment

Early detection and appropriate intervention may help to maximize communication outcomes in individuals with hearing loss. Universal neonatal hearing screening programs are effective in the early identification of many children with congenital hearing loss. Early Detection and Hearing Intervention (EDHI) programs are mandated in more than 35 states in the United States. Diagnosis of severe to profound hearing loss and implementation of early intervention portends better outcomes than diagnosis after 2 years of age. Failure to reach developmental milestones, parental concern, or the pres-

371

ence of risk factors for hearing loss, including stigmata of a hearing loss syndrome, should also trigger formal audiologic testing. Referral to a clinical geneticist is recommended when inherited forms of hearing loss are diagnosed or suspected.5 A clinical geneticist may be helpful in making the diagnosis of a hereditary syndrome when findings are equivocal or subtle. Families can also benefit from counseling available through a clinical geneticist in terms of prognosis and recurrence risk. Protocols for the evaluation of the child with hearing loss have been developed by expert groups.4,6 After hearing loss has been diagnosed, families should be encouraged to explore all available communication options and to choose a method that is consistent with the child’s corrected hearing level and their own willingness to learn new communication skills. Medical interventions may range from auditory amplification with hearing aids to cochlear implantation. The Food and Drug Administration approved cochlear implantation in children in 1990. Currently, over 50% of implants are placed in children. They are usually placed before age 2 years with excellent result in language.7 Limiting medical intervention and adopting a nonverbal form of communication is also a viable option. A large number of national, regional, and local organizations have been formed to provide information and support to families.8 References (Prelingual Hearing Loss) 1. Toriello HV, Reardon W, Gorlin RJ: Hereditary Hearing Loss and Its Syndromes, ed. 2. Oxford University Press, New York, 2004. 2. Van Camp G, Smith R: Hereditary Hearing Loss Homepage. http:// www.uia.ac.be/dnalab/hhh. 3. Green GE, Scott DA, McDonald JM, et al.: Carrier rates in the Midwestern United States for GJB2 mutations causing inherited deafness. JAMA 281:2211, 1999. 4. Kenneson A, Van Naarden Braun K, Boyle C: GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med 4:258, 2002. 5. Tomaski SM, Grundfast K: A stepwise approach to the diagnosis and treatment of hereditary hearing loss. Pediatr Clin N Am 46:35, 1999. 6. Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiology diagnosis of congenital hearing loss. Genet Med 4:162, 2002. 7. Francis HW, Mpankd JK: Cochlear implantation update. Pediatr Clin N Am 50:341, 2003. 8. Cherow E, Dickman DM, Epstein S: Organization resources for families of children with deafness or hearing loss. Pediatr Clin N Am 46:153, 1999.

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11 Nose M. Michael Cohen, Jr.

F

ormation of the nose is entirely dependent on development of the forebrain.1,2 Any insult that prevents the brain’s frontal development may disturb the anatomy of the nose. Nasal development first becomes evident histologically as thickenings of ectoderm, called olfactory placodes, by 26 days postfertilization (stage 12). The placodes are normally widely spaced on the anterolateral aspect of the frontal prominence (Fig. 11-1).1,3 The placodes become distinctive topographically by invaginating to form the nasal pits. With the rapid expansion of the forebrain, the nasal pits appear to converge toward the anterior midline. The lateral rims of the nasal pits (the nasolateral processes) fuse with the maxillary processes, forming the alae nasi. The medial rims of the nasal pits (nasomedial processes) grow faster than the nasolateral processes, extending anteriorly to form the ridge, tip, and columella of the nose and toward the oral plate to form the philtrum and medial portion of the upper lip. The nasomedial process fuses with the maxillary processes, which grow in from the lateral aspect of the face, completing a solid transverse bridge that separates the nose and mouth. The nasal pits become deeper by the overgrowth of the surrounding medial and lateral processes and by further invagination, eventually breaking through into the oral cavity. The anterior nares (nostrils) are now defined at the external opening of the nasal struc-

tures and the posterior nares (choanae) at the point of breakthrough into the oral cavity. The nasal air chamber thereafter becomes separated from the oral chamber by lengthening and fusion of the palatal shelves. Growth of the midfacial structures during the 3rd and 4th months advances the nose beyond the overhanging forehead and obliterates the frontonasal indentation. Further midface advancement continues at a slow pace until adult life. The landmarks for measuring nasal anatomy are shown in Figure 11-2.4 Growth of the nose is most rapid during the first 2 years of life; thereafter, growth assumes a slower rate until the skeleton is mature and then an even slower rate thereafter. Unlike many facial features, the nose continues to grow throughout life. Growth curves for nasal width, height (length), and protrusion and columella length during infancy and childhood are available.5,6

Fig. 11-1. Schematic of embryologic development of the nose and adjacent facial structures. The nasal placodes become evident by day 26 (B); nasal pits form in the placodes during week 5 (C); the lateral rims of the nasal pits merge with the maxillary processes during week 6 (D); the

medial rims of the nasal pits merge with each other, forming the nasomedial process during weeks 6 and 7 (E); and the nasomedial process merges with the maxillary processes to form the upper lip by week 8 (F,G). (Adapted from Patten1 and from Tuchmann-Duplessis and Haegel.3)

References 1. Patten BM: The normal development of the facial region. In: Congenital Anomalies of the Face and Associated Structures. S Pruzansky, ed. Charles C Thomas, Springfield, IL, 1961, p 11. 2. Stark RB, Ehrmann NA: The development of the center of the face with particular reference to surgical correction of bilateral cleft lip. Plast Reconstr Surg 21:177, 1958.

373

374

Craniofacial Structures

Fig. 11-3. Complete absence of the nose.

Fig. 11-2. Top: landmarks of nasal anatomy. Bottom: the configuration of the base, tip, and bridge of the nose as well as the columella, nares, and alae nasi, which vary widely. (From Hall et al.4)

3. Tuchmann-Duplessis H, Haegel P: Illustrated Human Embryology. Springer Verlag, New York, 1982. 4. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, New York, 1989. 5. Goodman RM, Gorlin RJ: The Malformed Infant and Child. Oxford University Press, New York, 1983. 6. Farkas LG, Munro IR: Anthropometric Facial Proportions in Medicine. Charles C Thomas, Springfield, IL, 1987.

11.1 Arhinia Arhinia is absence of the nose. An occasional blind dimple is present where the nostrils should be. Diagnosis is based on clinical inspection (Fig. 11-3). With complete absence of the nose, the site of the external nose is flat and covered with normal skin. The maxilla is hypoplastic, the palate highly arched, and the upper lip normal. The nasal cavity is completely absent, and there is bilateral bony choanal atresia.1 Occasional cases may be associated with microphthalmia, iris coloboma, hypertelorism, meningocele, or submucous cleft palate.2 All cases have been sporadic. The condition is extremely rare. Because of complete obstruction of the nasal air passage, respiratory difficulty and cyanosis occur, especially during feeding. However, the affected infant can survive, adjust to oral breathing, and develop normally. The two patients reported by Gifford et al. had minimal airway and feeding difficulties.3 Surgical establishment of a normal airway can be deferred, and a nasal prosthesis can be constructed. Intelligence is usually normal.

References (Arhinia) 1. Wang MKH: Congenital anomalies of the nose. In: Reconstructive Plastic Surgery, vol II, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1181. 2. Shubich I, Sanchez C: Nasal aplasia associated with meningocele and submucous cleft palate. Ear Nose Throat J 64:259, 1985. 3. Gifford GH Jr, Swanson L, MacCollum OW: Congenital absence of the nose and anterior nasopharynx. Report of two cases. Plast Reconstr Surg 50:5, 1972.

11.2 Unilateral Arhinia, Heminasal Aplasia Unilateral absence of one nostril occurs with an occasional blind dimple where a nostril should be. Unilateral arhinia is a different malformation than cebocephaly, which has a single midline nostril. Diagnosis is based on clinical inspection (Figs. 11-4 and 11-5). One nostril is absent and may be associated with a blind dimple, skin tag, or proboscis. There may be a scar or slight bony tubercle just above the inner canthus. Bony abnormalities in the involved area include absent cribriform plate, nasal septum deviated to the unaffected side, loss of structures of the lateral wall of the nasal chamber on the affected side, absence or hypoplasia of the paranasal sinuses on the affected side, absent nasal bone, and disrupted lacrimal bone. The ipsilateral olfactory tract and bulb are usually absent. The eye on the affected side may be microphthalmic, absent, or have various anomalies. Orofacial clefting has been associated with some cases.1,2 All cases have been sporadic, and the condition is extremely rare. Plastic surgical procedures and/or prosthesis should be considered. Intelligence is usually normal, unless there are associated central nervous system malformations. References (Unilateral Arhinia, Heminasal Aplasia) 1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001.

Nose

375 2. Wang MKH: Congenital anomalies of the nose. In: Reconstructive Plastic Surgery, vol II, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1181.

11.3 Small Nose

Fig. 11-4. Unilateral absence of the nose associated with absent eye and hypoplastic ear on the same side.

Fig. 11-5. Unilateral absence of the nose associated with nose tag, absent eye with low-set eyebrow, and craniofacial asymmetry.

A small nose measures 2 standard deviations (SD) or more below the mean for one or more standard nasal measurements. Nasal height is a vertical measurement between the base of the columella and the nasion (Fig. 11-2). Nasal width is the horizontal measurement between the outer margins of the alae nasi. Nasal protrusion (depth) is the measurement from the tip of the nose to the base of the columella. Standards for childhood nasal measurements have been published by Hall et al.1 The nose is one of the most variable of facial landmarks.2 In clinical practice the nose is rarely measured, and identification of the small nose is made subjectively. Flattening of the bridge of the nose, hypoplasia of the alae nasi, and anteversion of the nares are anatomic changes that can contribute to the impression that the nose is small. In most cases, the small nose is an isolated finding, representing the lowest 2.5% of the continuous distribution of nose sizes. In general, the configuration of the nose is more helpful in syndrome delineation than is size of the nose. Infants with prenatal exposure to warfarin have small noses with accentuation of the junction of the alae nasi and the tip of the nose (Fig. 11-6). The entire nose is recessed because of midface hypoplasia. In Hallermann-Streiff syndrome the nose is small and pointed, with very little subcutaneous tissue. A similar nose but with more soft tissue in the early years is present in progeria. A small nose with anteversion of the nares occurs in Aarskog, Robinow, de Lange, Williams, Pfeiffer, and a number of other

Fig. 11-6. Small nose with accentuation of the demarcation between the tip of the nose and the alae in an infant exposed prenatally to warfarin.

376

Craniofacial Structures

recognizable syndromes. A small nose with depression of the nasal bridge occurs in acrodysostosis (a form of Albright hereditary dystrophy), in many of the lysosomal storage disorders, and in most skeletal dysplasias that are detectable in the newborn period. The fact that the nose normally tends to have an underdeveloped nasal bridge and anteverted nares early in life lessens the diagnostic usefulness of these findings during this period. Underdevelopment of the alae nasi or a pinched appearance to the nose is present in Johanson-Blizzard, oculodentoosseous, Apert, whistling face, Schwartz-Jampel, Waardenburg, and femoral hypoplasia-unusual facies syndromes. References (Small nose) 1. Hall JG, Froster-lskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, New York, 1989. 2. Goodman RM, Gorlin RJ: Atlas of the Face in Genetic Disorders, ed 2. CV Mosby, St. Louis, 1977.

11.4 Nostril Coloboma

2. Stupka W: The etiology of lateral nasal clefts. Am J Pathol 26:1085, 1950. 3. Stutz L: Angeborene seitliche Nasenspalte verbunden mit gleichseitiger Choanalatresie. Ohrenheik 65:202, 1912. 4. Webster JP, Deming EG: The surgical treatment of the bifid nose. Plast Reconstr Surg 6:1, 1950.

11.5 Bifid Nose The nose may be bifurcated by a central groove (Fig. 11-8). Diagnosis is based on clinical inspection. Ocular hypertelorism with widening of the nasal bridge may be present in many cases.1–3 Median cleft of the upper lip may also occur (Fig. 11-9). This anomaly is present in some cases of frontonasal dysplasia.1 Bifurcation with a central groove in the nose probably results from infolding of the median nasal process. Cases are usually sporadic, and the condition is rare. Surgical repair is the appropriate treatment. References (Bifid Nose)

A nostril coloboma is a triangular cleft involving the ala of the nose. The diagnosis is based on clinical inspection. Lateral nasal clefting usually occurs on one side (Fig. 11-7). Either side may be affected. Bilateral nostril colobomas are rare. Associated anomalies include unilateral anophthalmia, lower lid coloboma, frontal glioma, and ocular hypertelorism.1–4 The defect may be caused by inadequate mesenchyme between the median and lateral portions of the nasal ridge. All cases have been sporadic, and the condition is rare. The appropriate treatment is surgical repair. References (Nostril coloboma) 1. Nash WG: Congenital absence of the right eye and fissure of the nose. Lancet 1:28, 1858.

Fig. 11-7. Nostril coloboma, frontal encephalocele, and ocular hypertelorism.

1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 2. Webster JP, Deming EG: The surgical treatment of the bifid nose. Plast Reconstr Surg 6:1, 1950. 3. DeMyer W: The median cleft face syndrome. Differential diagnosis of cranium bifidum occultum, hypertelorism, and median cleft nose, lip, and palate. Neurology 17:961, 1967.

Fig. 11-8. Bifid nose. Note also the hypoplastic ear and ocular hypertelorism.

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377

has been observed in a father and daughter and in two sisters.3 The treatment is surgical. References (Nostril Atresia) 1. Brown LG: Congenital and hereditary nasal deformity. Proc R Soc Med 22:523, 1929. 2. Panebianco G: Atresia congenita bilaterale incompleita delle narici. Otorinol Ital 27:286, 1929. 3. Washburn AC: Congenital atresia of the anterior nares. Report of two cases in sisters. Arch Otolaryngol 16:789, 1932.

11.7 Choanal Atresia

Fig. 11-9. Bifid nose in association with median orofacial clefting and ocular hypertelorism. (From DeMyer.3)

11.6 Nostril Atresia Nostril atresia is the failure of formation of one nostril. The diagnosis is based on physical examination. The nostril may be closed by membrane, cartilage, or, rarely, bone.1–3 The anomaly is rare, and most cases have been sporadic. However, the condition

Choanal atresia is congenital obstruction of the posterior choana or choanae. The clinical appearance varies widely, from cyanosis and respiratory distress to simple nasal discharge. Diagnosis is based on clinical examination and computed tomography (CT) scans. Bilateral choanal atresia results in complete nasal obstruction with immediate onset of respiratory distress at birth. Unilateral atresia rarely causes respiratory distress; the most common finding is unilateral mucoid discharge. Atresia may be simply membranous, membranous with a bony rim, or completely bony. The condition may be unilateral or bilateral and complete or incomplete.1,2 If a rubber catheter or metal probe cannot be passed more than 32 mm into the nostril, the presumptive diagnosis of choanal atresia can be made. The anomaly may be demonstrated with CT.1,2 The most commonly accepted theory for the pathogenesis of choanal atresia is failure of the nasobuccal membrane to break down. The condition occurs once in approximately 7000 livebirths. The male to female ratio is 1:2 and the unilateral to bilateral ratio is 2:1. Ninety percent are bony, and 10% are membranous. Associated anomalies occur in approximately 50% of the cases and include particularly the CHARGE syndrome (Table 11-1)3–19 Choanal

Table 11-1. Conditions with choanal stenosis or atresia Syndrome

Prominent Features

Causation Gene/Locus

Antley-Bixler4

Craniosynostosis, frontal bossing, humeroradial synostosis, femoral bowing, joint contractures

AR (207410)

Bamforth5

Bifid epiglottis or cleft palate, pili torti, hypothyroidism

Unknown

Braham: hyperostotic dysplasia

Progeroid features, cortical hyperostosis, symphalangism, dentin hypoplasia

Unknown (151050)

CHARGE7

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies or deafness

Sporadic (214800) CHD7, 8q12

Crouzon8

Craniosynostosis, proptosis, midface hypoplasia, beak nose

AD (123500)

Marshall-Smith9

Prominent forehead, growth and developmental failure, accelerated and dysharmonic bone age, early death Craniosynostosis, broad thumbs and halluces

Unknown

Schinzel-Giedion11

Midface retraction, growth and developmental retardation, wormian bones

AR (269150)

Treacher Collins

Lid coloboma, downward-slanting palpebral fissures, malar hypoplasia, ear anomalies, deafness

AD (154500)

Pfeiffer10

AD (101600)

Does not include the reports of Flannery12 (imperforate oropharynx-skeletal anomalies), Salinas et al.13 (craniosynostosis-lid colobomas-lower lip cleft), Seemanova et al.14 (microcephaly-immunodeficiency), Kaplan et al.15 (acro-cranio-facial dysostosis), Hurst et al.16 (cardiac defect-short stature-choanal atresia), Greenberg17 (choanal atresia-absent nipples), Goldblatt and Viljoen18 (radial defectchoanal atresia), and Edwards et al.19 (microphthalmia-microcephaly-brain anomalies).

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Craniofacial Structures

stenosis may also occur in a number of disorders, including hyperostotic skeletal dysplasias that affect the cranium.6,20,21 With unilateral choanal atresia, definitive surgical treatment can be carried out at any time during childhood. With bilateral involvement, an artificial airway is required. Rarely is tracheotomy necessary. Neonates are obligate nosebreathers. Mouthbreathing is a learned response, occurring approximately 4 to 6 weeks after birth. Prognosis is usually good, provided other abnormalities, particularly those of CHARGE syndrome, are not present.1,2 References (Choanal Atresia) 1. Converse JM, Wood-Smith D, Shaw WW: Congenital choanal atresia. In: Reconstructive Plastic Surgery. Principles and Procedures in Correction, Reconstruction and Transplantation, vol 2, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1163. 2. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 3. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 4. Escobar LF, Bixler D, Sadove M, et al.: Antley-Bixler syndrome from a prognostic perspective: report of a case and review of the literature. Am J Med Genet 29:829, 1988. 5. Bamforth JS, Hughes IA, Lazarus JH, et al.: Congenital hypothyroidism, spiky hair and cleft palate. J Med Genet 26:49, 1989. 6. Lenz WD, Majewski F: A generalized disorder of the connective tissues with progeria, choanal atresia, symphalangism, hypoplasia of dentine and craniodiaphyseal hypostosis. Birth Defects Orig Artic Ser X(12):133, 1974. 7. Siebert JR, Graham JM Jr, MacDonald C: Pathological features of the CHARGE association: support for involvement of the neural crest. Teratology 31:331, 1985. 8. Cohen MM Jr, MacLean RE: Craniosynostosis, Diagnosis, Evaluation, and Management, ed 2. Oxford University Press, New York, 2000. 9. Fitch N: The syndromes of Marshall and Weaver. J Med Genet 17:174, 1980. 10. Pfeiffer RA: Associated deformities of the head and hands. Birth Defects Orig Artic Ser XI(5):99, 1975. 11. Donnai D, Harris R: A further case of a new syndrome including midface retraction, hypertrichosis, and skeletal anomalies. J Med Genet 16:483, 1978. 12. Flannery DB: Syndrome of imperforate oropharynx with costovertebral and auricular anomalies. Am J Med Genet 32:189, 1989. 13. Salinas CF, Jorgenson RJ, Strickland A: Case report 38: colobomas of lower lids, malar hypoplasia, antimongoloid slant and clefting. Synd Ident IV(1):5, 1976. 14. Seemanova E, Passarge E, Beneskova D, et al.: Familial microcephaly with normal intelligence, immunodeficiency, and risk for lymphoreticular malignancies: a new autosomal recessive disorder. Am J Med Genet 20:639, 1985. 15. Kaplan P, Plauchu H, Fitch N: A new acro-cranio-facial dysostosis syndrome in sisters. Am J Med Genet 29:95, 1988. 16. Hurst JA, Berry AC, Tettenbom MA: Unknown syndrome: congenital heart disease, choanal stenosis, short stature, developmental delay, and dysmorphic facial features in a brother and sister. J Med Genet 26:407, 1989. 17. Greenberg F: Choanal atresia and athelia: methimazole teratogenicity or a new syndrome. Am J Med Genet 28:931, 1987. 18. Goldblatt J, Viljoen D: New autosomal dominant radial ray hypoplasia syndrome. Am J Med Genet 28:647, 1987. 19. Edwards JG, Lampert RP, Hammer ME, et al.: Ocular defects and dysmorphic features in three generations. J Clin Dysmorphol 2:8, 1984. 20. Schaefer B, Stein S, Oshman D, et al.: Dominantly inherited craniodiaphyseal dysplasia: a new craniotubular dysplasia. Clin Genet 30:381, 1986. 21. Gorlin RJ, Spranger J, Koszalka MF: Genetic craniotubular bone dysplasias and hyperostoses. A critical analysis. Birth Defects Orig Artic Ser V(4):78, 1969.

Fig. 11-10. Diprosopia with double nose. (From Gruber.3)

11.8 Polyrrhinia Polyrrhinia is partial or complete duplication of the nose. Diagnosis is based on clinical inspection. Two separate noses each with two nostrils may occur with diprosopia, a condition in which partial duplication of the face occurs (Fig. 11-10). Partial duplication may occur with lesser degrees of facial duplication. Supernumerary nostrils have been described, one above the other.1–3 All cases have been sporadic. The condition is extremely rare. Some cases of facial duplication are incompatible with life. An exception is the case reported by Obwegeser et al.4 in which extraordinary craniofacial reconstruction was carried out successfully. References (Polyrrhinia) 1. Lindsay B: A nose with supernumerary nostrils. Trans Pathol Soc Lond 57:329, 1906. 2. Tawse HB: Supernumerary nostril and cavity. Prac R Sac Med 13:28, 1919. 3. Gruber GB: Diprosopia triorbaria und Prosopothorakopagia (Bin Beitrag zur Frage teratologischer Abbildungen). Zbl Allg Path 108:546, 1966. 4. Obwegeser HL, Weber G, Freihoffei HP, et al.: Facial duplication—the unique case of Antonio. J Max-Fac Surg 6:179, 1978.

11.9 Proboscis Definition

A proboscis is a blind-ended, tubelike structure, commonly located in the midface.

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379

Fig. 11-11. Cyclopia (E, arrowheads) with proboscis (P). (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Diagnosis

Diagnosis is based on clinical inspection. There are four types: holoprosencephalic proboscis, lateral nasal proboscis, supernumerary proboscis, and disruptive proboscis. In holoprosencephaly, proboscis formation is found in many but not all cases of cyclopia (Fig. 11-11). It is formed in all cases of the rarely occurring ethmocephaly (Fig. 1112). In cebocephaly, no proboscis formation occurs per se, but a single-nostril nose is present. With median cleft lip, the nose is extremely underdeveloped, although no proboscis formation occurs.1 Lateral nasal proboscis represents incomplete formation of one side of the nose; it is found instead of a nostril (Fig. 11-13). The proboscis predicts absence of the ipsilateral olfactory tract

and bulb. The patient is frequently otherwise normal, although cleft palate may occur in some instances, and an occasional case has been reported with unilateral microphthalmia. When both nostrils are formed and a proboscis occurs additionally, it represents accessory proboscis formation arising from a supernumerary olfactory placode (Fig. 11-14). Rarely, a lateral proboscis located beyond the limits of the outer canthus has been reported.2–7 Disruptive proboscis formation can occur if an early embryonic hamartoneoplastic lesion arises in the primitive prosencephalon. Figure 11-15 shows bilateral nasal proboscides arising from an early embryonic hypothalamic hamartoblastoma.8 Etiology and Distribution

Fig. 11-12. Ethmocephaly.

With proboscis formation, the lateral nasal process fails to fuse with the median nasal process and with the maxillary process. It is etiologically and pathogenetically heterogeneous. Holoprosencephalic proboscis, lateral nasal proboscis, and supernumerary nasal proboscis are malformations. Proboscis may be considered a disruption when it arises from a hamartoneoplasia affecting the prosencephalon. Holoprosencephaly occurs with a frequency of 0.63 per 10,000 livebirths in nonchromosomal cases; it is obviously higher if chromosomal cases are included (Table 11-2). However, no accurate overall birth prevalence has been determined to date.1 Many cases of holoprosencephaly do not have proboscis formation. Other types of proboscis are rare. Prognosis and Treatment

Prognosis depends on the overall pattern of anomalies. If associated with holoprosencephaly, the prognosis is poor. For nonholoprosencephalic isolated proboscis formation, plastic surgical repair is indicated. References (Proboscis) 1. Cohen MM Jr: Perspectives in holoprosencephaly. Part I. Epidemiology, genetics, and syndromology of holoprosencephaly. Teratology 40:211, 1989. 2. Biber JJ: Proboscis lateralis. A rare malformation of the nose, its genesis and treatment. J Laryngol Otol 63:734, 1949.

380

Craniofacial Structures

Fig. 11-13. Two children with unilateral proboscis and normal nostril on the other side. (Left, courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE; right, courtesy of Dr. T. Coetzee, Pietermaritzburg, South Africa.)

Fig. 11-14. Lateral nasal proboscis in association with cleft lip/ palate. (From McLaren.5)

3. Antoniades K, Baraister M: Proboscis lateralis: a case report. Teratology 40:193, 1989. 4. Wang S, Wang Y, Roy FH: Proboscis lateralis, microphthalmos, and cystic degeneration of the optic nerve. Ann Ophthalmol 15:756, 1983. 5. McLaren LR: A case of cleft lip and palate with ploypoid nasal tubercle. Br J Plast Surg 8:57, 1956. 6. Rontal M, Duritz G: Proboscis lateralis: case report and embryologic analysis. Larynogoscope 87:996, 1977.

Fig. 11-15. Bilateral nasal proboscides. Diffuse pigmentation of the conjunctiva of the right eye is present. The left eye is anophthalmic. Proboscides resulted from disruption by a large, early embryonic, hamartoneoplastic lesion developing between the two cerebral hemispheres. (From Gitlin and Behar.8) 7. Cohen MM Jr, Jirasek JE, Guzman RT, et al.: Holoprosencephaly and facial dysmorphia: nosology, etiology and pathogenesis. Birth Defects Orig Artic Ser VII(7):125,1971. 8. Gitlin G, Behar AJ: Meningeal angiomatosis, arhinencephaly, agenesis of the corpus callosum and large hamartoma of the brain with neoplasia in an infant having bilateral nasal proboscis. Acta Anat 41:56, 1960.

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381

Table 11-2. Conditions with holoprosencephaly Monogenic holoprosencephaly

Aicardi (XLD, 304050) Autosomal dominant holoprosencephaly (AD, 157170) Autosomal recessive holoprosencephaly (AR, 236100) Grote: holoprosencephaly-polydactyly-heart defect (uncertain) Holoprosencephaly-fetal hypokinesia (XLR, 306990) Martin: holoprosencephaly-skeletal anomalies (AD) Meckel (AR, 249000) Steinfeld: limb defects-visceral defects-holoprosencephaly (AD) Velocardiofacial (AD, 19430) Environmental holoprosencephaly

Maternal diabetes Chromosomal holoprosencephaly

Triploidy Trisomies 13, 18 Duplication 3p Deletions 13q, 18p, 7(pter q32) Uncommonly in trisomies 20, 21, 22; duplications or deletions of chromosomes 1,2,5,6,9,11,14,21,22,X; and XXX Holoprosencephaly of unknown cause

Aprosencephaly-radial aplasia-genital defects Hartsfield: holoprosencephaly-ectrodactyly Holoprosencephaly-ectopic cordis-embryonal tumors

Fig. 11-16. Notching of both nostrils in a child with ocular hypertelorism and unilateral microphthalmia. (From Sedano et al.9)

Majewski-like chondrodysplasia Pseudotrisomy 13 Holoprosencephaly-neural tube defect Holoprosencephaly-frontonasal dysplasia From Cohen.1

11.10 Noses of Distinction A number of minor anomalies affect the nose. The nose may be large or small, short or long, thick or thin, symmetric or asymmetric, and curved, humped, or concave. The nostrils may be anteverted. The nasal septum may extend below the alae. The nasal tip may be pointed, round, or broad. The alar wings may be hypoplastic or notched (Fig. 11-16). The nostrils may be of similar size, or one nostril may be larger. The nasal bridge may be high or low and wide or narrow. Rarely, a skin tag may appear on the nose or in close proximity.1,2 Unusual Noses

Wrinkling of the nose (Fig. 11-17) is encountered on occasion and is usually associated with ocular hypertelorism. It may also occur with frontonasal dysplasia. Its pathogenesis is unknown.3 Potato nose, a perjorative term, is used here to describe a condition that is only known by that term in the literature. The

Fig. 11-17. Wrinkling of the nose. (Courtesy of Dr. H. Tsur, Tel Aviv, Israel.)

nose is characterized by marked broadening of a mobile septum, nasal tip, and nasal bridge. The outer wall of the nose has a balloon shape. The nasal bones are absent, and the lateral nasal walls are composed of an ill-defined cartilaginous mass. A tear duct anomaly may be associated. The condition has autosomal dominant inheritence.4 Orangutan nose, a perjorative term, is the only one known to describe an unusual broadening and flattening of the nose. The

382

Craniofacial Structures

Fig. 11-18. Erupted tooth in nostril.

nasal root is short, and the nasal bridge is broad and grooved with a flat nasal tip. The nostrils are widened and directed outward. Hyperpneumatization of the nasal cavity, paranasal sinuses, and mastoids are characteristic. The pharynx is hypoplastic. Myoclonic torsion dystonia is a feature, and the condition probably has autosomal dominant inheritance.5 Nasal teeth occur rarely when a tooth bud develops in the region of the nose (Fig. 11-18). Syndromic Noses

In Binder syndrome, the nasofrontal angle is absent and the nose is hypoplastic with flattening of the alae and nasal tip (Fig. 11-19). Radiographically there is aplasia or hypoplasia of the anterior nasal spine, together with localized maxillary hypoplasia. Although the face may appear ‘‘arhinencephaloid,’’ no brain abnormalities are observed. The sense of smell is completely normal. The overwhelming majority of cases are sporadic.6,7 In chondrodysplasia punctata, the nose is hypoplastic. There are various forms of the

disorder, including an X-linked dominant type, an X-linked recessive type, and an autosomal recessive form.6 Craniometaphyseal dysplasia is a monogenic condition with both autosomal dominant and autosomal recessive forms. Although the condition is present in the zygote, the root of the nose begins to broaden, with an elevated wing of bone gradually extending over the nasal bridge to the zygomas from the 1st year of life until the time of adolescence (Fig. 11-20). Increasing bony sclerosis narrows the nasal lumen, leading to obstruction.6 Craniorhiny combines craniosynostosis with unusual nasal abnormalities. Characteristic features include wide nose, anteverted nostrils, nasal hirsutism, and bilaterally symmetric spherical cystlike formations with small fistulas located just below the nose (Fig. 11-21). Inheritance is autosomal dominant.8 In the de Lange syndrome, primordial growth deficiency occurs together with mental retardation, anomalies of the extremities, and a characteristic facial appearance (Fig. 11-22). Most cases are sporadic. The nose is small with a flat nasal bridge. The nostrils are anteverted. The fetal face syndrome, also known as Robinow syndrome, consists of a characteristic facial appearance, mesomelic brachymelia of the arms, short fingers, and hypoplastic genitalia. An autosomal dominant form of the disorder occurs more commonly than an autosomal recessive form.6 The nose is short and broad, and the nostrils are upturned and anteverted (Fig. 11-23). In the prenatal warfarin syndrome, a characteristic pattern of craniofacial alterations and other defects may be observed. The midface is hypoplastic, with severe underdevelopment of the nose (Fig. 11-6). Choanal atresia may be present.6 Frontonasal dysplasia is characterized by ocular hypertelorism, broad nasal root, lack of nasal tip, widow’s peak, and anterior cranium bifidum occultum. Associated defects may include midline clefting of the nose (Fig. 11-24). The nasal alae may be notched or colobomatous. Most cases are sporadic.6,9 The Hallermann-Streiff syndrome is a distinct disorder consisting of dyscephaly, hypotrichosis, microphthalmia, cataracts, beaked nose, micrognathia (Fig. 11-25), and proportionate short stature. Virtually all cases have been sporadic to date.6

Fig. 11-19. Binder syndrome with hypoplastic flattened nose and absence of nasofrontal angle. (Courtesy of Dr. Robert J. Gorlin, University of Minnesota School of Dentistry, Minneapolis.)

Nose

Fig. 11-22. De Lange syndrome. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Fig. 11-20. Craniometaphyseal dysplasia with bony widening of the root of the nose.

Fig. 11-21. Craniorhiny. (From Mindikoglu et al.8)

Fig. 11-23. Fetal face syndrome (Robinow syndrome). Fig. 11-24. Frontonasal dysplasia. (From Sedano et al.9)

383

384

Craniofacial Structures

Fig. 11-25. Hallermann-Streiff syndrome.

Features of the Johanson-Blizzard syndrome include a characteristic facial appearance, severe mental and somatic retardation, sensorineural hearing loss, and malabsorption due to pancreatic insufficiency. The nose is characteristic, with severely hypoplastic or aplastic nasal alae (Fig. 11-26). The disorder has autosomal recessive inheritance.6 The oral-facial-digital-syndrome, type I, is characterized by hyperplastic frenulae, multilobulated tongue, hypoplasia of the nasal alar cartilages, median pseudocleft of the upper lip, asymmetric cleft palate, and various malformations of the digits. In-

Fig. 11-26. Johanson-Blizzard syndrome with hypoplasia of the alae nasi. (Courtesy of Dr. D.W. Day, Dallas, TX.)

heritance is X-linked dominant limited to females and lethal in males. Nasal alar flaring is absent, and in some instances nostril size may be asymmetric, being more hypoplastic on one side.6 In Potter sequence, compression deformities of the face and limbs occur together with pulmonary hypoplasia, wrinkling of the skin, and growth restriction resulting from oligohydramnios. The condition is both etiologically and pathogenetically heterogeneous.6 The nose may be blunted, with a downturned nasal tip (Fig. 11-27). Autosomal dominant rhiny is a localized disorder affecting the midface.8 The nose is extremely short, with upturned small nares facing directly anteriorly (Fig. 11-28).

Fig. 11-27. Craniofacial profile in Potter sequence showing flattened nasal tip and prominent alae nasi. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

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Fig. 11-28. Rhiny. (From Mindikoglu et al.8)

The constellation of broad thumbs and halluces, characteristic facial dysmorphism, growth retardation, and mental deficiency make up the Rubinstein-Taybi syndrome. The overwhelming majority of cases are sporadic.6 The nasal bridge is broad and the nose beaked, with the nasal septum extending below the alae (Fig. 11-29). Trichorhinophalangeal syndrome (TRP) is characterized by cone-shaped epiphyses, sparse and fine hair, bulbous nose with lack of alar flare (Fig. 11-30), and variable growth retardation. Vertical transmission has been demonstrated in a great many families, although horizontal transmission also occurs. It has been conclusively demonstrated that TRP type I is due to deletion of 8q24.12. The more severe TRP type II is due to a larger deletion.6

Fig. 11-30. Trichorhinophalangeal syndrome.

Williams syndrome consists of characteristic facial appearance, mental retardation, growth deficiency, and cardiovascular anomalies.6 The midface is flat, the nasal bridge is depressed, the nares are anteverted, and the philtrum is long (Fig.11-31). References (Noses of Distinction) 1. Cohen MM Jr: Noses nobody knows. Proc Greenwood Genet Center 6:183, 1987.

Fig. 11-29. Rubinstein-Taybi syndrome.

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Craniofacial Structures

References (Deviation of the Nasal Septum) 1. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 2. Gray LP: Deviated nasal septum, incidence and etiology. Ann Otol Rhinol Laryngol 87 (suppl):50, 1978.

11.12 Turbinate Deformity Diagnosis is based on clinical examination. When the nasal septum is displaced, there may be overdevelopment of the inferior or middle turbinates. In addition, if the ethmoid air cells invade the middle turbinate, a rounded bulbous configuration may occur and create nasal obstruction on one side.1 Overdevelopment of the turbinates is compensatory to severe, long-standing displacement of the nasal septum. Surgical repair may be performed for severe involvement. Reference (Turbinate Deformity) 1. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718.

Fig. 11-31. Williams syndrome. (Courtesy of Dr. John M. Opitz, Salt Lake City, UT.)

2. Cohen MM Jr: The Child With Multiple Birth Defects. Raven Press, New York, 1982. 3. Cohen MM Jr: Personal observations. 4. Nieuwenhuijse AC: Continuation of the pedigree of hereditary potato nose (Benjamin-Stibbe). Acta Oto-Laryngol 38:112, 1950. 5. Benedek L, Rakonitz E: Heredopathic combination of a congenital deformity of the nose and of myoclonic torsion dystonia. J Nerv Ment Dis 91:608, 1940. 6. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 7. Olow-Nordenram M: Maxillonasal dysplasia (Binder’s syndrome): a study of craniofacial morphology, associated malformations and familial relations. Swedish Dent J Suppl 47:1, 1987. 8. Mindikoglu AN, Partington MW, Cohen MM Jr: Noses nobody knows—for real: rhiny and craniorhiny. Am J Med Genet 40:250, 1991. 9. Sedano HO, Cohen MM Jr, Jirasek J, et al.: Frontonasal dysplasia. J Pediatr 76:906, 1970.

11.11 Deviation of the Nasal Septum The nasal septum is considered to be deviated when it has significant asymmetry. Diagnosis is based on a clinical examination. If septal deviation is significant, particularly in association with turbinate deformity, blockage of the nasal passage may occur on one side.1 Approximately 80% of individuals have at least some deformity of the nasal septum. Significant deviation is much less common.1 Deviation may be due to intrauterine constraint or may result from a birth canal injury. Gray2 found septal deformities in 4% of infants born with normal vaginal deliveries and 13% for difficult deliveries. In contrast, infants delivered by cesarean section rarely had septal deviation. Most newborn nasal deformities are either self-correcting or can be corrected by gentle manipulation.1

11.13 Arrhinencephaly Arrhinencephaly is agenesis of the olfactory tracts and bulbs without more extensive holoprosencephalic involvement. Diagnosis is based on neurologic testing for anosmia, on recognition of a syndrome with absent olfactory tracts and bulbs, or as an autopsy finding. Magnetic resonance imaging scans can be confirmatory, particularly during infancy. Pathogenesis is based on failure of development of the olfactory bulbs. It is etiologically heterogeneous and occurs in various conditions listed in Table 11-3.1 The frequency has been estimated as one in 2500 births. Prognosis depends on diagnosis of the overall condition. Mental deficiency may be a feature in some cases. Other cases may not be compatible with life. Associated malformations may require surgical treatment, depending on various factors.1 Reference (Arrhinencephaly) 1. Cohen MM Jr.: Perspectives on holoprosencephaly: part I. Epidemiology, genetics, and syndromology. Teratology 40:211, 1989.

11.14 Hemangioma of the Nose Hemangioma of the nose is a benign vascular tumor affecting the soft tissues. Diagnosis is based on clinical examination. Hemangiomas may be capillary, cavernous, mixed, hypertrophic, or juvenile (Figs. 11-32 and 11-33). Capillary or mixed hemangiomas are readily diagnosed by the strawberry-reddened skin surface of the lesion on the nose. Pure cavernous lesions may be distinguished by bluish tinge, soft texture, diffuse outline, and collapsibility.1,2 Although hemangiomas commonly occur in the head and neck region, they only infrequently involve the nose.1 Nasal involvement may occur with Sturge-Weber angiomatosis and with Roberts syndrome.

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Table 11-3. Conditions associated with arhinencephaly Syndrome

Prominent features

Causation

Anosmia, isolated, type I

None

XLR

Anosmia, isolated, type II

None

AD

Anosmia-humeroradial synostosis

Humeroradial synostosis, Robin anomaly

Uncertain

Arhinencephaly-Di George

Cardiac defects, absent or hypoplastic thymus and parathyroid

Heterogeneous

Arhinencephaly-Goldenhar

Ocular, auricular, mandibular, and vertebral anomalies

Unknown, but heterogeneous

Campomelic dysplasia

Globular head, cleft palate, bowed long bones, lethal

AR

Chromosome anomalies

Various anomalies and arhinencephaly seen in dup 1q, 6p, 6q, and 16q; tetrasomy 12p; and XXXXY

Chromosomal

Fitch

Absent corpus callosum, hydrocephaly, diaphragmatic defect, ventricular septal defect, absent fingernails

Uncertain

Johnson

Dysplastic ears, deafness, alopecia, hypogonadism

Kallmann, type I

Ocular hypertelorism, mental retardation, hypogonadism, unilateral renal agenesis

XLR

Kallmann, type II

Hypogonadism, diabetes mellitus, deafness

AR

Perrin

Ichthyosis, hypogonadism, mental retardation

XLR

Va´radi

Cleft lip and palate, tongue nodule, polydactyly, heart defect, growth and mental retardation

AR

From Cohen.1

Fig. 11-32. Flat hemangiomatous lesions of midline involving the nose. Patient also had complete absence of all four limbs.

Conservative management with careful observation is the treatment of choice for most lesions, because they tend to regress. Surgical treatment is necessary for rapidly invasive lesions or for those with involvement of contiguous structures causing respiratory embarrassment.1

Fig. 11-33. Hemangioma of nose, causing enlargement.

388

Craniofacial Structures

References (Hemangioma of the Nose) 1. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 2. Wang MKH, Macomber WB: Congenital tumors of the nose. In: Reconstructive Plastic Surgery: Principles and Procedures in Correction, Reconstruction and Transplantation, vol 2, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1169.

11.15 Dermoid Cyst of the Nose A dermoid cyst of the nose is a benign tumor containing ectodermal and mesodermal elements. The diagnosis is based on physical examination. Magnetic resonance imaging and computed tomography scanning should be carried out and can detect rare intracranial extension through a bony defect. A dermoid may present as an external nasal mass, an intranasal mass, a dermoid sinus without a cyst, a dermoid cyst without a fistula, or an extracranial/intracranial mass. A dimple, indentation, or pit with an extruding hair occurs commonly. Lesions are firm, noncompressible, and occasionally lobulated.1–3 Dermoids represent embryonic defects. Theories include failure of neuropore closure and abnormal obliteration of the prenasal space. Most cases occur sporadically, although a familial tendency has rarely been reported. Nasal dermoids account for about 10% of all dermoids in the head and neck region. There is a slight male predominance. Complete surgical excision is necessary to prevent progressive expansion, infection, or fistula formation. Plastic surgical reconstruction may be required.1–3 References (Dermoid Cyst of the Nose) 1. Crawford H, Maguire C, Georgiade N, et al.: Dermoid cysts of the nose presentation of 7 cases. Plast Reconstr Surg 16:237, 1955. 2. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 3. Wang MKH, Macomber WB: Congenital tumors of the nose. In: Reconstructive Plastic Surgery: Principles and Procedures in Correction, Reconstruction and Transplantation, vol2, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1169.

Fig. 11-34. Frontonasal encephalocele in a 10-month-old infant exposed prenatally to hydantoin.

11.16 Glioma of the Nose A glioma of the nose is a tumor composed of neuroglia at some stage of its development that involves the nose. Diagnosis is based on clinical examination. Computed tomography (CT) or magnetic resonance imaging scans should be used to rule out intracranial involvement. Extranasal gliomas appear most often near the root of the nose. They are smooth, firm, and noncompressible. Intranasal gliomas are reddish, firm, and polypoid. Large gliomas involving the nasal cavity may result in nasal obstruction and septal deviation. Ocular hypertelorism may be associated. Approximately 15% of intranasal gliomas are connected by a fibrous stalk to the dura through the cribriform plate of the ethmoid bone.1–4 The etiology of nasal gliomas is unknown. Males are more frequently affected than females, with a 3:1 ratio. Extranasal lesions occur in 60%, intranasal lesions in 30%, and combined lesions in 10%.2 Surgical intervention is required. An extracranial approach is sufficient unless CT reveals a bony defect in the skull. References (Glioma of the Nose) 1. Dawson RLG, Muir IFK: The fronto-nasal glioma. Br J Plast Surg 8:136, 1955. 2. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 3. Walker EA, Resler DR: Nasal glioma. Laryngoscope 73:93, 1963. 4. Wang MKH, Macomber WB: Congenital tumors of the nose. In: Reconstructive Plastic Surgery: Principles and Procedures in Correction, Reconstruction and Transplantation, vol 2, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1169.

11.17 Encephalocele Involving the Nose Encephalocele involving the nose consists of herniation of brain tissue through an anterior defect in the skull bones. Diagnosis is by clinical examination together with computed tomography or magnetic resonance imaging. Most cases present in the midline, and some type of bony defect is invariably present (Fig. 11-34). Sincipital encephaloceles may present nasofrontally, nasoethmoidally, or

Nose

nasoorbitally. Large anterior encephaloceles may be associated with ocular hypertelorism. Basal encephaloceles may herniate through the cribriform plate, superior orbital fissure, or posterior clinoid fissure. Lesions may be transethmoidal, sphenoethmoidal, transsphenoidal, and sphenoorbital. Sphenoethmoidal lesions may be associated with hypertelorism and hypothalamic-pituitary dysfunction.1,2 Although the pathogenesis of encephaloceles is not certain, two views predominate. The first is that these neural tube defects are primary malformations, and the second is that they represent disruptive defects secondary to rupture of a distended neural tube. Nasofrontal and basal encephaloceles are very uncommon. Nasal

389

encephaloceles occur in 1 per 35,000 livebirths, but are found in 1 per 6000 births in Southeast Asia. Surgical repair of these defects is required. Prognosis depends on size and extent of the lesion together with associated anomalies. Mental deficiency is common. Associated anomalies occur in 30–40% of cases. References (Encephalocele Involving the Nose) 1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 2. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718.

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12 Lips Marilyn Jones

W

hen reduced to the simplest construct, the human face forms from five mounds of tissue that surround the stomodeum or future mouth. The largest is the central and rostrally located frontonasal process that will give rise to the forehead, the nose, the central portion of the upper lip, and the premaxilla or primary palate. Lateral to the frontonasal process are the paired maxillary processes that form the cheeks, the secondary palate, and the lateral portion of the upper lip. The paired mandibular processes form the lower jaw and lower lip. The maxillary and mandibular processes are derivatives of the first pharyngeal arch. Over the last 10 years much has been learned about the genes that direct the process of facial formation as well as the interactions among cells that populate the face.1–4 In the embryonic disc, the ectodermal layer of the oropharyngeal membrane is dorsally oriented and attached directly to the underlying endoderm (Fig. 12-1). Growth of the overlying neural tissue causes cephalic folding and swings the oropharyngeal membrane into the embryonic interior where it forms the stomodeum (by stage 12, or about 26 days) and persists briefly as the cephalic-most limit of the foregut. Externally, the stomodeum becomes surrounded by the five advancing facial processes outlined above (Fig. 12-2). The mesenchyme that populates the facial primordial derives primarily from neural crest cells migrating from hindbrain neuromere segments just prior to neural tube formation.5 Migration of neural crest cells is spatially and temporally regulated by homeobox genes that create a positional identity for them. Based on interactions with various epithelial and extracellular matrix substances, crest cells give rise to neural, skeletal, connective, dermal, and dental structures in the face. Voluntary muscles of the face derive from paraxial (somatic) mesoderm. A large number of developmental genes, some of which are candidates for nonsyndromic cleft lip and cleft palate, are involved in these processes. At the inferolateral edges of the frontonasal process, nasal placodes begin to invaginate (by stage 11, or about 24 days). The placodes appear to sink into the surrounding tissues as the medial nasal and lateral nasal processes proliferate. By stage 16, or about 37 days, the upper lip has formed on the lateral aspect of the stomodeum. By stage 17, or 41 days, the maxillary process of the first pharyngeal arch has made contact with the medial nasal process of the frontonasal process establishing continuity of the upper lip. This process requires loss of the contacting surface epithelial cells

Fig. 12-1. Schematic of cranial region in stage 10 (A) and stage 12 (B) embryos showing the change in orientation of the oropharyngeal membrane brought about by the cephalic fold. (Reprinted with permission from Moore KL: The Developing Human, ed 4. CV Mosby Co, St. Louis, 1988.)

391

392

Craniofacial Structures

Fig. 12-2. Schematic of facial features of embryos at stages 15 (33 days), 18 (45 days), 21 (52 days), and 23þ (60 days). The lip is a mosaic structure composed of the frontonasal (1), left maxillary (2), left mandibular (3), right mandibular (4), and right maxillary (5)

processes. (Adapted from Tuchmann-Duplessis H, Haegel P: Illustrated Human Embryology, vol 2. Springer-Verlag, New York, 1972, and from Patten BM: Human Embryology, ed 3. McGraw-Hill, New York, 1968.)

(the nasal fin) either through cellular transformation or apoptosis. Failure of this process to occur results in cleft lip. Once continuity is established, the central premaxillary process is invaded by cells from the maxillary process.6 The structure of the philtrum and the characteristic Cupid’s bow configuration of the upper lip are a function of orientation of the labial levators and thickened dermal appendages.7 The palate is formed by the coalescence of three structures: the medial, anterior frontonasal process that forms the primary palate (the premaxillary segment with the four upper incisors as well as the nasal septum) and the two lateral palatal processes projecting from the maxillary part of the first pharyngeal arch. Thus, most of the hard and soft palate is derived from the first arch. After the upper lip has formed, the tongue occupies the stomodeum.8 During the 8th week postconception, growth of the stomodeum and initiation of oromuscular movement drops the tongue below the level of the palatal shelves, allowing horizontal movement of palatal shelf tissue. Contact is rapidly established between the anterior primary palate, the lateral palatal shelves, and the nasal septum. The epithelial tissue covering each of these processes is transformed into mesenchyme, allowing fusion to occur (Fig. 12-3). A number of patterning and signaling genes are involved in this process. The soft palate is invaded by mesenchymal tissue from the first and fourth pharyngeal arch to give rise to the tensor palatini, levator palatini, and uvular muscles, which have complex innervation.9

Facial clefts may be classified either considering pathogenesis (what went wrong during the process of morphogenesis) or etiology (what caused the problem to begin with). Both approaches have relevance with respect to prognosis and recurrence risk. When considering pathogenesis (Fig. 12-4), clefts may be classified either as malformations (errors in normal morphogenesis), deformations (alteration secondary to constraint of a structure that has differentiated normally), disruptions (destruction of a previously normally formed structure), or dysplasias (abnormal organization and growth of cells).10 Malformations are structural abnormalities that represent failures of normal structural development. They are present at birth and do not resolve or improve spontaneously. Most have a multifactorial etiology, as discussed below. Deformations may improve over time as evidenced by the catch-up growth of the chin in many children with Robin type clefts. Disruptions generally have a very low risk for recurrence. Dysplasias need longitudinal follow-up for persistence of the dysplastic process. Neoplasms may develop in some dysplasias. The vast majority of clefts occur as a consequence of malformation. Of these roughly two-thirds will represent failure of the medial nasal and maxillary processes to fuse (cleft lip with or without cleft palate [CL/P]) and one-third will represent failure of the palatal shelves to fuse (cleft palate [CP]). Other mechanisms are represented less frequently. Among over 1700 children presenting to a treatment clinic over a 23-year period in San Diego, 10 children had midline clefts of the lip in association with holoprosencephaly compared

Fig. 12-3. Schematic of closure of secondary palate. (Reprinted with permission from Moore KL: The Developing Human, ed 4. CV Mosby Co, St. Louis, 1988.)

Lips

393

Fig. 12-5. Isolated incomplete median cleft lip (left). Complete median cleft lip associated with holoprosencephaly (right). Fig. 12-4. Pathogenesis of facial clefting.

to ~1000 with CL/P and 500 with CP. The other three mechanisms were represented much less frequently than malformation. In the same population, roughly 100 had clefts classified as Robin type or secondary to micrognathia, 40 had disruptions (amnion rupture sequence or clefts as part of a pattern with a presumptive vascular mechanism), and four had palatal tumors including two nasal gliomas, one teratoma, and one probable epignathus (dysplasia). References 1. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams and Wilkins, Philadelphia, 2004. 2. Sperber GH: Craniofacial embryogenesis: normal developmental mechanisms. In: Understanding Craniofacial Anomalies: The Etiopathogenesis of Craniosynostoses and Facial Clefting. MP Mooney, MI Siegel, eds. Wiley-Liss, Inc., New York, 2002, p 31. 3. Sperber GH: Formation of the primary palate and palatogenesis: closure of the secondary palate. In: Cleft Lip and Palate: From Origin to Treatment. DF Wyszynski, ed. Oxford University Press, New York, 2002, p 5. 4. Moore KL, Persaud TVN, Schmitt W: The Developing Human: Clinically Oriented Embryology. WB Saunders Company, Philadelphia, 1998. 5. LaBonne C, Bronner-Fraser M: Molecular mechanisms of neural crest formation. Annu Rev Cell Dev Biol 15:81, 1999. 6. Viers W: Transmedian innervation of the upper lip: an embryologic study. Laryngoscope 83:1, 1973. 7. Namnoum JD, Hisley KC, Graepel S, et al.: Three-dimensional reconstruction of the human fetal philtrum. Ann Plast Surg 38:202, 1997. 8. Kimes KR, Mooney MP, Siegel MI, et al.: Size and growth rate of the tongue in normal and cleft lip and palate human fetal specimens. Cleft Palate Craniofac J 28:212, 1991. 9. Cohen SR, Chen L, Trotman CA, et al.: Soft palate myogenesis: a developmental field paradigm. Cleft Palate Craniofac J 30:441, 1993. 10. Spranger JW, Benirschke K, Hall JG, et al.: Errors of morphogenesis: concepts and terms. J Pediatr 100:160, 1982.

12.1 Median Cleft Lip Definition

Median cleft lip is the deficiency of the central portion of the lip, including the central vermillion, the philtrum, the premaxilla, and the nasal columella. The defect may range from a subtle notch in the middle of the lip to absence of the premaxilla with a flaplike nose.

holoprosencephaly are increasingly detected with prenatal ultrasonographly.1 The majority of midline clefts of the lip occur as part of the holoprosencephaly sequence.2,3 Early loss of midline structures in the developing prosencephalon causes this pattern of malformation. The phenotype ranges from cyclopia at the severe end of the spectrum, to varying degrees of ocular hypotelorism with a flaplike nose, an absent columella, and midline cleft lip, to a single central incisor. Holoprosencephaly is etiologically heterogeneous and may occur in chromosomal abnormalities (e.g., trisomy 13 and deletion 18p) and single gene disorders (e.g., Smith-Lemli-Opitz syndrome). It may be caused by mutations in a variety of genes important in early brain formation (e.g., sonic hedgehog and zinc finger protein 2) or by teratogenic exposures in early pregnancy (e.g., poorly controlled maternal diabetes). The presence of a midline cleft lip should raise concerns about a serious defect in brain development. Rarely, midline clefts of the lip occur in otherwise normal individuals, in Ellis-van Creveld syndrome, and in the oral-facialdigital syndromes associated with accessory frenulae and lobulations of the tongue. Table 12-1 lists syndromes associated with midline clefts of the lip. Prognosis, Treatment, and Prevention

The most significant factor in determining the outcome of midline cleft lip is the presence of a severe defect in brain development.4 Infants with holoprosencephaly have a reduced lifespan. Survivors have varying degrees of cognitive impairment, seizures, and diabetes insipidus.5 A variety of surgical techniques have been employed for reconstructing the lip depending upon the degree of tissue deficiency. Elias and colleagues outlined a strategy for approaching reconstruction in this population.6 Prevention depends on the etiology of the midline cleft. Holoprosencephaly secondary to poorly controlled maternal diabetes may be prevented with proper management of the diabetes prior to subsequent conception. Prenatal diagnosis with chorionic villus sampling (CVS) or amniocentesis could be offered in cases of chromosome abnormalities. First-degree relatives of infants with holoprosencephaly should be evaluated for minor manifestations such as a single central incisor before genetic counseling is provided. Isolated nonsyndromic midline clefts of the lip are generally sporadic. Prenatal diagnosis with ultrasound has not been reported for isolated midline clefts of the lip. References (Median Cleft Lip)

Diagnosis

The diagnosis is easily made by physical examination at the time of birth (Fig 12-5). Midline clefts of the lip in association with

1. Blaas HG, Eriksson AG, Salvesen KA, et al.: Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases. Ultrasound Obstet Gynecol 19:24, 2002.

394

Craniofacial Structures

Table 12-1. Syndromes commonly featuring midline cleft lip Causation Gene/Locus

Syndrome

Prominent features

Branchio-oculo-facial

Cervical aplasia cutis congenita, pseudoclefts, eye defects

AD (113620)

Ellis-van Creveld

Short limbs, nail dysplasia, polydactyly, cardiac defects

AR (225500) EVC, 4p16

Frontonasal malformation

Hypertelorism, widow’s peak, bifid nose

Usually sporadic

Holoprosencephaly

Cyclopia, hypotelorism, premaxillary agenesis

AD (142945) SHH, 7q36 AD (157170) SIX3, 2p21 AD (142946) TGIF, 18p11 Trisomies 13, 18; del 7q, 13q, 18p, dup 3p, maternal diabetes

Hydrolethalis

Hydrocephaly, crossed polydactyly, cardiac defect

AR (236680) 11q23-25

OFD syndromes

Oral frenulae, lobulated tongue, digital anomalies

XLD (311200) CXorf5, Xp22 AR (252100)

Diagnosis

2. DeMyer W: Median facial malformations and their implications for brain malformations. Birth Defects Orig Artic Ser XI(7): 155, 1975. 3. Lacbawan FL, Muenke M: Central nervous system embryogenesis and its failures. Pediatr Dev Pathol 5:425, 2002. 4. Plawner LL, Delgado MR, Miller VS, et al.: Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain. Neurology 59:1058, 2002. 5. Barr M Jr, Cohen MM Jr: Holoprosencephaly survival and performance. Am J Med Genet 89:116, 1999. 6. Elias DL, Kawamoto HK Jr, Wilson LF: Holoprosencephaly and midline facial anomalies: redefining classification and management. Plast Reconstr Surg 90:951, 1992.

12.2 Cleft Lip With or Without Cleft Palate (CL/P) Definition

Cleft lip with or without cleft palate is a defect in the upper lip just lateral to the philtral pillar on the affected side, resulting from Fig. 12-6. Complete bilateral cleft lip and palate (left). Complete unilateral cleft lip and palate (right).

failure of the medial nasal process to establish continuity with the maxillary process. The subtlest manifestation of cleft lip may be a fibrous band of scarlike tissue along the philtral ridge. More typically, there is an obvious gap between the premaxillary and lateral aspects of the upper lip with flattening of the nasal alar rim on the affected side and deviation of the nasal septum toward the noncleft side.

The diagnosis is made on physical examination at the time of birth (Figs. 12-6 and 12-7). Increasingly, clefts of the lip and primary palate (alveolus) are detected prenatally using twodimensional and three-dimensional imaging.1,2 Multiple studies over the last 30 years have documented the frequency with which clefts occur in association with other anomalies. All have confirmed that cleft palate (CP) is more frequently associated with other defects than CL/P, which in turn is more associated than is cleft lip (CL) alone. Methodologic differences among studies make it very difficult to compare specific numbers. In FoghA˚ndersen’s 1942 data, roughly 10% of affected individuals had associated defects.3 Numbers typically less than 15% have been seen in studies of CL/P that depended upon birth certificates or review of medical records to document the associated defects.4,5 With improved ability to document the frequency of minor as well as major malformations, frequencies ranging from 14–45% were documented despite the fact that most clinic-based populations did not include newborns with clefts as part of conditions with limited survival.6–9 Rigorous birth defects surveillance programs have published frequencies of associated defects with CL/P ranging from 26.2% to 36.8%.10,11 Gorlin’s authoritative text documents well over 300 syndromes, sequences, and associations in which CL/P may represent one feature.12 The clinical importance of recognizing associated malformations is that anomalies do not occur together at random. Clustering suggests the presence of a pattern of malformation of significance with respect to prognosis, recurrence risk, or both. Table 12-2 lists the more common conditions associated with CL/P. Etiology and Distribution

Table 12-3 sets forth population-based characteristics of CL/P. For the past 30 years, the multifactorial threshold model has been widely accepted as the explanation for the familial clustering of facial clefts. The model assumed that liability to a discrete birth defect such as CL/P or CP was determined by the additive effect of many genetic and environmental factors, each of which had a small but equal individual impact. According to the model, an overt

Lips

Fig. 12-7. Incomplete bilateral cleft lip (left). Incomplete bilateral cleft lip (right) with overt cleft below the right nostril and occult cleft below the left nostril.

phenotype occurred when a threshold was exceeded, converting a continuous liability for a specific defect into an all-or-none expression of a malformation.13 Although the model accounted for the less than 100% concordance of defects in monozygotic (MZ) twins, the impact of gender and the degree of malformation on recurrence risk, and the nonlinear decline in risk to relatives depending on the degree of relationship, complex segregation analysis has suggested that the multifactorial model is not biologically true. Rather, CL/P is most likely determined by a small number (two to eight) of genes acting in a multiplicative fashion and in conjunction with specific environmental risk factors. Each locus is estimated to increase the risk for first-degree relatives three- to sixfold.14–16 New approaches to complex trait analysis afforded by major advances in the fields of genetics and molecular biology have allowed identification of several genes with major impact on nonsyndromic clefting. Interestingly, some of these genes cause a mixed cleft phenotype (cleft palate alone and cleft lip with or without cleft palate in affected members of the same family). Genes conferring susceptibility for clefting have been identified through a variety of strategies, including linkage or association studies, cloning of chromosomal break points, Mendelian models, animal models, and human and mouse expression studies.17 The five genes of greatest interest currently include PVRL1 (identified through a Mendelian phenocopy), TBX22 (identified through a Mendelian phenocopy, see cleft palate below), MSX1 (evaluated because of the phenotype in the mouse knockout), FGFR1 (identified through linkage and chromosomal abnormality mapping a different phenotype), and IRF6 (identified through a Mendelian phenocopy). A polymorphism in transforming growth factor alpha (TGFa) on chromosome 2p13 was the earliest gene associated with nonsyndromic CL/P in humans.18 The gene was initially selected because of its role in CP in the mouse. Since the first report, multiple confirmatory and nonconfirmatory studies have been published reflecting the difficulty with association studies in general as well as population differences among the study samples.19 Several reports link polymorphisms in TGFa with an increased risk for CL/P in the face of maternal cigarette smoking.20,21 Other studies have failed to confirm this interaction.22 Homozygous mutations in the poliovirus receptorlike 1 gene (PVRL1) at 11q23-24 have been shown to cause cleft lip/palate– ectodermal dysplasia, an autosomal recessive disorder with high prevalence on Margarita Island in the Caribbean Sea.23 Heterozygous mutations in the same gene, whose product functions as a cell–cell adhesion molecule in keratinocytes, also accounted for nonsyndromic CL/P in an adjacent population in Venezuela.24

395

Mutations in the gene MSX1, a homeobox gene on chromosome 4p16.1, have been shown to cause Witkop syndrome, an autosomal dominant condition with mixed clefting, hypodontia, and nail dysplasia.25 Although early association studies between MSX1 and CL/P yielded mixed results, more recent reports have documented an association between CL/P and MSX1 if the clinical phenotype included missing teeth outside of the cleft region.26–28 Mild nail hypoplasia may be seen in affected patients. Deletion of MSX1 may account for the high frequency of clefts in children with deletion 4p. Mutations in MSX1 may account for 2% of cases of CL/P. The gene may also be a modifier locus. Mutations in fibroblast growth factor receptor 1 (FGFR1) at 8p11 have recently been identified as part of the search for the cause of autosomal dominant Kallmann syndrome. Using linkage and overlapping interstitial deletions in two affected individuals, Dode´ et al. found that FGFR1 emerged as a candidate for Kallmann syndrome, which is associated with anosmia (secondary to absence of the olfactory bulbs and tracts) and hypogonadotrophic hypogonadism (secondary to deficiency of gonadotropin-releasing hormone). CL/P, CP, and hypodontia are occasional features of Kallmann syndrome. Inactivating mutations in FGFR1 account for Kallmann syndrome, whereas activating mutations in the same gene produce craniosynostosis.29 The frequency with which mutations account for nonsyndromic CL/P and CP remains to be determined. It is possible that mutations in FGFR1 underlie the olfactory deficits previously documented in boys with facial clefts.30 Mutations and deletions in transcription factor interferon regulatory factor 6 (IRF6) located at 1q32-41 have been shown to account for Van der Woude syndrome and popliteal pterygium syndrome, two of the more frequently encountered recognizable patterns of malformation occurring among the CL/P and CP populations.31 Van der Woude syndrome is the prototype Mendelian disorder with clefting and lip pits, the only other manifestation of this single gene disorder. Recently, a polymorphism (V2741 allele) in IRF6 has been documented to track with the cleft phenotype in varied populations of individuals with CL/P but not CP.32 Variations in IRF6 may account for 5% of nonsyndromic cleft lip and palate. Interestingly, hypodontia and mixed clefting are characteristics of IRF6 mutations. Mutations in p63, the gene responsible for ectrodactylyectodermal dysplasia-clefting syndrome (EEC), Hay-Wells syndrome, and split hand–split foot malformation, have not been identified in patients with nonsyndromic clefts. 33 Polymorphisms in transforming growth factor beta (TGFb) on chromosome 14q24 have been investigated because cleft palate is a consistent finding in the knockout mouse model.34 Results in human populations have been mixed. Likewise, inconsistent results have been published in studies of the methylene tetrahydrofolate reductase (MTHFR) gene on chromosome 1p36, the retinoic acid receptor alpha (RARA) gene on chromosome 17q21.1, the proto-oncogene BCL3 on chromosome 19q13.1, and the gamma-aminobutyric acid receptor (GABRB3) on chromosome 15q11.2.35–39 Multiple environmental factors are known to interfere with lip and palate development in experimental systems, including isotretinoin, anticonvulsants, smoking, alcohol, corticosteroids, and nutritional factors. Population studies in humans have documented fairly convincingly an association between nonsyndromic clefting and exposure to maternal cigarette smoking, maternal diabetes, a variety of anticonvulsant agents (phenytoin, valproic acid, trimethadione, and primidone), folic acid antagonists, and

396

Craniofacial Structures Table 12-2. Syndromes commonly featuring cleft lip with or without cleft palate alone Prominent features

Causation Gene/Locus

Down

Flat face, small ears, cardiac defects, single transverse palm crease

Trisomy 21

Trisomy 13

Aplasia, cutis congenita, heart defect, omphalocele, polydactyly

Trisomy 13

Trisomy 18

Growth deficiency, petite facies, camptodactyly, short sternum

Trisomy 18

Del 4p

Hypertelorism, short philtrum, scalp defect, ear pit

Del 4p

Del 22q (VCFS, DiGeorge)

Short palpebral fissures, small ears, alar hypoplasia, conotruncal cardiac defect

Del 22q11.22

Aarskog

Short stature, shawl scrotum, round face

XLR (305400) FGD1, Xp11

Basal cell nevus

Jaw keratocysts, basal cell carcinomas, bifid ribs

AD (109400) PTCH, 9q22.3

CHARGE

Ocular colobomas, choanal atresia, micropenis, cardiac defect

AD (214800) CHD7, 8q12

Coffin-Siris

Sparse scalp hair, coarse facies, hirsutism, nail hypoplasia

Uncertain (135900)

Distal arthrogryposis, type 2

Camptodactyly, dimples

AD (114300)

EEC

Ectrodactyly, ectodermal dysplasia

AD (129900) P63, 3q27

Fryns

Diaphragmatic hernia, coarse face, digital hypoplasia

AR (229850)

Opitz

Hypertelorism, hypospadias

XLD (300000) MID1, Xp22 AD (145410) 22q11.2

Popliteal pterygium

Lip pits, popliteal web, genital anomalies

AD (119500) IRF6, 1q32-41

Van der Woude

Lower lip pits

AD (119300) IRF6, 1q32-q41

Waardenburg

White forelock, deafness, iris heterochromia

Type 1: AD (193500) PAX3, 2q35 Type 2: AD (193510) MITF, 3p13

Amnion rupture

Ring constrictions, limb amputations, cephaloceles

Sporadic

FAV/OAV spectrum

Microtia, ear tags, cardiac defect, epibulbar dermoid

Usually sporadic

Alcohol

Microcephaly, short palpebral fissures

Alcohol

Anticonvulsants

Microcephaly, coarse facies, cardiac defects, nail hypoplasia

Hydantoin, valproic acid, trimethadione

Maternal diabetes

Heart defect, caudal regression

Poorly controlled diabetes

Syndrome

Chromosomal Disorders

Single Gene Disorders

Other

Teratogens

corticosteroids.40–51 Clefts are a consistent feature among the multiple anomalies induced by isotretinoin exposure.52 Clefts represent one feature of the fetal alcohol syndrome. Heavy maternal drinking has been associated with an increased risk for nonsyndromic CL/P,53,54 whereas lower levels of alcohol consumption have not.55 No environmental agent induces clefting with every exposure; thus, current research is focused on the genetic factors that underlie susceptibility to teratogen-induced malformation. Since poverty in and of itself appears to increase the risk for CL/P, nutritional factors are under investigation.56

Prognosis, Treatment, and Prevention

For nonsyndromic CL/P, the outcome with appropriate treatment is excellent. Reconstruction is accomplished in a staged fashion as an individual grows and develops, mandating longitudinal followup. Treatment decisions necessarily weigh aesthetic and speech concerns against issues of facial growth.57–60 The former dictate early repair, because there is some evidence that speech results are better if repair of the palate is performed prior to 1 year of age. In contrast, study of facial growth in untreated adult Sri Lankans

Lips Table 12-3. Epidemiologic characteristics of cleft lip with or without cleft palate Characteristic

Summary Information

Prevalence

One per 1000 total births

Geographic variation

High prevalence in Australia (Aborigines), Canada, the Far East Lower prevalence in Southern Europe and Africa

Racial/ethnic differences

In general, populations of Asian origin have higher rates than Caucasians, who have higher rates than Africans

Gender differences

M/F 2:1

Laterality

Two-thirds of unilateral defects are left-sided

Temporal trends

Mostly stable rates over time

Maternal age

No convincing maternal age effect when syndromic cases are meticulously excluded

Birth weight/ gestational age

Lower mean birth weight in some studies; no convincing increase in prematurity

Twinning

No clear increase in twins MZ twin concordance rate is 6–1 9 times higher than DZ concordance rate DZ twin same as full siblings

Familial patterns

Familial cases 15–25% Sibling recurrence 3–5%

Data from references 4, 6, 9, 10, 14, 16, 51, 56, 90, 91.

with CL/P demonstrated that the unoperated maxilla for the most part grows normally.61 A variety of strategies have been proposed to optimize the outcome, given these two warring factors. Although much literature has been written on the subject of treatment, there is a paucity of randomized control trials to compare treatment protocols in any standardized way. Data from a sixcenter international collaborative project have documented better outcomes in multidisciplinary centers using a few experienced operators and relatively simple protocols as opposed to centers with multiple providers and no consistent approach to treatment, at least if facial growth and dental relationships were used as the objective measure of outcomes.62–64 It is beyond the scope of this chapter to address treatment comprehensively. Parameters of care for affected children have been published by the American Cleft Palate-Craniofacial Association.65 The 2002 text edited by Wyszynski covers the subject comprehensively.66 The first step in treating an infant with CL/P is to establish feeding.67,68 Otherwise normal infants with clefts have normal rooting, latching, sucking, and swallowing reflexes. With the exception of those infants with Robin-type clefts, they are not at risk for aspiration, although nasopharyngeal reflux is nearly universal if the secondary palate is cleft. A variety of devices have been invented to feed infants with CL/P. All use a squeeze mechanism to circumvent the decrease in suction caused by the cleft. With appropriate support, breast-feeding is possible in some infants.69 In a prospective randomized study, breast-feeding immediately following lip repair posed no problem for wound disruption and promoted better growth.70 Middle ear problems are frequent and may present as recurrent infection or reduced middle ear compliance with hearing loss. Ventilation tubes are commonly placed in conjunction with either the lip or the palate repair. Breast milk may provide some protection against otitis media.71

397

The goal of the initial lip repair in a unilateral cleft is to align the vermillion, establish muscle continuity across the upper lip, reconstruct the philtral pillar, and reposition the alar cartilages, although considerable variation in technique exists.72 In a bilateral cleft lip, the alar cartilages may be repositioned for reconstruction of the columella at the time of the initial repair.73 The goal of the palate repair is to generate length and mobility in the palate such that air can be directed through the oral cavity during speech production. Many children require speech therapy after surgery. Up to 25% may need secondary palatal surgery to address residual velopharyngeal insufficiency. The defect in the alveolus (at the junction of the primary and secondary palates) is reconstructed using autologous bone from the iliac crest, calvarium, or rib.74 There is considerable controversy as to the timing of this procedure. The applicability of bone substitutes is being explored. Revisions of the lip and nose are typically considered prior to kindergarten, in preadolescence, and after completion of facial growth.75 Two studies of linear growth in children with nonsyndromic CL/P documented mildly reduced stature compared to population norms.76,77 Most children with nonsyndromic CL/P function in regular classes in school and have normal psychosocial adjustment, despite the fact that a wide variety of learning and emotional issues have been identified in this population.78 Comprehensive assessments have demonstrated subtle cognitive differences between CL/P subjects and noncleft controls.79,80 Some of these differences can be measured as quantitative measures on magnetic resonance scanning of the brain.81 Brain imaging is not standard in the evaluation of an otherwise normal child with CL/P; however, comprehensive neurodevelopmental testing should be considered in any child with CL/P who is struggling in school. No testing is yet available to identify genes conferring susceptibility to CL/P. Avoidance of environmental factors known to increase the risk, such as cigarette smoking, is a mainstay of prevention. Although preconception folic acid supplementation is known to reduce the risk of occurrence and recurrence of neural tube defects, the role of folic acid in prevention of CL/P remains controversial.82–84 Supplementation at the 0.4mg level currently recommended by the Center for Disease Control and Prevention is suggested. Although the multifactorial-threshold model for CL/P has been challenged as addressed above, families are still counseled with respect to recurrence risk based upon the empirical data from which the model derived. Table 12-4 outlines recurrence risk for both CL/P and CP.13 Cleft lip and palate is increasingly recognized on prenatal ultrasound.85–87 As with other malformations, the natural history of a prenatally identified CL/P is different from one identified in the newborn period, with a much higher proportion having chromosome abnormalities, serious defects in brain development, or patterns of malformation.88 In a small series of prenatally diagnosed CL/P fetuses (no other anomalies noted and normal chromosomes) the risk that an affected infant would have other anomalies was 10%.89 References (Cleft Lip With or Without Cleft Palate) 1. Chmait R, Pretorius D, Jones M, et al.: Prenatal evaluation of facial clefts with two-dimensional and adjunctive three-dimensional ultrasonography: a prospective trial. Am J Obstet Gynecol 187:946, 2002. 2. Stoll C, Clementi M, Euroscan study group: Prenatal diagnosis of dysmorphic syndromes by routine fetal ultrasound examination across Europe. Ultrasound Obstet Gynecol 21:543, 2003.

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Craniofacial Structures

Table 12-4. Risks of cleft lip and cleft lip/palate given several family situations Risk to next child

Situation

Proband has CL/CP (%)

Proband has CP (%)

4

2

Parents not affected and There are no other affected relatives There is an affected relative

4

7

Affected child also has another malformation

2

2

Parents are related

4

–

Parents not affected but have two affected children

9

1

One parent affected, no child affected

4

6

One parent affected, one child affected

17

15

Adapted in part from Fraser.13

3. Fogh-A˚ndersen P: Inheritance of Hare Lip and Cleft Palate. Arnold Busck, Nordisk Forlag, Copenhagen, 1942. 4. Fraser GR, Calnan JS: Cleft lip and palate. Seasonal incidence, birth weight, birth rank, sex, site, associated malformations, and parental age. Arch Dis Child 36:420, 1961. 5. Knox G, Braithwaite F: Cleft lips and palates in Northumberland and Durham. Arch Dis Child 38:66, 1963. 6. Welch J, Hunter AGW: An epidemiological study of facial clefting in Manitoba. J Med Genet 17:127, 1980. 7. Rollnick BR, Pruzansky S: Genetic services at a center for craniofacial anomalies. Cleft Palate J 18:304, 1981. 8. Shprintzen RJ, Siegel-Sadewitz VL, Amato J, et al.: Anomalies associated with cleft lip, cleft palate, or both. Am J Med Genet 20: 585, 1985. 9. Jones MC: Etiology of facial clefts: Prospective evaluation of 428 patients. Cleft Palate J 25:16, 1988. 10. Croen LA, Shaw GM, Wasserman CR, et al.: Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983–1992. Am J Med Genet 79:42, 1998. 11. Stoll C, Alembik Y, Dott B, et al.: Associated malformations in cases with oral clefts. Cleft Palate Craniofac J 37:41, 2000. 12. Gorlin RJ, Cohen MM, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 13. Fraser FC: The genetics of cleft lip and palate. Am J Hum Genet 22:36, 1970. 14. Farrall M, Holder SE: Familial recurrence pattern analysis of cleft lip with or without cleft palate. Am J Hum Genet 50:270, 1992. 15. Mitchell LE, Risch N: Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis. Am J Hum Genet 51:323, 1992. 16. Mitchell LE, Christensen K: Analysis of the recurrence patterns for nonsyndromic cleft lip with or without cleft palate in the families of 3,073 Danish probands. Am J Med Genet 61:371, 1996. 17. Spritz RA: The genetics and epigenetics of orofacial clefts. Current Opinion Pediatr 13:556, 2001. 18. Ardinger HH, Buetow KH, Bell GI, et al.: Association of genetic variation of the transforming growth factor alpha gene with cleft lip and palate. Am J Hum Genet 45:348, 1989. 19. Mitchell LE: Transforming growth factor alpha locus and nonsyndromic cleft lip with or without cleft palate. A reappraisal. Genet Epidmiol 14:231, 1997. 20. Shaw GM, Wasserman CR, Lammer EJ, et al.: Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. Am J Hum Genet 58:551, 1996.

21. Beaty TH, Maestri NE, Hetmanski JB, et al.: Testing for interaction between maternal smoking and TGFA genotype among oral cleft cases born in Maryland 1992-1996. Cleft Palate Craniofac J 34:447, 1997. 22. Christensen K, Olsen J, Norgaard-Pedersen B, et al.: Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991–1994. Am J Epidemiol 149:248, 1999. 23. Suzuki K, Hu D, Bustos T, et al.: Mutations of PVRL1, encoding a cellcell adhesion molecule/herpes receptor, in cleft lip/palate-ectodermal dysplasia. Nat Genet 25:427, 2000. 24. So¨zen MA, Suzuki K, Tolarova MM, et al.: Mutation on PVRL1 is associated with sporadic, nonsyndromic cleft lip/palate in northern Venezuela. Nat Genet 29:141, 2001. 25. Jumlongras D, Bei M, Stimson JM, et al.: A nonsense mutation in MSX1 causes Witkop syndrome. Am J Hum Genet 69:67, 2001. 26. van den Boogaard MJH, Dorland M, Beemer FA, et al.: MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 24:342, 2000. 27. Jezewski PA, Vieira AR, Nishimura C, et al.: Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet 40:399, 2003. 28. Slayton RL, Williams L, Murray JC, et al.: Genetic association studies of cleft lip and/or palate with hypodontia outside the cleft region. Cleft Palate Craniofac J 40:274, 2003. 29. Dode´ C, Levilliers J, Dupont JM, et al.: Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33:463, 2003. 30. Richman RA, Sheehe PR, McCanty T, et al.: Olfactory deficits in boys with cleft palate. Pediatrics 82:840, 1988. 31. Kondo S, Schutte BC, Richardson RJ, et al.: Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 32:285, 2002. 32. Zucchero T, Cooper M, Caprau D, et al.: Am J Hum Genet 73S:162, 2003. 33. Barrow LL, van Bokhoven H, Daack-Hirsch S, et al.: Analysis of the p63 gene in classical EEC syndrome, related syndromes, and nonsyndromic orofacial clefts. J Med Genet 39:559, 2002. 34. Kaartinen V, Voncken JW, Shuler C, et al.: Abnormal lung development and cleft palate in mice lacking TGF beta-3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11:415, 1995. 35. Shaw GM, Rozen R, Finnell RH, et al.: Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip. Am J Med Genet 80:196, 1998. 36. Gaspar DA, Matioli SR, Pavanello RC, et al.: Evidence that BCL3 plays a role in the etiology of nonsyndromic oral clefts in Brazilian families. Genet Epidemiol 23:364, 2002. 37. Scapoli L, Martinelli M, Pezzetti F, et al.: Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate. Hum Genet 110:15, 2002. 38. Mitchell LE, Murray JC, O’Brien S, et al.: Retinoic acid receptor alpha gene variants, multivitamin use, and liver intake as risk factors for oral clefts: a population-based case-control study in Denmark, 1991–1994. Am J Epidemiol 158:69, 2003. 39. van Rooij IA, Vermeij-Keers C, Kluijtmans LA, et al.: Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate? Am J Epidemiol 157:583, 2003. 40. Abrishamchian AR, Khoury MJ, Calle EE: The contribution of maternal epilepsy and its treatment to the etiology of oral clefts: a population based case-control study. Genet Epidemiol 11:343, 1994. 41. Rodriguez-Pinilla E, Martinez-Frias ML: Corticosteroids during pregnancy and oral clefts: a case-controlled study. Teratology 58:2, 1998. 42. Lieff S, Olshan AF, Werler M, et al.: Maternal cigarette smoking during pregnancy and the risk of oral clefts in newborns. Am J Epidemiol 150: 683, 1999. 43. Chung KC, Kowalski CP, Kim HM, et al.: Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate. Plast Reconstr Surg 105:485, 2000.

Lips 44. Hernandez-Diaz S, Werler MM, Walker AM, et al.: Folic acid antagonists during pregnancy and the risk of birth defects. N Eng J Med 343:1608, 2000. 45. Lorente C, Cordier S, Goujard J, et al.: Tobacco and alcohol use during pregnancy and risk of oral clefts. Occupational exposure and congenital malformation working group. Am J Public Health 90:415, 2000. 46. Park-Wyllie L, Mazzotta P, Pastuszak A, et al.: Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 62:385, 2000. 47. A˚berg A, Westbom L, Ka¨lle´n B: Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Develop 61:85, 2001. 48. Pradat P, Robert-Gnansia E, Di Tanna GL, et al.: Contributors to the MADRE database. First trimester exposure to corticosteroids and oral clefts. Birth Defects Res Part A Clin Mol Teratol 67:968, 2003. 49. Matalon S, Schechtman S, Goldzweig G, et al.: The teratogenic effect of carbamazepine: a meta-analysis of 125 exposures. Reprod Toxicol 16:9, 2002. 50. Vieira AR, Orioli IM, Murray JC: Maternal age and oral clefts: a reappraisal. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94:530, 2002. 51. Shaw GM, Croen LA, Curry CJ: Isolated oral cleft malformations: association with maternal and infant characteristics in a California population. Teratology 43:225, 1991. 52. Lammer EJ, Chen DT, Hoar RM, et al.: Retinoic acid embryopathy. N Eng J Med 313:837, 1985. 53. Werler MM, Lammer EJ, Rosenberg L, et al.: Maternal alcohol use in relation to selected birth defects. Am J Epidemiol 134:691, 1991. 54. Munger RG, Romitti PA, Daack-Hirsch S, et al.: Maternal alcohol use and risk of orofacial cleft birth defects. Teratology 54:27, 1996. 55. Meyer KA, Werler MM, Hayes C, et al.: Low maternal alcohol consumption during pregnancy and oral clefts in offspring: the Slone Birth Defects Study. Birth Defects Res Part A Clin Mol Teratol 67:509, 2003. 56. Clark JD, Mossey PA, Sharp L, et al.: Socioeconomic status and orofacial clefts in Scotland, 1989 to 1998. Cleft Palate Craniofac J 40: 481, 2003. 57. Peterson-Falzone SJ: The relationship between timing of cleft palate surgery and speech outcome: what have we learned and where do we stand in the 1990s? Semin Orthod 2:185, 1996. 58. Mølsted K, Asher-McDade C, Brattstro¨m V, et al.: The RPS. A sixcenter international study of treatment outcome in patients with clefts of the lip and palate: Part 2. Craniofacial form and soft tissue profile. Cleft Palate Craniofac J 29:398, 1992. 59. Kirschner RE, LaRossa D: Cleft lip and palate. Otolaryngol Clin North Am 33:1191, 2000. 60. Rohrich RJ, Love EJ, Byrd HS, et al.: Optimal timing of cleft palate closure. Plast Reconstr Surg 106:413, 2000. 61. McCance AM, Roberts-Harry D, Sherriff M, et al.: A study model analysis of adult unoperated Sri Lankans with unilateral cleft lip and palate. Cleft Palate J 27:146, 1990. 62. Shaw WC, Asher-McDade C, Brattstro¨m V, et al.: The RPS. A sixcenter international study of treatment outcome in patients with clefts of the lip and palate: Part 1. Principles and study design. Cleft Palate Craniofac J 29:393, 1992. 63. Molsted K: Treatment outcome in cleft lip and palate: issues and perspectives. Crit Rev Oral Biol Med 10:225, 1999. 64. Mars M, Asher-McDade C, Brattstro¨m V, et al.: A six-center international study of treatment outcome in patients with clefts of the lip and palate: Part 3. Dental arch relationships. Cleft Palate Craniofac J 29:405, 1992. 65. Parameters for evaluation and treatment of patients with cleft lip/ palate or other craniofacial anomalies. American Cleft Palate-Craniofacial Association. Cleft Palate Craniofac J 30(suppl):S1, 1993. 66. Wyszynski DF, ed: Cleft Lip and Palate: From Origin to Treatment. Oxford University Press, New York, 2002.

399 67. Wyszynski DF, Sarkozi A, Vargha P, et al.: Birth weight and gestational age of newborns with cleft lip with or without cleft palate and with isolated cleft palate. J Clin Pediatr Dent 27:185, 2003. 68. Clarren SK, Anderson B, Wolf LS: Feeding infants with cleft lip, cleft palate, or cleft lip and palate. Cleft Palate J 24:244, 1987. 69. Fisher JC: Feeding children who have cleft lip and palate. West J Med 154:207, 1991. 70. Darzi MA, Chowdri NA, Bhat AN: Breast feeding or spoon feeding after cleft lip repair: a prospective, randomized study. Br J Plast Surg 49:24, 1996. 71. Paradise JL, Elster BA, Tan L: Evidence in infants with cleft palate that breast milk protects against otitis media. Pediatrics 94:853, 1994. 72. Schendel SA: Unilateral cleft lip repair—state of the art. Cleft Palate Craniofac J 37:335, 2000. 73. Mulliken JB: Repair of the bilateral complete cleft lip and nasal deformity—state of the art. Cleft Palate Craniofac J 37:342, 2000. 74. Vig KW: Alveolar bone grafts: the surgical/orthodontic management of the cleft maxilla. Ann Acad Med Singapore 28:721, 1999. 75. Cutting CB: Secondary cleft lip nasal reconstruction: state of the art. Cleft Palate Craniofac J 37:538, 2000. 76. Duncan PA, Shapiro LR, Soley RL, et al.: Linear growth patterns in patients with cleft lip or palate or both. Am J Dis Child 137:159, 1983. 77. Cunningham ML, Jerome JT: Linear growth characteristics of children with cleft lip and palate. J Pediatr 131:707, 1997. 78. Endriga MC, Kapp-Simon KA: Psychological issues in craniofacial care—state of the art. Cleft Palate Craniofac J 36:3, 1999. 79. Broder HL, Richman LC, Matheson PB: Learning disability, school achievement, and grade retention among children with cleft: a twocenter study. Cleft Palate Craniofac J 35:127, 1998. 80. Nopoulos P, Berg S, VanDemark D, et al.: Cognitive dysfunction in adult males with non-syndromic clefts of the lip and/or palate. Neuropsychologia 40:2178, 2002. 81. Nopoulos P, Berg S, Canady J, et al.: Structural brain abnormalities in adult males with clefts of the lip and/or palate. Genet Med 4:1, 2002. 82. Tolarova M, Harris J: Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 51:71, 1995. 83. Shaw GM, Nelson V, Carmichael SL, et al.: Maternal periconceptional vitamins: interactions with selected factors and congenital anomalies? Epidemiology 13:625, 2002. 84. Botto LD, Olney RS, Erickson JD: Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet 125C:12, 2004. 85. Forrester MB, Merz RD, Yoon PW: Impact of prenatal diagnosis and elective termination on the prevalence of selected birth defects in Hawaii. Am J Epidemiol 148:1206, 1998. 86. Grandjean L, Larroque D, Levi S, et al.: The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study. Am J Obstet Gynecol 181:446, 1999. 87. Jones MC: Prenatal diagnosis of cleft lip and palate: detection rates, accuracy of ultrasonography, associated anomalies, and strategies for counseling. Cleft Palate Craniofac J 39:169, 2002. 88. Berge SJ, Plath H, von Lindern JJ, et al.: Natural history of 70 fetuses with a prenatally diagnosed orofacial cleft. Fetal Diagn Ther 17:247, 2002. 89. Jones MC: The risk that an apparently isolated cleft lip with or without cleft palate will be associated with anomalies that impact outcome: follow-up of 32 cases ascertained through prenatal diagnosis. Proc Greenwood Genet Center 19:122, 2000. 90. Global strategies to reduce the health-care burden of craniofacial anomalies: report of WHO meetings on International Collaborative Research on Craniofacial Anomalies, Geneva, Switzerland 5-8 November 2000. Park City, Utah, 24-26 May 2001. Geneva, Switzerland: WHO, Human Genetics Program, 2002. 91. Sipek A, Gregor V, Horacek J, et al.: Facial clefts from 1961 to 2000— incidence, prenatal diagnosis and prevalence by maternal age. Ceska Gynekol 67:260, 2002.

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12.3 Cleft Palate Definition

Incomplete fusion of the palatal shelves on either side of the midline results in cleft palate (CP). Abnormalities in closure occur posterior to the incisive foramen and thus derive from problems in the secondary rather than primary palate. Clefts may involve the hard and soft palates or the soft palate alone, or may be submucous in nature, involving muscle discontinuity with an intact overlying mucosa. Diagnosis

Overt clefts of the secondary palate are readily identified on physical examination in the newborn period, provided the oral cavity is adequately examined (Fig. 12-8). In wide clefts, the vomer bone is clearly visualized in the midline. Clefts may have a V-shaped or U-shaped appearance. Hanson and Smith distinguished U-shaped palatal defects from more typical V-shaped clefts and postulated that U-shaped clefts might be deformational defects occurring when the tongue was retropositioned in the oral cavity secondary to micrognathia such that palatal closure was mechanically blocked.1 The Robin sequence (micrognathia, cleft palate, and glossoptosis) was offered as evidence of this hypothesis. Both U-shaped and V-shaped clefts have been noted in association with micrognathia.2 In hindsight, this is not surprising given the phenotypes associated with the genetic abnormalities that may underlie CP alone. In the author’s experience, it is usually possible to distinguish classical Robin-type clefts from V-shaped clefts with micrognathia and some airway issues. This observation has been born out by Printzlau and Andersen in a review of Robin sequence in Denmark.3 Although etiologically heterogeneous, the triad of features (U-shaped cleft palate, micrognathia, and glossoptosis) constituted a well-defined pattern readily identified in the newborn period. Shprintzen et al. documented that well over half of infants with the Robin sequence as the presenting problem have an underlying diagnosis, with 50% having Stickler syndrome as a specific diagnosis.4 Both Stickler syndrome and deletion 22q11.2 (velocardiofacial syndrome) occurred commonly in the series reported by van den Elzen et al.5

Fig. 12-8. Isolated V-shaped cleft palate (left). U-shaped cleft palate associated with micrognathia and glossoptosis (right).

Submucous clefts are more problematic and are frequently not identified at birth. Infants with submucous clefts of the palate present with frequent nasal regurgitation of fluids, recurrent ear infections, and/or velopharyngeal insufficiency. The diagnosis of a submucous cleft rests on the triad of (1) notching of the posterior border of the hard palate, (2) muscular diastasis with mucosal integrity, and (3) a bifid uvula. Roughly 2% of the population may have an isolated bifid uvula.6 Cleft palate has been diagnosed indirectly prenatally based on the finding of severe micrognathia in images assessing the fetal profile.7 The ‘‘cleft palate’’ frequently referenced in the prenatal diagnosis literature is actually the primary palate or alveolar ridge, not the secondary palate. Posterior structures are very difficult to visualize with current technology. As outlined above, the frequency with which clefts occur in association with other anomalies is much greater than initially recognized. Virtually all studies have confirmed that CP is more frequently associated with other defects than cleft lip with or without cleft palate (CL/P), no matter what the methodology used to identify associated defects (birth or medical record review, birth defect surveillance study, or ongoing clinical evaluation). Emanuel and colleagues documented a 40% rate of associated defects among children with CP alone ascertained through birth and hospital record review compared to 24% with CL/P.8 Surveys of clinic populations that afford the ability to document the frequency of minor as well as major malformations have published numbers ranging from 55–61% despite the exclusion of newborns with clefts as part of conditions with limited survival.4,9,10 Among carefully evaluated patients with submucous clefts of the palate, 77% will have an associated abnormality.4 Rigorous birth defects surveillance programs have documented frequencies of associated defects with CP ranging from 46.7–51.7%.11,12 Gorlin’s text documents the numerous syndromes, sequences, and associations in which CP may represent one feature.13 The clinical importance of recognizing associated malformations has been reviewed above. Table 12-5 lists some common conditions associated with CP. Of particular note is the frequency with which the disorders of type 2 collagen (Stickler syndrome and spondyloepiphyseal dysplasia congenita) occur in the population. In the author’s series, over 5% of all children presenting for treatment with CP will have Stickler syndrome. Early recognition of this condition is critical to monitor patients for the devastating ocular

Table 12-5. Syndromes commonly featuring cleft palate alone Syndrome

Prominent features

Causation Gene/Locus

Chromosomal Disorders Del 22q (VCFS, DiGeorge)

Short palpebral fissures, small ears, alar hypoplasia, conotruncal cardiac defects

22q11.22

Down

Flat face, small ears, cardiac defects, single transverse palmar creases

Trisomy 21

Beckwith

Overgrowth, macroglossia, hemihypertrophy, omphalocele

Multiple mechanisms perturb imprinted loci 11p15

Branchio-oto-renal

Cup ears, ear pits, branchial arch remnants, Mondini defect

AD (113650) EYA1, 8q13

Campomelic dysplasia

Short bowed tibias with dimpling, flat face, sex reversal

AD (114290) SOX9, 17q24-q25

CHARGE

Ocular colobomas, choanal atresia, micropenis, cardiac defects

AD (214800) CHD7, 8q12

Cleft palate-ankyloglossia

Ankyloglossia

XLR (303400) TBX22, Xq21

De Lange

Growth deficiency, hirsutism, limb defects, cardiac defects

Sporadic (122470) NIPBL, 5p13.1

Diastrophic dysplasia

Short limb dwarfing, hitch-hiker thumb, scoliosis

AR (222600) SLC26A2, 5q32-33

Distichiasis-lymphedema

Double row of eyelashes, peripheral edema, cardiac defects

AD (153400) FOXC2, 16q24

Single Gene Disorders

Multiple pterygium

Multiple pterygia, short neck, scoliosis with vertebral defects

AR (265000)

Nager

Radial limb defects, ear malformation, zygomatic hypoplasia

AD (154400)

Oralfacial digital type 1

Lobulated tongue, oral frenula, milia, alopecia

XLD (311200) CXORF5, Xp22

Otopalato digital type 1

Broad nasal root, deafness, broad distal phalanges

XLR (311300) FLNA, Xq28

Popliteal pterygium

Lip pits, popliteal web, genital anomalies

AD (119500) IRF6, 1q32-q41

Rapp-Hodgkin ectodermal dysplasia

Coarse dry hair, anhidrosis, alopecia

AD (129400) P63, 3q27

SED congenita

Short limb dwarfing, myopia, pulmonary hypoplasia

AD (183900) COL2A1, 12q13

Smith-Lemli-Opitz

Ptosis, hypospadias, 2–3 toe syndactyly

AR (270400) DHCR7, 11q12-13

Stickler

Flat face, myopia, Robin sequence (non-ocular form)

AD (108300) COL2A1, 12q13 AD (604841) COL11A1, 1p21 AD (184840) COL11A2, 6p21.3

Treacher Collins

Microtia, zygomatic hypoplasia, micrognathia

AD (154500) TCOF1, 5q32-33

Van der Woude

Lower lip pits

AD (119300) IRF6, 1q32-q41

FAV/OAV spectrum

Microtia, ear tags, cardiac defects, epibulbar dermoid

Usually sporadic

Kabuki

Large palpebral fissures, fetal finger pads, cardiac defect

Sporadic

Sixth and seventh cranial nerve palsy, clubfoot, other cranial nerve palsy

Sporadic

Anticonvulsants

Microcephaly, coarse facies, cardiac defects, nail hypoplasia

Hydantoin

Alcohol

Microcephaly, short palpebral fissures, smooth philtrum

Alcohol

Retinoic acid

Anotia, conotruncal cardiac defect, brain defect

Isotretinoin

Other

Mobius sequence

Teratogens

401

402

Craniofacial Structures

complications that may occur.14 Although many affected infants will have flat facial profiles, micrognathia, and the Robin sequence, ophthalmologic evaluation to screen for early onset myopia is warranted when the diagnosis is suspected. Etiology and Distribution

Table 12-6 sets forth population-based characteristics of CP. As discussed above in greater detail, segregation analyses have challenged the multifactorial/threshold model for clefting, although fewer studies have specifically addressed cleft palate alone.15–17 In general, linkage and association studies have been more problematic in CP than in CL/P, probably reflecting heterogeneity in the populations under investigation. Beaty et al.18 documented an association between MSX1 and isolated CP, later confirmed by Fallin et al.19 Mutations in MSX1, FGFR1, and IRF6 produce mixed clefting phenotypes (discussed above) and may account for a proportion of nonsyndromic CP. The most interesting gene thus far identified with specificity for CP is TBX22, mutations which are responsible for X-linked cleft palate with ankyloglossia.20 Recent investigations in broader populations have suggested that inactivating mutations in TBX22 may account for 2–4% of nonsyndromic CP in North America and Brazil, but not the Philippines.21 The most convincing environmental agent associated with nonsyndromic CP is maternal cigarette smoking.22 It is the author’s belief that the difficulty in demonstrating teratogenicity as well as genetic associations in the CP population relates to heterogeneity within nonsyndromic CP and to pitfalls in identifying which individuals are truly nonsyndromic. Prognosis, Treatment, and Prevention

For nonsyndromic CP the outcome with appropriate treatment is excellent. As discussed in detail above, establishing oral feeding is the first step in treatment. Children with CP are at increased risk for middle ear effusions and otitis media. Speech, language, and facial growth are monitored after the palate is repaired, with appropriate intervention (speech therapy/orthodontic treatment) if problems are identified. Not all submucous clefts of the palate require surgical management. Repair is usually reserved for those associated with velopharyngeal incompetence or recurrent otitis media.23,24 Although most children with nonsyndromic CP func-

Table 12-6. Epidemiologic characteristics of cleft palate alone Characteristic

Summary Information

Prevalence

One per 2000 total births

Geographic variation

Higher in Australia, Scandinavia, Scotland, France

Racial/ethnic differences

Slightly higher in Asians

Gender differences

Slight preponderance of F

Temporal trends

Mostly stable rates over time

Maternal age

No evidence for maternal age effect when syndromic cases are meticulously excluded

Birth weight/gestational age

Lower mean birth weight in some studies; no convincing increase in prematurity

Twinning

No clear increase in twins DZ concordance rate same as full siblings

Familial patterns

Familial cases 10% Sibling recurrence 2–3

tion in regular classes in school, a significant number have language impairment and reading disabilities.25,26 Neurodevelopmental testing should be considered for any child who struggles in school. Although the multifactorial-threshold model for CP is likely not correct, as addressed above, families are still counseled with respect to recurrence risk based on the empirical data from which the model derived. Table 12-4 outlines recurrence risk for CP. Currently, no tests of genetic susceptibility are available. Prevention focuses on avoidance of exposure to agents, such as cigarette smoking, known to increase the risk. Prenatal diagnosis using ultrasound can be considered for those syndromic cases in which severe micrognathia is a consistent feature.27 References (Cleft Palate) 1. Hanson JW, Smith DW: U-shaped palatal defect in the Robin anomaly: developmental and clinical relevance. J Pediatr 87:30, 1975. 2. Rintala A, Ranta R, Stegars T: On the pathogenesis of cleft palate in the Pierre Robin syndrome. Scand J Plast Reconstr Surg 18:237, 1984. 3. Printzlau A, Andersen M: Pierre Robin sequence in Denmark: A retrospective population-based epidemiological study. Cleft Palate Craniofac J 41:47, 2004. 4. Shprintzen RJ, Siegel-Sadewitz VL, Amato J, et al.: Anomalies associated with cleft lip, cleft palate, or both. Am J Med Genet 20: 585, 1985. 5. Van den Elzen AP, Semmekrot BA, Bongers EM, et al.: Diagnosis and treatment of the Pierre Robin sequence: results of a retrospective clinical study and review of the literature. Eur J Pediatr 160:47, 2001. 6. Lindemann G, Riss B, Sewerin I: Prevalence of cleft uvula among 2732 Danes. Cleft Palate J 14:226, 1977. 7. Pilu F, Romero R, Reece EA, et al.: The prenatal diagnosis of Robin anomalad. Am J Obstet Gynecol 154:630, 1986. 8. Emanuel I, Culver BH, Erickson JD, et al.: The further epidemiological differentiation of cleft lip and palate: a population study of clefts in King County, Washington, 1956-1965. Teratology 7:271, 1973. 9. Rollnick BR, Pruzansky S: Genetic services at a center for craniofacial anomalies. Cleft Palate J 18:304, 1981. 10. Jones MC: Etiology of facial clefts: prospective evaluation of 428 patients. Cleft Palate J 25:16, 1988. 11. Stoll C, Alembik Y, Dott B, et al.: Associated malformations in cases with oral clefts. Cleft Palate Craniofac J 37:41, 2000. 12. Croen LA, Shaw GM, Wasserman CR, et al.: Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983–1992. Am J Med Genet 79:42, 1998. 13. Gorlin RJ, Cohen MM, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 14. Snead MP, Yates JR: Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353, 1999. 15. Chung CS, Ching GHS, Morton NE: A genetic study of cleft lip and palate in Hawaii. II. Complex segregation analysis and genetic risks. Am J Hum Genet 26:177, 1974. 16. Demenais F, Bonaiti-Pelie J, Briard ML, et al.: An epidemiological and genetic study of facial clefting in France. II Segregation analysis. J Med Genet 21:436, 1984. 17. Clementi M, Tenconi R, Forabosco P, et al.: Inheritance of cleft palate in Italy. Evidence for a major autosomal recessive locus. Hum Genet 100:204, 1997. 18. Beaty TH, Wang H, Hetmanski JB, et al.: A case-control study of nonsyndromic oral clefts in Maryland. Ann Epidemiol 11:434, 2001. 19. Fallin MD, Hetmanski JB, Park J, et al.: Family-based analysis of MSX1 haplotypes for association with oral clefts. Genet Epidemiol 25:168, 2003. 20. Moore GE, Ivens A, Chambers J, et al.: Linkage of an X-chromosome cleft palate gene. Nature 326:91, 1987. 21. Marcano ACB, Doudney K, Braybrook C, et al.: TBX22 mutations are a frequent cause of cleft palate. J Med Genet 41:68, 2004. 22. Wyszynski DF, Duffy DL, Beaty TH: Maternal cigarette smoking and orofacial clefts: a meta-analysis. Cleft Palate Craniofac J 34:206, 1997.

Lips 23. Pensler JM, Bauer BS: Levator retropositioning and palatal lengthening for submucous clefts. Plast Reconstr Surg 82:765, 1988. 24. Ysunza A, Pamplona MC, Mendoza M, et al.: Surgical treatment of submucous cleft palate: a comparative trial of two modalities for palatal closure. Plast Reconstr Surg 107:9, 2001. 25. Richman LC, Eliason MJ, Lindgren SD: Reading disability in children with clefts. Cleft Palate J 25:21, 1988.

403 26. Richman LC, Eliason M: Type of reading disability related to cleft type and neuropsychological patterns. Cleft Palate J 21:1, 1984. 27. Vettraino IM, Lee W, Bronsteen RA, et al.: Clinical outcome of fetuses with sonographic diagnosis of isolated micrognathia. Obstet Gynecol 102:801, 2003.

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13 Tongue Robert J. Gorlin

I

am surprised at how often one encounters the faulty perception that ‘‘the mouth begins at the tonsils.’’ In the medical curriculum, because little to no time is allocated to disorders of the mouth, we will devote some effort to the elucidation of this subject. The mouth can be easily examined digitally using a 22 gauze, a good light, and a mouth mirror. The tongue is the most important soft tissue structure within the oral cavity. Speech, deglutition, some taste (sweet, salt, bitter, sour, metallic, and so forth [most taste is really smell]), and participation in the immune system (through the lingual tonsils) are its main functions. During embryonal development, if the tongue fails to descend to its normal position and the mandible is small, the tongue will interfere with the approximation of the palatal shelves (processes) in the midline. These shelves form the secondary palate; if tongue interference occurs, the palate will be cleft. Abnormal embryonal development of the tongue may produce alterations in the formation of the thyroid gland, with resultant ectopia (lingual thyroid). Alterations in tongue formation (absence of fungiform and circumvallate papillae) may be associated with lack of taste sensation as in familial dysautonomia (Riley-Day syndrome). Midline clefting of the mandible may be associated with absent, cleft, or adherent tongue. Tongue enlargement, as in Beckwith-Wiedemann syndrome, will influence tooth position and alignment. In addition, microstomia will be present if the tongue is nearly absent, as in hypoglossia-hypodactyly syndromes or in otocephaly. Speech alterations may be present in cases of marked ankyloglossia; diastema of mandibular incisors occurs in cases of thick lingual frenulum with insertion into the anterior labial mucosa. The normal anatomy of the oral floor is altered by the formation of dermoid cysts and salivary gland hamartomas associated with cleft or maldeveloped tongue.

Embryology/Anatomy

At about the end of the 4th embryologic week, a somewhat rhomboidal elevation is seen, behind the buccopharyngeal membrane, in the floor of the pharynx just rostral to the foramen cecum (the depression from which the thyroid gland arises). This unpaired tubercle (tuberculum impar) or median tongue bud is soon joined on each side by lateral lingual tubercles. The posterior third of the tongue is formed by two elevations that develop caudal to the foramen

cecum: the copula (hypobranchial eminence) and the still more caudal epiglottal swelling. The second arch plays no role in tongue development. The muscles of the tongue are derived from myoblasts that migrate from the myotomes of occipital somites. Connective tissue, lymphatics, and blood vessels of the tongue (and possibly some muscle fibers) are derived from the branchial arch mesenchyme. The tongue is usually considered to have two parts: the anterior two-thirds of the tongue (the oral portion), which is separated from the posterior third (the pharyngeal portion) by the sulcus terminalis. The tongue surface becomes covered with papillae, beginning around day 54. Both vallate and foliate papillae appear earliest and have a relationship to the terminal branches of the glossopharyngeal nerve. The fungiform papillae, also scattered over the same area but fewer in number, arise somewhat later embryologically, having a relationship to the termination of the chorda tympani branch of the facial nerve. The filiform papillae covering the dorsum of the anterior two-thirds of the tongue appears after week 12. The vallate papillae appear along the sulcus terminalis and the foliate papillae on the posterolateral surface of the tongue. The sensory nerve supply to the anterior two-thirds of the tongue is from the lingual branch of the mandibular division of the trigeminal nerve. The taste buds of the anterior two-thirds of the tongue are innervated by the chorda tympani branch of the seventh nerve. The foliate papillae and the posterior one-third of the tongue are innervated by the glossopharyngeal nerve. The superior laryngeal branch of the vagus nerve supplies a small area of the tongue just anterior to the epiglottis, and, as indicated earlier, the muscles of the tongue are supplied by the hypoglossal nerve, except for the palatoglossus, which is supplied by the vagus. The tongue has two groups of muscles: extrinsic and intrinsic. The extrinsic group (genioglossus, hypoglossus, styloglossus, and palatoglossus) are responsible for the gross positioning of the tongue. The intrinsic muscles (superior and inferior longitudinal muscles and transverse and vertical muscles) govern its shape.1 Excellent review of molecular embryology are those of Yamane et al.2 and Jung et al.3 References 1. Velcek FT, Klatz DH, Hill CH: Tongue lesions in children. J Pediatr Surg 14:238, 1979. 405

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2. Yamane A, Mayo MI, Bringas P Jr, et al.: TGF-alpha, EGF, and their cognate EGF receptor are co-expressed with desmin during embryonic, fetal and neonatal myogenesis in mouse tongue development. Dev Dyn 209:353, 1997. 3. Jung HS, Oropeza V, Thesleff I: Shh, Bmp-2, Bmp-4 and Fgf-8 are associated with initiation and patterning of mouse tongue papillae. Mech Develop 81:179, 1999.

13.1 Aglossia, Hypoglossia, Microglossia Aglossia, hypoglossia, and microglossia cover the range of total to partial absence of the tongue. Diagnosis is established on clinical inspection. Aglossia is an inaccurate term because some tongue remnants are always present (hypoglossia), with the rudimentary tongue located at the level of the genioglossal processes (Fig. 13-1). The tongue bud generally is capable of some movement that is accentuated laterally and anteriorly by the muscular folds of the oral floor. Isolated aglossia (hypoglossia) is very rare.1 It forms part of the oromandibular-limb hypogenesis group of syndromes and is seen specifically in hypoglossia-hypodactylia and Moebius syndromes.2–8 Persistence of the buccopharyngeal membrane or remnants of it has been frequently associated with aglossia.9 Brecht and Johnson5 reported a case of complete mandibular agenesis with microstomia, choanal atresia, cleft soft palate, persistence of the buccopharyngeal membrane, and almost total aglossia. There is no evidence that heredity plays an etiologic role in this condition. All examples of hypoglossia-hypodactylia and Moebius syndrome (oromandibular-limb hypogenesis) have been sporadic. Rarely, hypoglossia may be found without hypodactyly. There is usually reduction of mandibular incisors to but a single one. The mandible is severely constricted.6 Situs inversus7 and anterior maxillo-mandibular fusion8 have also been found. The prevalence of this tongue malformation is extremely rare.4 No therapy exists for this condition. Patients are capable of achieving an acceptable level of speech.

Fig. 13-1. Rudimentary malformed tongue in hypoglossiahypodactyly syndrome.

Fig. 13-2. Absence of the lingual frenulum.

References (Aglossia, Hypoglossia, Microglossia) 1. Bousten M, Mercier J, Delaire J: Les syndromes malformatifs oromandibulaires et des membres. Rev Stomatol Chir Maxillofac 88:168, 1987. 2. Chicarilli ZN, Polayes IM: Oromandibular limb hypogenesis syndromes. Plast Reconstr Surg 76:13, 1985. 3. Hall BD: Aglossia-adactylia. Birth Defects Orig Artic Ser VII (7):233, 1971. 4. Schuhl JF: Aglossia-adactylia. Review of the literature. Ann Pediatr 33:137, 1986. 5. Brecht K, Johnson CM: Complete mandibular agenesis. Arch Otolaryngol 111:132, 1985. 6. Yamada A, Konno N, Imai Y, et al.: Treatment of hypoglossia-hypodactyly without extremity anomalies. Plast Reconstr Surg 106:274, 2000. 7. Amor DJ, Craig JE: Situs inversus totalis and congenital hypoglossia. Clin Dysmorphol 10:47, 2001. 8. Arshad AR, Goh CS: Hypoglossia congenita with anterior maxillomandibular fusion. Br J Plast Surg 47:139, 1994. 9. Grippaudo FR, Kennedy DC: Oromandibular-limb hypogenesis syndromes: A case of aglossia with an intraoral band. Br J Plast Surg 51: 480, 1998.

The tongue originates from the first, third, and fourth pharyngeal arches. The two lateral lingual swellings and a median swelling (tuberculum impar), which form the anterior two-thirds of the tongue, are derived from the first arch. During early stages of development, the tongue is fused to the floor of the mouth. Separation is achieved by extensive cellular degeneration, the frenulum being the only remaining tissue in this area. Absence of the frenulum occurs when the cellular degeneration extends beyond the normal limits. Absence of the frenulum has been reported in the aglossia-adactylia syndrome.1 Review of the literature failed to disclose isolated cases of this condition. We have observed the occurrence of absent lingual frenulum in two sisters and their mother. Absence of the lingual frenum has been reported in Ehlers-Danlos syndrome, type 12 and in a variant of Rapp-Hodgkin syndrome.3 Prognosis is excellent. References (Absence of Lingual Frenulum)

13.2 Absence of Lingual Frenulum Complete absence of lingual frenulum with the ventral surface of the tongue folding in the floor of the mouth can occur (Fig. 13-2).

1. Schuhl FJ: Aglossia-adactylia. Review of the literature. Ann Pediatr 33:137, 1986. 2. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001, p 517. 3. Kantaputra PN, Pruksachatkunakorn C, Vanittanakom P: RappHodgkin syndrome with palmoplantar keratoderma, glossy tongue,

Tongue

407

congenital absence of the lingual frenum and sublingual caruncles. Am J Med Genet 79:343, 1998.

13.3 Macroglossia Macroglossia denotes enlargement of the tongue, some cases having congenital etiology and others acquired. Enlargement may produce airway obstruction and be associated with noisy breathing, drooling, slurred speech, difficult swallowing, spreading of teeth, and open bite. Pressure of the teeth on the tongue may cause marginal scalloping1 (Table 13-1). An enlarged tongue, from whatever cause, may be especially distressing to parents because the child may appear mentally retarded. Vogel et al.1 have classified tongue enlargement into two categories: (a) true macroglossia and (b) relative macroglossia. True macroglossia, in turn, is divided into congenital and acquired causes. Congenital causes, described elsewhere in this section, include hemangioma and lymphangioma. Muscular enlargement would include such disorders as hemihyperplasia (hemihypertrophy) (Fig. 13-3),2 and Beckwith-Wiedemann syndrome.3–5 Glycogen storage disease type II (Pompe disease); mucopolysaccharidoses (MPS) I, II, and VI; mannosidosis; and I-cell disease are among the systemic diseases associated with tongue enlargement.6 Neoplastic enlargement (various hamartomas and choristomas, cysts, and neurofibromatoses) is discussed extensively elsewhere in this section (see also Table 13-2).7,8 Acquired macroglossia includes such categories as neoplasms (lymphoma, carcinoma), systemic disorders (amyloidoses), and local reactive change (angioneurotic edema) (Table 13-2). Relative macroglossia refers to a tongue that appears large in spite of its normal size. This is usually due to a malfunction of the tongue for any of various reasons (e.g., jaw underdevelopment, lingual dystonia). Again, relative macroglossia has been divided into congenital (trisomy 21, cretinism) and acquired (edentulousness, myxedema) causes (Table 13-3).9,10 Many quite diverse conditions can produce a large tongue, and there have been a number of classifications that have attempted to encompass all known causes of tongue enlargement.1 One of the better recent publications addressing this problem is that of Vogel et al.1 As they point out, clinical presentation is variable. Depending on the size of the tongue and on the nature of the disorder, the infant can exhibit noisy breathing, have difficulty with

Fig. 13-3. Macroglossia associated with hemihyperplasia. (Courtesy of Dr. James E. Vogel, Johns Hopkins Hospital, Baltimore, MD.) Table 13-2. Clinical classification of true macroglossia Congenital

Vascular malformation (lymphatic, venous, capillary) Muscular enlargement (hemihypertrophy, Beckwith-Wiedemann syndrome) Systemic disorder (mucopolysaccharide storage disorders) Tumor (dermoid cyst, rhabdomyoma) Acquired

Tumor (lymphoma, epidermoid carcinoma) Table 13-1. Clinical presentations of macroglossia

Systemic disorder (amyloidosis, gigantism) Local reactive change (edema, vascular congestion)

Airway obstruction Noisy breathing

From Vogel et al.1

Difficulty with chewing/swallowing Drooling

Table 13-3. Causes of relative macroglossia

Slurred speech

Congenital

Perception of mental retardation

Systemic disorder (Down syndrome, cretinism)

Widened interdental spaces Scalloping/crenations

Acquired

Open-bite deformity/mandibular prognathism

Functional (postoperative maladaptation)

Dry/cracked tongue

Elevation (Ludwig’s angina, edentulous)

Ulceration/secondary infection/hemorrhage

Systemic disorder (myxedema)

From Vogel et al.1

From Vogel et al.1

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swallowing, and drool, and have open bite, wide interdental spaces, and slurred speech. If the tongue enlargement is massive, the dorsal surface may be dried, cracked, ulcerated, infected, or hemorrhagic. Anterior wedge resection usually is adequate to reduce tongue size.11 References (Macroglossia) 1. Vogel JE, Mulliken JB, Kaban LB: Macroglossia: a review of the condition and a new classification. Plast Reconstr Surg 78:715, 1986. 2. Wittman A: Macroglossia in acromegaly and hypothyroidism. Virchows Arch A 373:353, 1977. 3. Salman RA: Oral manifestations of Beckwith-Wiedemann syndrome. Spec Care Dentist 8:23, 1988. 4. Arons MS, Solataire GB, Grunt JA: The macroglossia of BeckwithWiedemann syndrome. Plast Reconstr Surg 45:341, 1970. 5. McManamny DS, Barnett JS: Macroglossia as a presentation of Beckwith’s syndrome. Plast Reconstr Surg 75:170, 1985. 6. Nyhan WL: Understanding inherited metabolic disease. Clin Symp 32:1, 1980. 7. Ayres WW, Delaney AJ, Backer MH: Congenital neurofibromatous macroglossia associated in some cases with von Recklinghausen’s disease. Cancer 5:721, 1952. 8. Basma NJ, Robin PE: Hemimacroglossia associated with plexiform neurofibromatosis. J Laryngol Otol 101:743, 1987. 9. Ardran GM, Harker P, Kemp FH: Tongue size in Down syndrome. J Ment Defic Res 16:160, 1972. 10. Farkas LG, Munro IR, Kolar JC: Abnormal measurements and disproportions in the face of Down syndrome patients. Plast Reconstr Surg 75:159, 1985. 11. Rizer FM, Schechter GL, Richardson MA: Macroglossia: etiologic considerations and management techniques. Int J Pediatr Otorhinolaryngol 8:225, 1985.

13.4 Bifid Tongue Clefting of the anterior tongue constitutes a bifid tongue. In bifurcation of the tongue tip, the degree of splitting varies from patient to patient. Differentiation must be made between true and false bifid tongue, the latter being observed during tongue protrusion in individuals with ankyloglossia (Cupid’s bow). Isolated bifid tongue is rare, but it can be associated with cleft mandible and various syndromes.1 In the oral-facial-digital syndromes, the Fig. 13-4. Bifid tongue and hyperplastic frenula that traverse the mucobuccal fold in oral-facial-digital syndrome type I. (Courtesy of Dr. M. Perko, Zurich, Switzerland.)

tongue may be bifid, trifid, or tetrafid (Fig. 13-4). Other considerations occasionally associated with bifidity of the tongue tip are median mandibular cleft, mandibulofacial dysostosis, and cleft palate.2–4 Bifid tongue has also been associated with natal teeth and hearing loss5 and with oral duplication.1 The tongue, anterior to the circumvallate papillae, is formed from two lateral tubercles derived from the first branchial arch that fuse in the midline between the 4th and 5th embryonal weeks. Failure of fusion of the tubercles causes cleft (bifid or lobulated) tongue. Sedano and Freyte6 reported a prevalence of 5.3 per 1000 or one affected per 189 school-aged Mexican children. There is a higher proportion of boys affected, with a prevalence male to female ratio of approximately 2:1.7 Bifid tongue can be corrected with plastic surgery. References (Bifid Tongue) 1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 2. Matheny M, Hall B, Manaligod JM: Otolaryngologic aspects of oralfacial-digital syndrome. Int J Pediatr Otorhinolaryngol 53:39, 2000. 3. Chidzonga MM, Shija JK: Congenital median cleft of the lower lip, bifid tongue with ankyloglossia, cleft palate and submental epidermoid cyst: report of a case. J Oral Maxillofac Surg 46:809, 1988. 4. Nocini PF, Urbani G, Manfrani F, et al.: Bifid tongue associated with other maxillofacial pathology. Minerva Stomatol 36:511, 1987. 5. Darwish S, Sastry KA, Ruprecht A: Natal teeth, bifid tongue and deaf mutism. J Oral Med 42:49, 1987. 6. Sedano HO, Freyte IC: Clinical orodental malformations in Mexican children. Oral Surg 68:300, 1989. 7. Almeida LE, Ulbrich L, Togni F: Mandible cleft: report of a case and review of the literature. J Oral Maxillofac Surg 60:681, 2002.

13.5 Fissured Tongue, Scrotal Tongue, Lingua Plicata Definition

Fissured tongue, scrotal tongue, and lingua plicata are multiple linear fissures of various depths on the dorsal surface of the tongue with variation of clinical appearance of lingual papillae (Fig. 13-5).

Fig. 13-5. Fissured tongue. Can be found in the normal population and has no significance.

Tongue

Diagnosis

On careful examination, most tongues present some degree of furrowing. Diagnosis of fissured tongue can be achieved by asking the patient to push the tip of the tongue against the anterior mandibular teeth, because during this maneuver the fissures become accentuated. A single central groove in the midline of the tongue is not considered a fissured tongue. Kullaa-Mikkonen1,2 and Kullaa-Mikkonen and Sorvari3,4 proposed two types of fissured tongue: (1) fissured tongue with normal-appearing filiform papillae and (2) so-called fissured tongue syndrome (FTS) characterized by fissured tongue with smooth-surfaced papillae preceded by geographic tongue. In FTS, geographic and fissured tongue are believed to be different manifestations of the same condition and to have autosomal dominant inheritance with variable penetrance. The tongue may become fissured and/or lobulated in patients with pernicious anemia or with Sjo¨gren syndrome. Fissured tongue is seen in 30% of patients with trisomy 21 and is part of MelkerssonRosenthal syndrome.5 Some authors have postulated that fissured tongue may be a mucosal manifestation of generalized pustular psoriasis.6,7 Hietanen et al.8 and Dawson6 found fissured tongue in 9.5% of patients with psoriasis. Considering that oral psoriasis is rare and that fissured tongue is seen in the general population with a prevalence that varies from 0.5% to 50% (according to the population examined), it is safe to assume that the 9.5% prevalence for fissured tongue in psoriatic patients probably represents a chance association and not a true oral manifestation of psoriasis. Etiology and Distribution

Fissured tongue is thought to have multifactorial etiology.9 It has been suggested that a combination of impaired immunologic mechanism and gastrointestinal disease (malabsorption) may play roles in the production of FTS.1 Based on the assumption that both generalized pustular psoriasis and fissured tongue are thought to be multifactorial in etiology with genetic predisposition being one of the factors, Hubler7 has suggested that the two entities may share genes. Prevalence values for fissured tongue have ranged from 3.2 to 538 affected per 1000 examined individuals,9–16 with this diversity of values being attributed to the possibility of one or more etiologic factors being present to a greater or lesser degree in the populations examined. Sedano et al.,15 in a recent survey of 43,000 school-aged Mexican children, reported a statistically significant difference between the prevalences in boys (168.3 per 1000) and girls (145.2 per 1000). This finding has been noted earlier.9–11,13 Aboyans and Ghaemmaghami17 reported no increase in the incidence of fissured tongue with age, but Sedano et al.15 found a prevalence value of 140.9 per 1000 for children aged 6 to 10 years and a prevalence of 193.0 per 1000 in children aged 11 to 14 years. This finding tends to agree with those of Chosack et al.11 and Halperin et al.,12 who reported a steady rise in the prevalence of fissured tongue with increasing age. Prognosis and Treatment

Prognosis is excellent. The condition does not require treatment. In occasional cases in which the fissures are extremely deep, superimposed infection with Candida albicans can occur. In those cases, antimycotic therapy and proper oral hygiene will effect a cure.

409

References (Fissured Tongue, Scrotal Tongue, Lingua Plicata) 1. Kullaa-Mikkonen A, Pentilla I, Kotilainen R, et al.: Hematological and immunological features of patients with fissured tongue syndrome. Br J Oral Maxillofac Surg 25:481, 1987. 2. Kullaa-Mikkonen A: Familial study of fissured tongue. Scand J Dent Res 96:366, 1988. 3. Kullaa-Mikkonen A, Sorvari TE: Lingua fissurata. A clinical, stereomicroscopic and histopathological study. Int J Oral Maxillofac Surg 15:525, 1986. 4. Kullaa-Mikkonen A, Sorvari TE: A scanning electron microscopic study of fissured tongue. J Oral Pathol 15:93, 1986. 5. Powell FC: Glossodynia and other disorders of the tongue. Dermatol Clin 5:687, 1987. 6. Dawson TAJ: Tongue lesions in generalized pustular psoriasis. Br J Dermatol 91:419, 1974. 7. Hubler WR Jr: Lingual lesions of generalized pustular psoriasis. Report of five cases and a review of the literature. J Am Acad Dermatol 11:1069, 1984. 8. Hietanen J, Salo OP, Kanerva L, et al.: Study of the oral mucosa in 200 consecutive patients with psoriasis. Scand J Dent Res 92:50, 1984. 9. Redman RS: Prevalence of geographic tongue, fissured tongue, median rhomboid glossitis and hairy tongue among 3,611 Minnesota schoolchildren. Oral Surg 30:390, 1970. 10. Bouquot JE, Gundlach KKH: Odd tongues: the prevalence of common tongue lesions in 23,616 white Americans over 35 years of age. Quintessence Int 17:719, 1986. 11. Chosack A, Zadik D, Eidelman E: The prevalence of scrotal tongue and geographic tongue in 70,359 Israeli schoolchildren. Community Dent Oral Epidemiol 2:253, 1974. 12. Halperin V, Kolas S, Jefferies KR, et al.: Occurrence of Fordyce glands, benign migratory glossitis, median rhomboid glossitis and fissured tongue in 2,478 dental patients. Oral Surg 6:1072, 1953. 13. Kullaa-Mikkonen A, Mikkonen M, Kotilainen R: Prevalence of different morphologic forms of the human tongue in young Finns. Oral Surg 53:152, 1982. 14. Sawyer DR, Taiwo EO, Mosadomi A: Oral anomalies in Nigerian children. Community Dent Oral Epidemiol 12:269, 1984. 15. Sedano HO, Carreon Freyre I, Garza de la Garza ML, et al.: Clinical orodental malformations in Mexican school aged children. Oral Surg 68:300, 1989. 16. Von Neuschulz B, Klammt J: Untersuchungen zur Lingua plicata. Zahn Mund Kieferheilkd 74:472, 1986. 17. Aboyans V, Ghaemmaghami A: The incidence of fissured tongue among 4,009 Iranian dental outpatients. Oral Surg Oral Med Oral Pathol 36:34, 1973.

13.6 Glossopalatine Ankylosis (Ankyloglossum Superius) Glossopalatine ankylosis involves a frenulum of variable thickness extending from the dorsal surface of the tongue to the hard palate or the maxillary alveolar ridge. The diagnosis is self-evident on intraoral clinical inspection. The frenulum is generally attached to the anterior portion of the tongue, the tongue tip being cleft. If there is cleft palate, the tongue may be attached to the nasal septum. Differentiation from persistent buccopharyngeal membrane is made on the basis of location, the latter being at the posterior portion of the tongue and at the level of the anterior tonsillar pillars. In glossopalatine ankylosis, the tongue is attached to the hard palate or to the maxillary alveolar ridge. The lingual attachment generally occurs in the anterior part of the tongue. Glossopalatine ankylosis is generally associated with other congenital anomalies such as cleft palate, ankyloglossia superior

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Craniofacial Structures

Fig. 13-6. Ankyloglossia superior syndrome. Child has a small mouth, attachment of the tongue to the hard palate, and reduction anomalies of the digits. (Courtesy of Dr. H. Gima, Okinawa, Japan.)

syndrome, underdeveloped mandible, and hypoplastic upper lip (Fig. 13-6).1–4 Hall5 and Gorlin et al.3 have included glossopalatine ankylosis as one of the findings in hypoglossia-hypodactyly or oromandibular-limb hypogenesis syndromes. This is borne out in the case of Zennano et al.6 Plastic surgery is used to liberate the tongue, with excellent results. References (Glossopalatine Ankylosis [Ankyloglossum Superius]) 1. Chicarilli ZN, Polayes IM: Oromandibular limb hypogenesis syndromes. Plast Reconstr Surg 76:13, 1985. 2. DeConinck A, Deleise M: Ankylose palato-linguale conge´nitale avec anomalies des extre´mitie´s. Acta Stomatol Belg 72:89, 1975. 3. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 4. Gima H, Yamashiro M, Tomoyose Y: Ankyloglossum superius syndrome. J Oral Maxillofac Surg 45:158, 1987. 5. Hall BD: Aglossia-adactylia. Birth Defects Orig Artic Ser VII(7):233, 1971. 6. Zennano O, Chabrol A, Mullon MH, et al.: Ankyloglossum superius. Rev Laryngol Otol Rhinol 1131:55, 1992.

13.7 Ankyloglossia: Tongue-tie, Partial Ankyloglossia, Total and Lateral Ankyloglossia Definition

Isolated partial ankyloglossia is characterized by a frenulum of variable size, generally located on the midventral surface of the tongue, that extends from the lingual gingival mucosa to nearly the tip of the tongue (Fig. 13-7). This frenulum restricts tongue

Fig. 13-7. Ankyloglossia. The lingual frenulum is attached to the mandibular gingiva. Minor adhesions of this type do not cause speech abnormalities.

movement and generally does not allow protrusion of the tip of the tongue beyond the vermilion border of the lower lip. Diagnosis

The diagnosis is established by clinical inspection. The presence of a thick, short ventral frenulum, with inability to protrude the tongue, is quite indicative of isolated partial ankyloglossia. When the tongue is protruded, the short frenulum creates a small notch on the tongue tip, mimicking a minor case of bifid tongue. In extreme cases of tongue-tie, minor alterations in speech may be present when articulating one or more tongue tip sounds such as t, d, l, th, and s.1 Partial (simple) attachment or tongue-tie comprises the majority of cases of ankyloglossia.

Tongue

Total and/or lateral ankyloglossia are rare conditions in which the tongue is extensively fused to the oral floor or alveolar gingiva. Patients with extensive ankyloglossia have presented with associated anomalies of the limbs. We suggest that these cases represent a form of oromandibular-limb hypogenesis syndrome. Ankyloglossia has been reported to be associated with the oral-facial-digital syndrome I and cleft mandible.2,3,14,15 Ankyloglossia has also been combined with cleft palate in Icelandic, Canadian, and German kindreds. In the Icelandic families, the males are all affected while only 70% of female carriers are affected. The gene maps to Xq21.31-q21.33.13 Etiology and Distribution

The tongue originates from the first, third, and fourth pharyngeal arches. The two lateral lingual swellings and a medial swelling (tuberculum impar) that form the anterior two-thirds of the tongue are derived from the first arch. During early stages of development, the tongue is fused to the floor of the mouth. Separation is achieved by extensive cellular degeneration, the frenulum being the only remaining tissue in this area. Ankyloglossia occurs when the resorption process is not completed. Although several authors have suggested autosomal dominant inheritance, in our view single gene inheritance of simple tongue-tie is untenable. The association of X-linked cleft palate and simple ankyloglossia is an obvious exception.4,13 De Porte and Parkhurst5 found 99 cases of ankyloglossia among 273,604 live births in New York State excluding New York City. McEnery and Gaines6 found four cases among 1000 children with speech defects, and Green7 reported 12 cases of tongue-tie among 40,000 children with speech defects. Sedano8 reported 8.3 cases per 1000 among Mexican school-aged children, the prevalence among males being 1.6 times that of females, values higher than those of previous reports.9–15

411

11. Sedano HO, Carreon Freyre I, Garza de la Garza ML, et al.: Clinical orodental malformations in Mexican school aged children. Oral Surg 68:300, 1989. 12. Wright JE: Tongue-tie. J Paediatr Child Health 31:276, 1995. 13. Braybrook C, Warry G, Howell G, et al.: Physical and transcriptional mapping of the X-linked cleft palate and ankyloglossia (CPX) critical region. Hum Genet 108:537, 2001. 14. Almeida LE, Ulbrich L, Togni F: Mandible cleft: report of a case and review of the literature. J Oral Maxillofac Surg 60:681, 2002. 15. Armstrong AP, Waterhouse N: Tessier 30 median mandibular cleft: case report and literature review. Br J Plast Surg 49:536, 1996.

13.8 Median Rhomboid Glossitis Median rhomboid glossitis is a somewhat rhomboid reddish area in the midline of the dorsum of the tongue, immediately anterior to the circumvallate papillae (Fig. 13-8). Its long axis lies in the median raphe. It usually measures about 1.52.5 cm. Although usually flat, it can be raised above the surface from 2 to 5 mm and may be fissured or mammilated. The pink or rosy color is due to an absence of filiform papillae and is not primarily inflammatory. Earlier investigators proposed that median rhomboid glossitis was due to persistence of the tuberculum impar, an unpaired structure arising between the first and second pharyngeal arches and normally overgrown by the lateral lingual tubercles. If the tuberculum impar is not overgrown, the persistent embryonal structure would give rise to a rhomboidal plaque. Theoretically, the anomaly could be somewhat anteriorly displaced and of any shape. More recent investigators have suggested that the condition is not congenital.1–4 Baughman1 believed that it was an inflammatory, infectious, or degenerative process that occurred only in adults. Redman,5 however, reported its occurrence in children. Farman et al.4 found Candida in about one-half of the cases, but did not

Prognosis and Treatment

Prognosis is excellent. Plastic surgery can be carried out in extreme cases to improve pronunciation. Surgery is indicated in cases of lateral and total ankylosis. References (Ankyloglossia) 1. Williams WN, Waldron CM: Assessment of lingual function when ankyloglossia (tongue-tie) is suspected. J Am Dent Assoc 110:353, 1985. 2. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 3. Russell AG, Staley CE: Congenital cleft mandible. J Oral Surg 19:257, 1961. 4. Bjo¨rnsson A, Arnason A, Tippet P: X-linked cleft palate and ankyloglossia in an Icelandic family. Cleft Palate J 26:3, 1989. 5. De Porte JV, Parkhurst E: Congenital malformations and birth injuries among the children born in New York State outside of New York City, in 1940–1942. NY State J Med 45:1097, 1945. 6. McEnery ET, Gaines FP: Tongue-tie in infants and children. J Pediatr 18:252, 1941. 7. Green JS: Anomalies of the speech mechanism and associated voice and speech disorders. NY State J Med 45:605, 1945. 8. Sedano HO: Congenital oral anomalies in Argentinian children. Community Dent Oral Epidemiol 3:61, 1975. 9. Catlin FI, De Haan V: Tongue-tie. Arch Otolaryngol 94:548, 1971. 10. Sawyer DR, Taiwo EO, Mosadomi A: Oral anomalies in Nigerian children. Community Dent Oral Epidemiol 12:2269, 1984.

Fig. 13-8. Median rhomboid glossitis. The lozenge-shaped bald area on the midline of the tongue extends to the sulcus terminalis.

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Craniofacial Structures

indicate a cause-and-effect relationship. Cooke2 was more certain of candidal etiology. However, the oral candidal organisms are so common that we are skeptical concerning the relationship. It may be that the disorder is developmental and that the area, being devoid of papillae, is more susceptible to hosting candidal organisms.6–8 Its reported frequency has ranged from one per 90 to 400 individuals. There appears to be a male to female ratio of 3:1 but no racial predilection.5,9–11 Microscopically, there is absence of filiform papillae. The epithelium is hyperplastic with marked downgrowth. Some serous salivary glands exhibit squamous metaplasia with epithelial pearl formation (pseudoepitheliomatous hyperplasia), which may erroneously be diagnosed as squamous cell carcinoma. A chronic inflammatory infiltrate is usually seen in the subepithelial layer, and often there is vascular dilation. Prognosis is excellent. No treatment is needed.

5. Chen YR, Noordhoff MS: Duplication of stomadeal structures. Report of three cases with literature review and suggestion for classification. Plast Reconstr Surg 84:733, 1989. 6. Lu CY, Teng RJ, Hou JW, et al.: Bifid tongue associated with midline cleft palate, mandible, cervical vertebrae, and linea alba. Eur J Pediatr 157:86, 1998.

References (Median Rhomboid Glossitis) 1. Baughman RA: Median rhomboid glossitis. A developmental anomaly? Oral Surg 31:56, 1971. 2. Cooke BE: Median rhomboid glossitis: candidiasis and not a developmental anomaly. Br J Dermatol 93:399, 1975. 3. Delemarre JFM, van der Waal I: Clinical and histopathologic aspects of median rhomboid glossitis. Int J Oral Surg 2:203, 1973. 4. Farman AG, van Wyck CW, Staz J, et al.: Central papillary atrophy of the tongue. Oral Surg 43:48, 1977. 5. Redman R: Prevalence of geographic tongue, fissured tongue, median rhomboid glossitis and hairy tongue among 3,611 Minnesota schoolchildren. Oral Surg 30:390, 1970. 6. Van der Wal N, van der Waal I: Candida albicans in median rhomboid glossitis. Int J Oral Maxillofac Surg 15:322, 1986. 7. Van der Waal I, Beemster G, van der Kwast WA: Median rhomboid glossitis caused by Candida? Oral Surg 47:31, 1979. 8. Ullmann W, Hoffman M: Glossitis rhombica mediana. Eine Studie an 4422 dermatologisch Patientin. Hautarzt 32:571, 1981. 9. Halperin V, Kolas S, Jefferis K, et al.: Occurrence of Fordyce spots, benign migratory glossitis, median rhomboid glossitis and fissured tongue in 2,478 dental patients. Oral Surg 6:1072, 1953. 10. Schaumann BF, Peagler F, Gorlin RJ: Minor craniofacial anomalies among a Negro population. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 29:566, 729, 1990. 11. Wright BA: Median rhomboid glossitis. Oral Surg 46:806, 1978.

13.9 Double Tongue Double tongue has been part of oral duplication on many occasions. The reader is referred to Gorlin et al.1 for more complete discussion. Examples are those of Calomeni and Jordan,2 Bartholdson et al.,3 Britto et al.,4 Chen and Noordhoff,5 and Lu et al.6 Cleft palate often accompanies double tongue. We suspect this overlaps bifid tongue. References (Double Tongue) 1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 2. Calomeni AA, Jordan JE: Multiple congenital defects. J Am Dent Assoc 107:432, 1983. 3. Bartholdson L, Hellstrom SO, Soderberg O: A case of double tongue. Scand J Plast Reconstr Hand Surg 25:93, 1991. 4. Britto JA, Ragoowansi RH, Sommerlad BC: Double tongue, intraoral anomalies, and cleft palate. Cleft Palate Craniofac J 37:410, 2000.

Fig. 13-9. Lingual thyroid presenting as a mass located at the foramen cecum. (Courtesy of Dr. M. R. Kamat, Riyadh, Saudi Arabia.)

Fig. 13-10. Enhanced axial CT scan shows homogeneous mass of a lingual thyroid (arrows) at the base of the tongue. (From Willinsky et al.5)

Tongue

413

Fig. 13-11. A and B. 131I scintigraphy in frontal and lateral planes showing a functional lingual thyroid at tongue base and absence of functional thyroid at normal site. C. Biopsy material from a lingual mass shows thyroid tissue covered by normal-appearing mucosa. (From van der Wal et al.10)

13.10 Lingual Thyroid Definition

Lingual thyroid is a nodule of variable size composed of normal thyroid tissue located on the dorsal surface of the tongue in the midline at the level of the foramen cecum or within the body of the tongue (Fig. 13-9). Diagnosis

Lingual thyroid should be suspected when a mass or nodule is located at the level of the foramen cecum in front of the terminal sulcus of the tongue. Nevertheless, differential diagnosis includes various tongue neoplasms, hamartomas, choristomas, and lingual tonsillitis.1,2 Radioactive iodine 123 or technitium 99m scanning and computed tomography scans will demonstrate the presence of thyroid tissue at the lingual location (Fig. 13-10).3–5 A biopsy procedure is not indicated unless it has been proven that the patient has a normally located and functional thyroid gland. Lingual thyroid generally presents as a round, purplish nodule 2 to 3 cm in diameter. Occasionally it can be hemorrhagic and, if very large, may displace the epiglottis.6 Ninety percent of cases occur at the level of the foramen cecum, but some patients may present thyroid tissue embedded in the body of the tongue, sublingually or rarely in the anterior portion of the tongue.7 Rarely, there is dual ectopic thyroid.26 On palpation the mass is firm and encapsulated. This aids in differentiation from lingual tonsillitis, which is soft and friable.1 In females, lingual thyroid increases in size during times of marked endocrine activity such as puberty, pregnancy, and menopause.8 It is during those periods that the majority of cases in women have been detected. Some patients may have obstructive problems such as dysphagia (50%), dysphonia (44%), or dyspnea (28%).5–9 Over 70% of patients with lingual thyroid have total absence of the normally located thyroid gland (Fig. 13-11). Infants with lingual thyroid may present symptoms of hypothyroidism.10 Etiology and Distribution

The thyroid gland is formed during weeks 3 to 4 of embryonal development by invagination of proliferating endoderm in the

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Craniofacial Structures

floor of the pharynx at the level of the future foramen cecum on the dorsal surface of the tongue, between the tuberculum impar and the copula. This tissue descends in front of the pharyngeal gut but remains attached to the tongue by a thin evanescent canal known as the thyroglossal duct. Ectopic thyroid tissue can be found at different levels of the duct, from the tongue base to the neck. Failure of descent of this epithelial proliferation results in ectopic thyroid. Over 400 cases of this anomaly have been reported in the literature with a female to male ratio of 4 to 5:1.6,10,11 Residual thyroid tissue is found in the vicinity of the foramen cecum in 10% of 200 routine autopsies, with equal distribution among the sexes. Baughman12 reported identical findings (9.8%) in 184 biopsies, but in a study of 100 autopsies, Soames13 did not find evidence of thyroid tissue in the tongue. Williams et al.14 reported the frequency of lingual thyroid at 1.3 per 10,000 births. Nearly all examples of lingual thyroid have been isolated. However, there are a few examples in siblings.15–17 Sensorineural hearing loss has been an associated finding in a few cases.18,19 Prognosis and Treatment

Occasional cases of a benign neoplasm arising in a lingual thyroid have been reported.2 Adenocarcinoma developing in the lingual thyroid has been reported in several instances, as has goiter.10,11,20,21 Airway obstruction, especially in children, has been observed in several cases.4,7,9 Myxedema will develop after surgical removal of the lingual thyroid if there is no orthopic gland. Thyroiditis can occur in the normal thyroid gland, when present, following surgical ablation of the ectopic lingual thyroid. Surgery is indicated only if the lingual thyroid is extremely large or if it does not respond to suppressive medical therapy with thyroxine or ablation with radioactive iodine.4 Laser surgery has been used to avoid profuse hemorrhage, as there is high vascularity of the lingual thyroid.9 Autotransplantation of the ectopic thyroid has been reported to have a 30% success rate.22 The rectus abdominis muscles or the neck are chosen as an autotransplant site because of easy access.23 Thyroglossal duct cyst refers to a cyst that develops from persistence and dilation of the embryonic thyroglossal tract. Although the tongue arises at the foramen cecum, the cyst usually presents below the tongue at the level of the hyoid bone. It has occasionally been noted in the oral floor.28 Rarely, there is familial occurrence of thyroid anomalies.15,16,24,25 Blandino et al.27 elegantly discuss magnetic resonance imaging findings. References (Lingual Thyroid) 1. Puar RK, Pura HS: Lingual tonsillitis. South Med J 79:1126, 1986. 2. Soni NK, Chatterji P: An unusual tumor mistaken as a lingual thyroid. J Laryngol Otol 98:1055, 1984. 3. Miller JH: Lingual thyroid gland: sonographic appearance. Radiology 156:83, 1985. 4. Kansal P, Sakati N, Rifai A, et al.: Lingual thyroid. Diagnosis and treatment. Arch Intern Med 147:2046, 1987. 5. Willinsky RA, Kassel EE, Cooper PW, et al.: Computed tomography of lingual thyroid. J Comput Assist Tomogr 11:182, 1987. 6. Baldwin RL, Copeland SK: Lingual thyroid and associated epiglottitis. South Med J 81:1538, 1988. 7. Chanin LR, Greenberg LM: Pediatric upper airway obstruction due to ectopic thyroid: classification and case reports. Laryngoscope 98:422, 1988. 8. Kalan A, Tariq M: Lingual thyroid gland: clinical evaluation and comprehensive management. Ear Nose Throat J 78:340, 1999. 9. Maddern BR, Werkhaven J, McBride T: Lingual thyroid in a young infant presenting as airway obstruction: report of a case. Int J Pediatr Otorhinolaryngol 16:77, 1988.

10. Van der Wal N, Wiener JD, van der Waal I: Lingual thyroid. A clinical and postmortem study. Int J Oral Maxillofac Surg 15:431, 1986. 11. Koch CA, Picken C, Clement SC, et al.: Ectopic lingual thyroid: an otologic emergency beyond childhood. Thyroid 10:511, 2000. 12. Baughman RA: Lingual thyroid and lingual thyroglossal tract remnants— a clinical and histopathologic study with review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 34:781, 1972. 13. Soames JV: A review of the histology of the tongue in the region of the foramen cecum. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 36:220, 1973. 14. Williams ED, Toyn CE, Harach HR: The ultimobranchial gland and congenital thyroid abnormalities in man. J Pathol 159:135, 1989. 15. Orti E, Castells S, Qazi GH, et al.: Familial thyroid disease. Lingual thyroid in two siblings and hypoplasia of the thyroid lobe in a third. J Pediatr 78:675, 1971. 16. Kaplan M, Kauli R, Raviv U, et al.: Hypothyroidism due to ectopy in siblings. Am J Dis Child 131:1264, 1977. 17. Rosenberg T, Gilboa Y: Familial thyroid ectopy and hemiagenesis. Arch Dis Child 55:639, 1980. 18. Elidan J, Christin R, Gay I: Lingual thyroid, sensorineural hearing loss and mental retardation: a coincidental association? Laryngol Otol 97:539, 1983. 19. Wetke R: Struma baseos linguae og bilateral perceptiv ha¨rensaettelse. Ugeskr Laeger 151:2734, 1989. 20. Fish J, Moore RM: Ectopic thyroid tissue and ectopic carcinoma: a review of the literature and report of a case. Ann Surg 157:212, 1963. 21. Weider DJ, Parker W: Lingual thyroid. Ann Otol Rhinol Laryngol 86:841, 1977. 22. Potdar GG, Desai PB: Carcinoma of lingual thyroid. Laryngoscope 81:427, 1971. 23. Al-Samarrai AYI, Crankson SJ, Al-Jobori A: Autotransplantation of lingual thyroid into the neck. Br J Surg 75:287, 1988. 24. Klin B, Serour F, Fried K, et al.: Familial thyroglossal duct cyst. Clin Genet 43:101, 1993. 25. Castillo-Toucher S, Castillo P: Autosomal dominant inheritance of thyroglossal duct cyst. Clin Genet 45:111, 1994. 26. Hazarika P, Siddiqui SA, Pujary K, et al.: Dual ectopic thyroid. J Laryngol Otol 112:393, 1998. 27. Blandino A, Salvi L, Scribano E, et al.: MRI findings in thyroglossal duct cysts. Eur J Radiol 11:207, 1990. 28. Dolata J: Thyroglossal duct cyst in the mouth floor: an unusual location. Otolaryngol Head Neck Surg 110:580, 1994.

13.11 Choristoma of Tongue: Enterogenous Cyst of Tongue Definition

An enterogenous cyst of the tongue is a cystic mass containing gastric or intestinal mucosa located in the tongue. A choristoma is a mass of tissue that is histologically normal for a part of the body other than the site at which it is located. The term choristoma derives from the Greek choristos—separated—and is used to indicate displaced or heterotopic tissue. Diagnosis

Heterotopic islands of gastric mucosa or enterogenous cysts (often called intestinal duplications) have been found in the esophagus, small intestines, mediastinum, vitelline duct, pancreas, gallbladder, and Meckel diverticulum and are dealt with in Sections 25.3 and 35.4 of this volume. Here, we will deal only with oral cysts lined by gastric or intestinal epithelium. The choristomatic cyst may be entirely enclosed within the body of the tongue or oral floor, or it may communicate with the surface (Fig. 13-12). The cystic wall may be composed partly (or rarely totally)

Tongue

415

Fig. 13-12. Choristoma of the tongue. Left: newborn infant with large cystic tongue preventing closure of the jaws. Right: microscopic view of the cyst lined with nonciliated columnar epithelium. (Courtesy of Dr. P. Arcand, Hospital Sainte-Justine, Montreal.)

of gastric mucosa of the type seen in the body and fundus of the stomach. Both parietal and chief cells may be found. Rarely there is associated pancreatic tissue. Often there is a smooth muscle coat. Intestinal or even esophageal mucosa may line the cyst and, upon occasion, gastric and intestinal mucosa. Rarely cartilage and pancreatic tissue has been found.

Where there is connection of the cyst to the oral cavity, the tubelike structure descending into the cyst is lined by stratified squamous epithelium with sebaceous glands emptying into it. Several authors have described a lingual epithelial-lined tube surrounded by sebaceous glands but without gastric or intestinal epithelium. Sebaceous glands, as an isolated finding, may be found in the same area.6 Respiratory epithelium and/or dermoid cyst may also be found.7

Etiology and Distribution

Prognosis and Treatment

The origin of the heterotopic gastric or intestinal epithelium is not known. It may be derived from misplacement of embryonal rests of undifferentiated mucosa. The tongue arises from the floor of the pharynx in the region of the first three pharyngeal (branchial) arches. In the embryo of 3 to 4 weeks, the undifferentiated primitive endoderm lies adjacent to the anlage of the tongue. In the fusion of the lateral lingual tubercles to form the anterior two-thirds of the tongue, rests may become entrapped. Lingual cysts lined by stratified and/or ciliated or nonciliated columnar epithelium are probably related embryologically, since the primitive foregut epithelium has the ability to differentiate along all these lines. Among the 65 cases of gastric or enterogenous cysts of the tongue, there is at least a male to female sex predilection of 3:1. The anterior two-thirds of the tongue was involved in most cases, the oral floor, hypopharynx, and submandibular salivary gland in decreasing order.1–8 A similar lesion has been reported in the lip.1

Prognosis is excellent. Recurrence following surgical removal or CO2 laser is unknown. References (Choristoma of Tongue: Enterogenous Cyst of Tongue) 1. Gorlin RJ, Myers SL: Gastrointestinal cyst of the tongue: a possible duplication cyst of foregut origin? J Oral Maxillofac Surg 55:629, 1997. 2. Daley TD, Wysocki GP, Lovas GL, et al.: Heterotopic gastric cyst of the oral cavity. Head Neck Surg 7:168, 1984. 3. Wurster CF, Ossoff RH, Rao MS, et al.: Heterotopic gastric mucous of the tongue. Otolaryngol Head Neck Surg 93:92, 1985. 4. Arcand P, Granger J, Brochu P: Congenital dermoid cyst of the oral cavity with gastric choristoma. J Otolaryngol 17:219, 1988. 5. Kinoshita Y, Honma Y, Otuka T, et al.: Gastrointestinal mucosal cyst of the oral cavity. J Oral Maxillofac Surg 52:1203, 1994. 6. Kovero O: A sebaceous gland in the dorsal surface of the tongue. Int J Oral Maxillofac Surg 18:206, 1989.

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7. Mirchandani R, Sciubba J, Gloster ES: Congenital oral cyst with heterotopic gastrointestinal and respiratory mucosa. Arch Pathol Lab Med 113:1301, 1989. 8. Willner A, Feghali J, Bassila M: An enteric duplication cyst occurring in the anterior two-thirds of the tongue. Int J Pediatr Otorhinolaryngol 21:169, 1991.

13.12 Choristoma of Tongue: Epidermoid Cyst of Tongue An epidermoid cyst of the tongue is a cystic mass that is lined with squamous epithelium. There are a few examples of lingual cysts lined by nonkeratinizing stratified squamous epithelium. These cysts are to be differentiated from dermoid cysts of the oral floor.1–5 We believe that these cysts are related to enterogenous cysts and to those that are lined by respiratory epithelium, that is, by incorporation of pluripotential embryonal rests. Excellent prognosis follows simple surgical excision. References (Choristoma of Tongue: Epidermoid Cyst of Tongue) 1. Goldberg AF: Dermoid cyst of the tongue. J Oral Surg 23:649, 1965. 2. Quinn JH: Congenital epidermoid cyst of anterior half of tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 13:1283, 1960. 3. Valtonen H, Nuuitinen J, Karla J, et al.: Congenital dermoid cysts of the tongue. J Laryngol Otol 100:965, 1986. 4. Dahlman B, Livaditis A: Congenital cyst of anterior half of tongue. Z Kinderchir 29:244, 1980. 5. Correa MS, Fonoff Rde N, Ruschel HC, et al.: Lingual epidermal cyst: case report in an infant. Pediatr Dent 25:591, 2003.

13.13 Choristoma of Tongue: Cyst Lined with Respiratory Epithelium or Nonciliated Columnar Epithelium A cystic mass of the tongue that contains respiratory epithelium is another type of choristoma. As with the more numerous enterogenous cysts of the tongue, cysts lined by either ciliated or nonciliated epithelium are entirely enclosed within the body of the tongue. Like enterogenous cysts, these cysts represent incorporation of epithelial rests having the potential of differentiating into this form of epithelium. The same explanation may be given for those lingual cysts lined by nonkeratinized stratified squamous epithelium. It should be remembered that the primitive foregut gives rise to parts of both the digestive system and the respiratory tract.1–9,12 A combination dermoid and bronchogenic cyst has been noted, as have an odd cyst of the mandible with respiratory epithelium resulting from postsurgical implant, and a congenital cystadenoma.10–13 Prognosis is excellent. Simple surgical removal is curative. References (Choristoma of Tongue: Cyst Lined with Respiratory Epithelium or Nonciliated Columnar Epithelium) 1. Crawley DE, Miller RH: Enterocystoma of the head and neck. Otolaryngol Head Neck Surg 91:492, 1983. 2. Constantinides CG, Davies MOQ, Cywes S: Intralingual cysts of foregut origin. S Afr J Surg 20:227, 1982. 3. Kim YS, Ahn SK, Lee SH: Sublingual foregut cyst. J Dermatol 25:476, 1998. 4. Boue´ DR, Smith GA, Kraus HF: Lingual bronchogenic cyst in a child. Pediatr Pathol 14:201, 1994.

5. Manor Y, Buchner A, Peleg M, et al.: Lingual cyst with respiratory epithelium: an entity of debatable genesis. J Oral Maxillofac Surg 57:124, 1999. 6. Akerson H, Granger J, Brochu P: Congenital dermoid cyst of the oral cavity with gastric choristoma. J Oral Surg 32:117, 1974. 7. Arcand P, Granger J, Brochu P: Congenital dermoid cyst of the oral cavity with gastric choristoma. J Otolaryngol 17:219, 1988. 8. Ohama K, Asano S, Tsukahara Y, et al.: An unusual alimentary duplication cyst at the floor of the mouth—a proposal of new criteria for alimentary duplications. Z Kinderchir 41:45, 1986. 9. Dahlman B, Livaditis A: Congenital cyst of the anterior half of the tongue. Z Kinderchir 29:244, 1980. 10. Obiechina AE, Arotiba JT, Ogenbiyi T: Coexisting congenital sublingual dermoid and bronchogenic cyst. Br J Oral Maxillofac Surg 37:58, 1999. 11. Koutlas IG, Gillum RB, Harris MW, et al.: Surgical (implantation) cyst of the mandible with ciliated respiratory lining. J Oral Maxillofac Surg 60:324, 2002. 12. Naidoo LCD: Median lingual cyst: review of the literature and report of a case. J Oral Maxillofac Surg 55:172, 1997. 13. Kacker A, de Serres LM: Congenital cystadenoma of the tongue in a neonate: case report with review of the literature. Int J Pediatr Otorhinolaryngol 60:83, 2001.

13.14 Choristoma of Tongue: Brain Tissue in Tongue Extracranial localization of brain tissue is not rare, being most often found in ovarian and testicular teratomas. However, nonteratomatous extracranial brain tissue is relatively uncommon, most examples being nasal gliomas. A few have been found in the oropharynx or palate. None has involved extension to the cranial cavity. There are few convincing examples of heterotopic brain tissue in the tongue (Fig. 13-13).1–12 While heterotopic brain tissue may be viewed as teratomatous, only neuroectodermal elements are present. These consist of glia and ependymal cells. A more likely explanation is displacement of neural elements in the floor of the anterior oral pharynx prior to the closure of the secondary palate. This is compatible with the finding of palatal defect in those with ectopic brain tissue in the nasopharynx. Most have caused dysphagia. Prognosis is excellent. Simple surgical removal is curative.

Fig. 13-13. Choristoma of the tongue. Microscopic view of a lingual inclusion nodule showing heterotopic brain tissue (glial elements) near the overlying stratified squamous epithelium. (From Bychkov et al.1)

Tongue

References (Choristoma of Tongue: Brain Tissue in Tongue) 1. Bychkov V, Gatti WM, Fresco R: Tumor of the tongue containing heterotopic brain tissue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 66:71, 1988. 2. Knox R, Pratt M, Garvin AJ, et al.: Heterotopic lingual brain in the newborn. Arch Otolaryngol Head Neck Surg 115:630, 1989. 3. Ofodile FA, Aghadiuno PO, Oyemade O, et al.: Heterotopic brain in the tongue. Plast Reconstr Surg 69:120, 1982. 4. Landini G, Kitano M, Urago A, et al.: Heterotopic central neural tissue of the tongue. Int J Oral Maxillofac Surg 19:334, 1990. ¨ ber Glioma linguae. Frankfurt Z Pathol 26:214, 1922. 5. Peterer F: U 6. Yokahama S, Nakayama I, Yamashita H, et al.: Heterotopic brain of the tongue. Acta Pathol Jpn 36:1327, 1986. 7. Abdelsayed RA, Wetherington RW, Bent JP III, et al.: Glial choristoma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87:215, 1999. 8. Garcia-Prats MD, Rodriguez-Peralto JL, Carello R: Glial choristoma of the tongue. J Oral Maxillofac Surg 52:977, 1994. 9. Strome SE, McClatchey K, Kileny PR, et al.: Neonatal choristoma of the tongue containing glial tissue: diagnosis and surgical considerations. Int J Pediatr Otorhinolaryngol 33:265, 1995. 10. Halfpenny W, Odell EW, Robinson PD: Cystic and glial mixed hamartoma of the tongue. J Oral Pathol Med 30:368, 2001. 11. Wallach SG, Weiss PR, Llena JF: Glioma of the tongue. Plast Reconstr Surg 100:1245, 1997.

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12. Morita N, Harada M, Sakamato T: Congenital tumors of heterotopic nervous system tissue in the oral cavity. Report of two cases. J Oral Maxillofac Surg 51:1030, 1993.

13.15 Choristoma of Tongue: Chondroma and Osteoma Definition

Chondroma and osteoma are benign cartilaginous or bony growths of the tongue. Diagnosis

The lingual chondroma, in contrast to the osteoma, can arise any place within the tongue, but most often is on or adjacent to a lateral margin or is mid-dorsum (Fig. 13-14). They are usually hard and are characterized by slow growth and considerable mobility. Sizes have ranged from 0.3 to 4.5 cm. Differential diagnosis of choristomas located on the posterior dorsum includes lingual thyroid, hyperplastic lingual tonsils, and neoplasm of minor salivary glands. Those on the lateral border of the tongue embrace so-called traumatic fibroma, granular cell schwannoma (myoblastoma), and neural tumors, whereas those on the ventral surface include tumors of minor salivary gland

Fig. 13-14. Choristoma of the tongue. Left: two separate chondromas of the lateral border of the tongue of a 35-year-old woman. Unlike osteomas, chondromas can occur at any site on the tongue. Right: photomicrograph showing cartilaginous tissue with overlying connective tissue and epithelium. (From Landini et al.3)

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Craniofacial Structures

origin, mucous retention phenomena (mucoceles), lipomas, and various neural tumors. The reports of chondromas of the tongue by Ramachandran and Viswanathan1 and by Plessier and Leroux-Robert2 appear to be examples of choristomas associated with oral-facial-digital syndrome type 1. Etiology and Distribution

Branchial arch cartilages related to the anterior two-thirds of the tongue are derived from Meckel cartilage. Elastic cartilage is found in the epiglottis and in some laryngeal cartilages. Since Landini et al.3 found elastic cartilage, the origin of the choristoma might be from proliferation of ectopic rests of elastic cartilaginous tissue probably from (a) the larynx or (b) proliferation of pluripotential mesenchymal cells of the tongue. While Gentscheff 4 found approximately 30% of both children and adults to have cartilage rests in the tongue on postmortem examination; van der Wal and van der Waal5 found neither bone nor cartilage in 113 autopsies. Cartilaginous tumors of the tongue are rare, there being no more than 40 reports. Of these, about 65% were composed of pure cartilage, the rest being osteocartilaginous.6–11,17 About 50 cases of osteoma of the tongue have been reported.5,10,12–16 Although presenting most often in the 3rd to 4th decades of life, the lingual osteoma is clearly a choristoma, not a neoplasm (Fig. 13-15). In 65%, it arises at or around the foramen cecum. About 25% arise in the lateral margins of the tongue. There is at least a female to male predilection of 3:1. Sizes have ranged from 0.5 to 2.0 cm.

¨ ber Skelettreste in der menschlichen Zunge. Virchows 4. Gentscheff C: U Arch [Anat] 293:129, 1934. 5. Van der Wal N, van der Waal I: Osteoma or chondroma of the tongue: a clinical and postmortem study. Int J Oral Maxillofac Surg 16:713, 1987. 6. Piattelli A, Fioroni M, Orsini G, et al.: Osteochondromatous choristoma of the tongue. J Oral Maxillofac Surg 58:1320, 2000. 7. Wesley RK, Zielinski RJ: Osteochondroma of the tongue. Clinical and histopathologic considerations. J Oral Surg 36:59, 1978. 8. Weitzner S, Stimson PG, McClendon JL: Cartilaginous choristoma of the tongue. J Oral Maxillofac Surg 45:185, 1987. 9. Segal K, Katsav Y, Sidi J, et al.: Chondroma of the tongue: report of two cases. Ann Otol Rhinol Laryngol 93:271, 1984. 10. Tohill MJ, Green JG, Cohen DM: Intraoral osseous and cartilaginous choristomas: report of three cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 63:506, 1987. 11. Yasuoka T, Handa Y, Watanabe F, et al.: Chondroma of the tongue. J Maxillofac Surg 12:188, 1984. 12. Main DMG: Osseous polyp of the tongue: osteoma or choristoma? Br Dent J 156:285, 1984. 13. Krolls SO, Jacoway JR, Alexander WN: Osseous choristomas (osteomas) of intraoral soft tissues. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 32:588, 1971. 14. Engel P, Cherrick HM: Extraosseous osteomas of the tongue. J Oral Med 31:99, 1976. 15. Ishikawa M, Mizukoshi T, Notani K, et al.: Osseous choristoma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 76:561, 1993. 16. Vered M, Lustig JP, Buchner A: Lingual osteomas: a debatable entity. J Oral Maxillofac Surg 56:9, 1998. 17. Mosqueda-Taylor A, Gonzalez-Guevara M, de la Piedre-Garza JM, et al.: Cartilagenous choristomas of the tongue. J Oral Path Med 27: 283, 1998.

Prognosis and Treatment

Surgical removal ensures complete cure. Recurrence is unknown. References (Choristoma of Tongue: Chondroma and Osteoma) 1. Ramachandran K, Viswanathan R: Chondroma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 25:487, 1968. 2. Plessier P, Leroux-Robert J: Dysembryoplasies linguales multiples a contenu cartilagineux. Ann Anat Pathol 9:432, 1932. 3. Landini G, Kitano M, Urago A, et al.: Chondroma and osteochondroma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 68:206, 1989.

13.16 Congenital Dermoid Cyst A congenital dermoid cyst is a cyst of the tongue in which the cavity is lined by stratified squamous epithelium with sebaceous epithelium and/or sweat glands in the cyst wall. Very few examples are known of such cysts in the anterior tongue (Fig. 13-16). Of all dermoid cysts, about 7% occur in the head and neck, with most examples involving the oral floor. Although related, they are not further considered in this section.

Fig. 13-15. Choristoma of the tongue. Left: osteoma of the tongue occurring near the foramen cecum, as is the usual case. Right: photomicrograph of lingual osteoma showing thin epithelial and connective tissue cover over a well-rounded and highly mature bony nodule. (From van der Wal and van der Waal.5)

Tongue

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Fig. 13-16. Dermoid cyst of tongue. Left: cystic tongue mass lined with keratinizing squamous epithelium. Right: sebaceous glands within the cyst wall. (From Flom et al.1)

As in the case of dermoids of the oral floor, it has been assumed by most investigators that the lingual dermoid arises from entrapment of epithelium during fusion of the first branchial arches. The anterior tongue arises from two lateral lingual tubercles that fuse and incorporate an unpaired tubercle.1–6 References (Congenital Dermoid Cyst) 1. Flom GS, Donovan TJ, Landgraf JR: Congenital dermoid cyst of the anterior tongue. Otolaryngol Head Neck Surg 100:602, 1989. 2. Mathur SK, Meron PRN: Dermoid cyst of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 50:217, 1980. 3. Velcek FT, Klotz DH, Hill CH, et al.: Tongue lesions in children. J Pediatr Surg 14:238, 1979. 4. Smolansky SJ, Cardinal JP, Saffos RO: Lingual dermoid cysts. Ear Nose Throat J 58:240, 1979. 5. Ruggieri M, Tine A, Rizzo R, et al.: Lateral dermoid cyst of the tongue. Int J Pediatr Otorhinolaryngol 30:79, 1994. 6. Reddy VS, Radhakrishna K, Rao PLNG: Lingual dermoid. J Pediatr Surg 26:1389, 1991.

13.17 Hamartoma: Lymphangioma of the Tongue Lymphangioma of the tongue consists of benign nodular masses of clear lymph-filled vesicles of various sizes elevated above the surface of the tongue. Some rupture, and others become papil-

lomatous, somewhat resembling granulation tissue. One can often see capillary tufts within the vesicles. Hamartoma refers to a benign, oddly arranged focal collection of histologically normal tissue indigenous to an area. Presenting very early in infancy, lymphangiomas usually grow slowly and remain essentially quiescent. Some are localized but more often are diffuse and involve the dorsal rather than the ventral surface. Involvement may be unilateral or bilateral. Some lesions bleed following minor trauma. There is no sex predilection. In about 40%, the lymphangioma may involve more than half the tongue, resembling granulation tissue (Fig. 13-17). The anterior two-thirds of the tongue is usually the preferred site, but it may involve other parts of the oral cavity (lip, cheeks, oral floor) or extend to the epiglottis or mediastinum. In about 5%, the lymphangioma is associated with cystic hygroma. Deeper examples can be complicated by glossitis, especially those that extend beyond the lips, in which cases the tongue appears dry, cracked or fissured, and hemorrhagic.1–6 Trauma and/or infection may suddenly cause enlargement (macroglossia) and severe pain. Occasionally there is associated fever. The macroglossia may make for airway obstruction, difficult mastication, drooling, dysphagia, deformity of mandible, and altered speech. Macroglossia may occur on either a permanent or an intermittent basis. Microscopically, the tumor consists of endothelial-lined cystic spaces filled with lymph, a few lymphocytes, and red blood cells.

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ence with speech, dental occlusion, and mastication. Unlike cutaneous angiomas, involution of the lingual hemangioma does not occur.2–8 We could find little to document frequency in infancy. Some series indicate that congenital angiomas of the tongue are relatively common lesions, others that they are rare. We hold the latter view. Depending on size, location, and type of involved tissue, resection or elimination of the hemangioma can be simple or quite challenging. For small, superficial lesions, argon laser therapy is quite effective. For larger lesions, the CO2 laser has been employed. Embolization has been employed for nonresectable hemangiomas or in preparation for surgery to lessen operative bleeding.2 Intralesional injection with steroids is less effective. Fig. 13-17. Superficial lymphangioma causing macroglossia. Note densely packed yellowish, red, or bluish-black vesicular elements more marked on distal portion of tongue. (From Brandrup.6)

The spaces are located within a stroma of thin fibrous connective tissue. It should be remembered that macroglossia is a nonspecific finding and can be associated with various congenital cysts or tumors, congenital anomalies (lingual thyroid), congenital hypothyroidism, and Beckwith-Wiedemann syndrome or can be acquired early in infancy (e.g., glycogen storage disease type II, GM1 gangliosidosis, Hurler syndrome). Surgery and/or laser photocoagulation are the treatments of choice. Radiation therapy and electrodessication are not recommended. References (Hamartoma: Lymphangioma of the Tongue) 1. Balakrishnan A, Bailey CM: Lymphangioma of the tongue. A review of pathogenesis, treatment and the use of surface laser photocoagulation. J Laryngol Otol 105:924, 1991. 2. Litzow TJ, Lash H: Lymphangiomas of the tongue. Proc Mayo Clin 36:229, 1961. 3. White MA: Lymphangioma of the tongue. ASDC J Dent Child 54:280, 1987. 4. Rice JP, Carson SH: A case report of lingual lymphangioma presenting as recurrent massive tongue enlargement. Clin Pediatr 24:47, 1985. 5. Postlethwaite KR: Lymphangiomas of the tongue. Br J Maxillofac Surg 24:63, 1986. 6. Brandrup F: Lymphangioma circumscriptum of the tongue. Dermatologica 153:191, 1976.

13.18 Hamartoma of the Tongue: Hemangioma Hemangiomas of the tongue are benign vascular tumors and may be capillary, cavernous, venous, or mixed with lymphangioma.1 They occur in various sizes, as small as a pea or as large as a child’s fist. They may be flat or rounded, red-purple to deep red, and superficial or deep, extending into the tongue muscle. Some seem to stop abruptly at the midline. Most become evident in the newborn period and grow pari passu with the child. Technically, one should include telangiectasias (hereditary hemorrhagic telangiectasia) and Sturge-Weber syndrome. Microscopically, there is a proliferation of endothelial-lined spaces that contain erythrocytes. In those that are superficial, trauma may produce bleeding or ulceration. With marked tongue enlargement, there is often interfer-

References (Hamartoma of the Tongue: Hemangioma) 1. Giunta J, Shklar G, McCarthy PL: Diffuse angiomas of the tongue. Arch Otolaryngol Head Neck Surg 93:83, 1971. 2. Brown DA, Smith JD: Late complication of congenital hemangiomas of the tongue. Head Neck Surg 9:299, 1987. 3. Vankova´ B, Barinka L: Haemangiomas of the tongue. Acta Chir Plast 29:242, 1987. 4. Rieblova´ V: Haemangiomas. Acta Chir Plast 24:219, 1982. 5. Gardner AF: Tumor and tumor-like lesions of the oral cavity in infants and children. J Dent Child 31:42, 1964. 6. Parkin JL, Dixon JA: Argon laser treatment of head and neck vascular lesions. Otolaryngol Head Neck Surg 93:211, 1985. 7. Shklar G, Meyer J: Vascular tumors of the mouth and jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 19:335, 1965. 8. Velcek FT, Klatz DH, Hill CH: Tongue lesions in children. J Pediatr Surg 14:238, 1979.

13.19 Hamartoma of the Tongue: Mixed Type (Mesenchymoma) A mixed-type hamartoma of the tongue is a benign tumor of the tongue that contains an oddly arranged and focal overgrowth of mixed tissue elements indigenous to the area.1–7 The hamartoma appears as a spherical mass covered by normal oral mucosa. It has limited growth capacity, does not invade surrounding tissues, and may arise in any area of the body. The color reflects the specific composition (mucous salivary glands, adipose tissue, nerves, smooth muscle, connective tissue, blood vessels) of the hamartoma. It is difficult to separate this lesion from the so-called benign mesenchymoma of the tongue.12 An osteolipoma is an example.8 Most occurrences have been found incidentally, often due to interference with feeding, and most have been located at the base of the tongue in the foramen cecum area.1–6,9,10,13,15 Exceptions to this are the one or more lingual hamartomas in several of the oralfacial-digital syndromes. The child described by Ishii et al.7 probably had oral-facial-digital syndrome type 1 (OFD1). The female child with an erroneous diagnosis of ectrodactyly-ectodermal dysplasia syndrome surely had OFD1.11 Lipoma of the tongue is rarely congenital14 but occurs principally near the surface in the mid-dorsum. All mixed type hamartomas have been successfully removed by surgical means. References (Hamartoma of the Tongue: Mixed Type) 1. Demuth RJ, Johns DF: Recurrent aspiration pneumonitis in a cleft palate child with hamartoma of the tongue. Cleft Palate J 18:299, 1979.

Tongue 2. Freedman PD, Chou MD, Diner H, et al.: Benign mesenchymoma of the oral soft tissues. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 53:606, 1982. 3. Herzog S, Bressman J, Giglio JA: Tongue mass in an infant. J Oral Maxillofac Surg 44:463, 1986. 4. Tashihara J, Oda A, Takahashi Y, et al.: Fibrous hamartoma of the tongue. Int J Pediatr Otorhinolaryngol 33:17, 1995. 5. Ide F, Shimoyama T, Horie N: Angiomyolipomatous hamartoma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85:581, 1998. 6. Takimoto T, Yoshizaki T, Umeda R: Hamartoma of the tongue. Int J Pediatr Otorhinolaryngol 18:157, 1989. 7. Ishii P, Takemori S, Suzuki J: Hamartoma of the tongue. Arch Otolaryngol 88:171, 1968. 8. Piattelli A, Fioroni M, Iezzi G, et al.: Osteolipoma of the tongue. Oral Oncol 37:468, 2001. 9. Kobayashi A, Amagasa T, Okada N: Leiomyomatous hamartoma of the tongue. J Oral Maxillofac Surg 59:337, 2001. 10. Goldsmith P, Soames JV, Meikle D: Leiomyomatous hamartoma of the posterior tongue. J Laryngol Otol 109:1190, 1995. 11. Hanna R, Argenyi ZB, Benda JA: Hamartoma of the tongue in an infant with a primary diagnosis of ectrodactyly-ectodermal dysplasia– cleft lip and palate syndrome. J Cutan Pathol 21:173, 1994. 12. Smith BC, Ellis GL, Meis-Kindblom JM, et al.: Ectomesenchymal chondromyxoid tumor of the anterior tongue. Nineteen cases of a new clinicopathologic entity. Am J Surg Pathol 19:519, 1995. 13. Owen G, Berry T, Bicknell P: Hamartoma of the tongue. J Laryngol Otol 107:363, 1993. 14. Yonezawa H, Harada K, Enomoto S: Congenital lipomatoid mass of the tongue. Int J Oral Maxillofac Surg 29:138, 2000. 15. Zalal GH, Patterson K, Cotton RT: Congenital tumors of the dorsum of the tongue. Int J Pediatr Otorhinolaryngol 28:219, 1994.

13.20 Congenital Teratoma A congenital teratoma of the tongue is a tumor that contains elements from all three germ layers. Most often immature neuroectodermal present; however, cartilage, bone, skin, cystlike structures lined by stratified squamous epithelium, pseudostratified ciliated columnar epithelium, intestinal epithelium, muscle, and nerve have been found. These congenital growths, unlike those of the ovary and/or testicle, appear to be uniformly benign. We have tabulated less than a dozen examples. Teratoma, in a few cases, has been within the body of the tongue, but occasionally has been attached to the base of the tongue by a pedicle or to the side of the tongue. They may be so large as to fill the mouth completely (Fig. 13-18). There does not appear to be any sex predilection. Although teratomas are thought to arise in the developing blastomere, some cells being displaced or separated, it is possible that normal muscle-forming cells migrating from the occipital myotomes have been accompanied by neuroectodermal and other cells. In a few examples, a second teratoma has been found in the proximate area.1–8 There is excellent prognosis following surgical excision. In spite of the rule (regarding ovarian teratomas) that the greater the immaturity and amount of neuroepithelium, the poorer the prognosis, there is overwhelming evidence that lingual teratomas are not malignant. Elevated carcinoembryonic antigen and alpha-fetoprotein levels have been found. In some cases urinary vanillyl mandelic acid and dopamine levels have also been increased.

421

Fig. 13-18. Massive tongue enlargement caused by a teratoma. (Courtesy of Dr. A. E. Rodin, Xenia, OH.)

References (Congenital Teratoma) 1. Rodin AE, Singula P: Teratoma of the tongue at birth. Pediatr Pathol 3:291, 1985. 2. Ashley JV, Shafer AD: Teratoma of the tongue in a newborn. Cleve Clin Q 50:34, 1983. 3. Lalwani AK, Engel TL: Teratoma of the tongue: a case report and review of the literature. Int J Pediatr Otorhinolaryngol 24:261, 1992. 4. Grier EA, MacNerland RH: Benign teratoma of the tongue. Ill Med J 132:43, 1967. 5. Mahour GH, Landing BH, Wooley MM: Teratomas in children: clinicopathologic studies in 133 children. Z Kinderchir 23:365, 1978. 6. Wood GH, Williams JE: Rare tumor of the tongue in a newborn child. Eye Ear Nose Throat Monthly 31:83, 1952. 7. Miller AP, Owens JB Jr: Teratoma of the tongue. Cancer 19:1583, 1966. 8. Uchida K, Urata H, Suzuki H: Teratoma of the tongue in neonates: report of a case and review of the literature. Pediatr Surg Int 14:79, 1998.

13.21 Abnormal Tongue Movements and Excessive Mobility of the Tongue Variations in the voluntary movement and configuration of the tongue are possible (Fig. 13-19). The ability to curl up the lateral borders of the tongue is called tongue-tubing or tongue-curling, whereas curling the lateral borders of the tongue downward is inverse tongue-tubing. Tongue-upfolding is the capacity to extend the tongue beyond the lips and to fold the tip back upon the body of the tongue without the aid of the teeth.19 Tongue-rolling is the ability to roll or twist the tongue from side to side. To trefoil the tongue refers to the ability to deform the anterior tongue at will into a cloverleaf

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Craniofacial Structures

Fig. 13-19. Lingual calesthenics. A. Tongue-tubing, a trait seen in 65% of the populace. B. Ability to flip-flop the tongue is found in 35%. C. About 7% are able to touch the nose with the tip of the tongue. D. Hyperextensible tongue seen in 50% of those with Ehlers-Danlos

syndrome (Gorlin sign). E. Tongue-upfolding. This trait, accomplished without the use of the teeth, is relatively rare. F. Trefoiling of the tongue. G. Inverse tongue-tubing. H. Placing the tongue into the nasopharynx.

pattern. Excessive mobility refers to the ability to place the tip of the tongue behind the soft palate into the nasopharynx. Another ‘‘talent of mobility’’ is that of touching the tip of the nose with the tip of the tongue or, still further, extending it into the nostrils. Tongue-tubing or tongue-curling can be done by about 65– 70% of the white population.1 Several authors have indicated that this ability does not have single gene inheritance.2–4 Discordance in identical twins has varied from 15–20% in various studies.2,3 To the best of our knowledge, there has been no study on the epidemiology of inverse tongue-tubing. Tongue-upfolding has been found in 2–3% of the population.5–8 Whitney9 reported that about

1.5% had the ability to upfold the tongue with the aid of the teeth, but only one per 600 individuals could do this to the extended tongue. Bat-Miriam,10 studying Ethiopian tribes, noted that 3–10% could upfold the tongue. While this trait has been seen in several generations, most cases are sporadic and we doubt single gene inheritance.11 Tongue-rolling can be accomplished by about 35% of the population. It, too, has occurred in several generations, but the vast majority of cases are sporadic. Martin18 suggested that there was no genetic basis for tongue-rolling. Approximately 2.5% can trefoil the tongue, according to Gahres.12 This is far more common than has been found in our experience. We have noted

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11. Hirschhorn HH: Transmission and learning of tongue gymnastic ability. Am J Phys Anthropol 32:451, 1970. 12. Gahres EE: Tongue rolling and tongue folding and other hereditary movements of the tongue. J Hered 43:221, 1952. 13. Hoch MO: Clover-leaf tongues. J Hered 40:132, 1949. 14. Matzker J: Abnorme Beweglichkeit der Zunge. HNO 14:181, 1977. 15. Stuart-Low W: Case showing an unusually large and long tongue. Proc R Soc Med (Laryngol Sect) 2:111, 1909. 16. Cinar F, Uzun L, Ugur MB, et al.: An unusual movement of the tongue. Plast Reconstr Surg 113:773, 2004. 17. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 18. Martin NG: No evidence for a genetic basis of tongue rolling or hand clasping. J Hered 66:179, 1975. 19. Cohen MM Jr: Lingual lesions and liabilities. Am J Med Genet 47:762, 1993. 20. Hennekam RCM: Lingua cochlearis in multiple pterygium syndrome. Am J Med Genet 47:761, 1993.

Fig. 13-20. Pigmented fungiform papillae.

this ability in siblings and in several generations, but, again, most cases are sporadic.8–12 There are no data available concerning the ability to place the tip of the tongue into the nasopharynx, but it is rare.13–16 The ability to touch the tip of the nose with the tongue is manifest in about 7% of the white population but apparently occurs with considerable frequency (approximately 50%) in those with Ehlers-Danlos syndrome type I (Gorlin sign).17 Lingua cochlearis refers to a spoon-shaped alteration in the tongue tip in multiple pterygium syndrome.20 References (Abnormal Tongue Movements and Excessive Mobility of the Tongue) 1. Urbanowski A, Wilson J: Tongue curling. J Hered 38:365, 1947. 2. Matlock P: Identical twins, discordant in tongue rolling. J Hered 43:24, 1952. 3. Reedy JJ, Szczes T, Downs TD: Tongue rolling among twins. J Hered 62:125, 1971. ¨ ber die Fa¨higkeit, die Zunge um die La¨ngsachse zu rollen. 4. Vogel F: U Acta Genet Med Gemellol 6:225, 1957. 5. Hsu TC: Tongue upfolding (a newly recognized hereditary character in man). J Hered 39:187, 1948. 6. Lee JW: Tongue-folding and tongue rolling in an American Negro population sample. J Hered 46:289, 1955. 7. Lee JW: A study of the inheritance of certain tongue characteristics in 72 pairs of Negro twins. J Hered 47:17, 1956. 8. Wooldridge HR: Relationship of marked mandibular arch symmetry and the ability to perform certain unusual tongue movements. Am J Orthodont 44:65, 1958. 9. Whitney DD: Tongue tip overfolding. J Hered 40:19, 1949. 10. Bat-Miriam M: A survey of some genetical characters in Ethiopian tribes. IX. Tongue folding and tongue rolling. Am J Phys Anthropol 20:198, 1962.

13.22 Pigmented Fungiform Papillae and Other Lingual Pigmentations Pigmented fungiform papillae of the tongue are relatively common in African Americans. They have rarely been noted in Asians and Whites (Fig. 13-20).1–3,6,7 Microscopic sections have shown multiple melanophages in the upper lamina propriae of the tongue. Rarely the pigmentation may be more diffuse,4,5 unrelated to Peutz-Jeghers syndrome, Addison disease, or minocycline therapy. Holzwanger et al.1 noted that 25–30% of black people have pigmented papillae versus 1% of white people. References (Pigmented Fungiform Papillae and Other Lingual Pigmentations) 1. Holzwanger JM, Rudolph RI, Heaton CL: Pigmented fungiform papillae of the tongue, a common variant of oral pigmentation. Int J Dermatol 13:403, 1974. 2. Kaplan BS, Hurley HJ: Prominent pigmented papillae of the tongue. Arch Dermatol 95:394, 1967. 3. Isogai Z, Kanzaki T: Pigmented fungiform papillae of the tongue. J Am Acad Dermatol 29:489, 1993. 4. Menni S, Boccardi D: Melanotic macules of the tongue in a newborn. J Am Acad Derm 44:1048, 2001. 5. Anavi Y, Mintz S: Unusual physiologic melanin pigmentation of the tongue. Pediatr Dermatol 9:123, 1992. 6. Ahn SK, Chung J, Lee SH, et al.: Prominent pigmented fungiform papillae of the tongue. Jap J Clin Dermatol 47:1009, 1993. 7. Oh CK, Kim MB, Jang HS, et al.: Pigmented fungiform papillae of the tongue in an Asian male. J Dermatol 27:350, 2000.

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

T

he presence of a complete and functional dentition is critical to the overall health and well-being of an individual. In fact, the size, shape, color, and alignment of teeth are determining characteristics of facial expression and impart uniqueness to each human. Individuals who lack a full complement of teeth as a result of disease, trauma, or genetic disorders often endure emotional hardship due to compromised facial aesthetics. Costly and sometimes complex dental care is needed to restore normal structure and function to dentition. Since teeth are critical for the proper mastication of complex food substances, inefficient grinding compromises digestion by salivary enzymes and may result in digestive problems. As seen in older individuals who have lost teeth to periodontal disease or dental caries, speech is often affected, as is vertical dimension and facial aesthetics. Anthropologists and paleontologists rely on the importance of teeth in evolution because they are the best-preserved organs in fossils. In fact, studies of fossilized teeth have revealed much about the behavior and feeding habits of humans and their ancestors. The presence of enamel, the hardest substance in the human body, on the crowns of teeth makes them indestructible and valuable resources for forensics. For developmental biologists, the forming tooth organ is a useful paradigm for organogenesis, offering a means to study how shape, size, and position are determined and how specialized mineralized tissues are formed. Notwithstanding these critical functions, the importance and uniqueness of teeth are frequently overlooked by health professionals. This chapter reviews the physical and histologic features of normal dentition and describes classic and modern literature about the cellular and molecular processes that result in a fully formed tooth. As a logical progression, disorders that affect the patterning of dentition, in particular those involving changes in the number, size, and shape of teeth, will be outlined. This will be followed by an overview of disorders that affect the mineralized matrices of teeth, namely enamel, dentin, and cementum. Since the development of dentition is not complete until teeth emerge from within their bony crypts into the oral cavity, it is justifiable to include a section on normal and abnormal tooth eruption.

The authors acknowledge the important contribution of Ronald J. Jorgenson to the first edition of this text, which provided the basis for this chapter.

During the past decade, several advances in understanding the molecular biology and genetics of tooth development have been made and genes that are responsible for the major disorders of dentition have been identified. General Description

In humans, teeth represent approximately 20–25% of the total surface area of the oral cavity or mouth. In contrast to the monophyodont dentition present in rodents, human dentition is a succedaneous dentition with two sets of teeth: a deciduous set that predominates from ages 6 months to 6 years and a permanent set that predominates from age 12 years onward. Between ages 6 and 12 years, teeth of both sets can be present and the dentition is said to be mixed. The word deciduous refers to the fact that the teeth exfoliate with time; primary is an acceptable alternative to deciduous and indicates the sequence of eruption. The word permanent refers to the lifelong status of the ‘‘adult’’ teeth. An acceptable alternative is secondary to reflect their place in the sequence. Teeth are described in terms that reflect their position, function, or morphology (Fig. 14-1). The shape of each tooth is closely adapted to its function. The incisors are shovel-shaped with thin, flat edges that are used for biting or incising. The canines are used for tearing tough food. The premolars with their sharp cusps are used for shredding. The molars, each with four to five flat cusps, are used for grinding the shredded food passed backward from the premolars. For heterodont mammalian dentition, the general dental formula in each quadrant is three incisors, one canine, four premolars, and three molars. In humans, one incisor and two premolars have been lost, while rodents have lost two incisors, the canine and premolars.1 There are 20 deciduous teeth and 32 permanent teeth (Fig. 14-1). The deciduous complement consists of two incisors, one canine, and two molars in each quadrant (a quadrant is half an arch). The permanent complement consists of two incisors, one canine, two premolars, and three molars in each quadrant. In ordinary circumstances, the deciduous teeth are smaller than permanent teeth that will eventually replace them and are consequently widely spaced. Permanent teeth that replace deciduous teeth are said to be succedaneous (ensuing): the premolars succeed the deciduous molars; the permanent molars, having no predecessors, are correctly termed nonsuccedaneous teeth. 425

426

Craniofacial Structures

old. Alternatively, the observations that point to mutations in two independent genes, MSX1 and PAX9, which both dominantly affect premolar and molar formation, suggests that each tooth family or ‘‘clone’’ may require a different genetic code or combination of genes during development. This selectivity may be best explained by the clone theory. Parts of Teeth

Fig. 14-1. Orientation of teeth in dental arches.

Patterning of Dentition

From an evolutionary genetic standpoint, mammalian dentition is considered a segmental or sequentially arranged organ system whose members are arrayed in specific number and in regionally differentiated locations along the linear axes of the jaws.2 For developmental biologists, the model of tooth development offers a useful paradigm for studying patterning and morphogenesis or the determination of position, size, shape, and number. Much of our understanding about the patterning of dentition comes from mouse studies. The use of transgenesis, gene targeting, expression analyses, and functional in vivo and in vitro tooth recombinations as well as bead implantation assays has greatly increased our understanding about the molecular mechanisms that influence the patterning of murine dentition. While there is good left–right symmetry in human dentition, anterior–posterior and buccal–lingual symmetries are highly varied, suggesting a patterning gradient along these axes. Two theories have been proposed to explain the patterning of dentition. The field theory assumes that all tooth primordia are initially identical and that varying concentrations of chemical morphogens create gradients of patterning in different regions of the jaws. The finding of an anterior–posterior (A–P) gradient of retinoic acid concentration in the developing murine mandible lends some support to the field theory.3 An alternate theory, the clone model, proposes that each family of teeth arises from a distinct group of neural crest stem cells that retain positional identity as they migrate to the arches.4 The role of Hox genes in controlling positional information along the A–P axis in Drosophila and other vertebrates has lent credibility to the clone theory.5 Furthermore, it has been shown that the final position of odontogenic mesenchyme in the maxilla and mandible is determined by the original position of these cells in the neural crest as well as the time when the cells migrate out of the crest, thus supporting the clone theory over the field theory.6 As will be evident from the following discussion on tooth agenesis, it is unclear which of the two theories explains some of the more consistent patterns of human tooth agenesis. For example, missing lateral incisors are often associated with second premolar agenesis, suggesting that teeth that are last to develop in a given morphogenetic field may fall below a developmental thresh-

Teeth are composed of crowns and roots. The crowns comprise the exposed portions of the teeth and are covered by enamel. Under the enamel is a thick layer of dentin and a soft central core, the pulp chamber. The terminology used to identify different surfaces and structural components of teeth is described in Fig. 14-2. Enamel is the hardest calcified structure in vertebrates and covers the crowns of the teeth. It varies from 2 to 3 mm in thickness over the bulkiest parts of the cusp to a knife-edge thickness at the cementoenamel junction. Because enamel is acellular, it is nonvital and cannot regenerate except by superficial remineralization. The latter happens as a result of an exchange of mineral ions that occurs on the surface of enamel. Enamel varies from translucent to yellowgrey in color, but most of the hue of enamel-covered crowns is the result of the dentin being visible through the enamel. Teeth that have a thin layer of enamel appear more yellow, to reflect the color of dentin. This is common in individuals of Asian descent. Enamel formation is described conceptually as occurring in three phases. The secretory phase is marked by the deposition of an organic matrix by ameloblasts. At this stage, these cells are called presecretory and secretory ameloblasts. They are elongated cells that show nuclear polarity and secretory organelles.7,8 In the second phase of mineralization, nucleation or crystal formation occurs. As crystals elongate the final phase of maturation of enamel matrix occurs. At this stage, the organic matrix, in particular amelogenin, is degraded by proteinases. The degradative products of amelogenins are reabsorbed back into the ameloblasts.9,10 The principal classes of enamel matrix proteins are amelogenin, ameloblastin, enamel, tuftelin, a metalloproteinase called enamelysin (MMP-20), a serine proteinase called enamel matrix serine proteinase 1 (EMPSP1), and traces of dentin sialophosphoprotein (DSPP). As will be discussed later, enamel malformations involve mutations in genes that encode some of these matrix proteins.11 The major constituents of enamel are rods, rod sheaths, and an interrod substance. The rods consist of networks of organic particles around which apatite crystals are coalesced. Each rod is surrounded by a sheath that is less highly calcified than the rod proper. The nature of the interrod structure is not well-known, although it is well-accepted that this area of enamel facilitates the spread of dental caries toward dentin.8,12 The dentin constitutes the bulk of the tooth. It is a living tissue that has many of the physical and chemical properties of

Fig. 14-2. Component parts of teeth.

Teeth

bone. The dentin is yellow in color and far less brittle than the enamel. The formation of dentin follows the same principles that guide the formation of other hard connective tissues in the body, namely cementum and bone. The first requirement is the presence of highly specialized cells that can synthesize and secrete a highly specialized organic matrix that is capable of accepting biologic apatite or mineral.13 Other prerequisites include a rich vascular supply and high levels of the enzyme alkaline phosphatase. Dentinforming cells or odontoblasts begin to secrete a predentin extracellular matrix (ECM). They retreat in a pulpal direction but remain connected to the matrix as it is being formed through cell extensions called odontoblastic processes. The organic predentin matrix is converted into a mineralized layer of dentin through a highly complex process that begins some distance away from the odontoblastic cell bodies. The outermost layer of dentin, which is the first layer to be formed, is the mantle dentin; the remainder is the circumpulpal dentin.14,15 Excellent reviews by Linde and Goldberg16 and Butler and Ritchie17 detail the composition of dentin matrix and the process of dentinogenesis. The organic phase of dentin is composed of proteins, proteoglycans, lipids, various growth factors, and water. Among the proteins, collagen is the most abundant and offers a fibrous matrix for the deposition of carbonate apatite crystals. The collagens that are found in dentin are primarily type I collagen with trace amounts of type V collagen and some type I collagen trimer. The importance of type I collagen as a key structural component of dentin matrix is illustrated by the inherited dentin disorder called dentinogenesis imperfecta (DGI) that is discussed later in this chapter. An important class of dentin matrix proteins is the noncollagenous proteins (NCPs).17 The dentin-specific NCPs are dentin phosphoproteins (DPP) or phosphophoryns and dentin sialoprotein (DSP). After type I collagen, DPP is the next most abundant of dentin matrix proteins and represents almost 50% of the dentin ECM. DPP is a polyionic macromolecule that is rich in phosphoserine and aspartic acid. Its high affinity for type I collagen as well as calcium makes it a strong candidate for the initiation of dentin mineralization. DSP accounts for 5–8% of the dentin matrix and has a relatively high sialic acid and carbohydrate content. Its role in dentin mineralization is unclear at the present time. For several years it was believed that DSP and DPP were two independent proteins encoded by different genes. DPP and DSP are specific cleavage products of a larger precursor protein that was translated from one large transcript.18 This single gene encoding for DSP and DPP is named dentin sialophosphoprotein (DSPP). The importance of DSPP in dentin formation was recently underscored with the discovery that mutations in this gene are responsible for the underlying dentinal defects seen in dentinogenesis imperfecta (DGI).19,20 The DGI locus maps to human chromosome 4 within q13-21 where several other dentin ECM genes reside. A second category of NCPs with Ca-binding properties is classified as mineralized tissue-specific because they are found in all the calcified connective tissues, namely dentin, bone, and cementum. These include osteocalcin (OC) and bone sialoprotein (BSP). A serine-rich phosphoprotein called dentin matrix protein 1 (Dmp-1), whose expression was first described as being restricted to odontoblasts,21 was later shown to be expressed by osteoblasts and cementoblasts22,23 and by brain cells. Other NCPs in this group include osteopontin (OP) and osteonectin (SPARC). The fourth category of dentin NCPs is not expressed in odontoblasts but is primarily synthesized in the liver

427

and released into the circulation. An example of a serum-borne protein is a2HS-glycoprotein. Diffusible growth factors that appear to be sequestered within dentin matrix constitute the fifth group of dentin NCPs. This group includes the bone morphogenetic proteins (BMP), insulinlike growth factors (IGF), and transforming growth factor beta (TGF-b).24 The pulp occupies the pulp chamber (the core of the crown) and the root canals. The incisal or occlusal surface of the pulp chamber is the roof. Projections along the mesial and distal aspects of the roof are the pulp horns. The apical surface of the pulp chamber is the floor and serves as the exit point for the nerves and vessels that traverse the root canals. Blood and lymph vessels are found in the pulp, as are sensory and motor nerves. The only sensation the pulp is able to transmit is pain. The bulk of the pulpal tissue is a loose connective tissue that contains cells of many types, fibroblasts, and the odontoblasts. Somatic stem cells from the dental pulp of a deciduous molar are capable of regenerating several tissues when transplanted in vivo. Cementum is another calcified tissue of mesodermal origin. The cementum covering the apical third of the root is cellular (contains cementocytes), while that of the remaining two-thirds is acellular. Cementum is less resorptive than bone, a fact that undoubtedly is related to its role in anchoring teeth and allowing teeth to move through bone during eruption. Development of Teeth

Teeth develop in distinct stages that are easily recognizable at the microscopic level. Hence, stages in odontogenesis are described in classic terms by the histologic appearance of the tooth organ. From early to late, these stages are described as the lamina, bud, cap, and bell (early and late) stages of tooth development.25,26 Recent advances made in the understanding of the molecular control of tooth development have led to the development of new terminology to describe tooth development as occurring in four phases: initiation, morphogenesis, cell or cytodifferentiation, and matrix apposition (Fig. 14-3). The dental lamina marks the first morphologic sign of the initiation of tooth development and is visible around 5 weeks of human development. At this stage, cells in the dental epithelium and underlying ectomesenchyme are dividing at different rates, the latter more rapidly. The inductive influence of the dental lamina to dictate the fate of the underlying ectomesenchyme has been confirmed by several researchers.27 The bud stage is characterized by the continual growth of cells of the dental lamina and ectomesenchyme. The latter is condensed and termed the dental papilla. At this stage, the inductive or tooth-forming potential is transferred from the dental epithelium to the dental papilla. The transition from the bud to the cap stage is an important step in tooth development because it marks the onset of crown formation. The tooth bud assumes the shape of a cap that is surrounded by the dental papilla. The ectodermal compartment of the tooth organ is referred to as the dental or enamel organ. The enamel organ and dental papilla become encapsulated by another layer of mesenchymal cells called the dental follicle that separate the tooth organ papilla from the other connective tissues of the jaws. A cluster of cells called the enamel knot is an important organizing center within the dental organ and is important for the formation of cusps.28,29 The enamel knot expresses a unique set of signaling molecules that influence the shape of the crown as well as the development of the dental papilla. Similar to the fate of signaling centers in other organizing tissues like the developing limb bud, the enamel knot

428

Craniofacial Structures

Fig. 14-3. Signaling in tooth development. Schematic description of the diffusible signals and transcription factors involved in epithelialmesenchymal interactions during mouse tooth development. Growth factors and morphogens involved are the bone morphogenetic proteins (BMP), fibroblast growth factors (FGF), Sonic hedgehog (SHH), and

Wingless protein (WNT). Several molecules function throughout odontogenesis. In humans, mutations in PITX2, SHH, MSX1, and PAX9 have been associated with Rieger syndrome, solitary median maxillary central incisor, premolar/third molar agenesis, and molar oligodontia, respectively. (Reprinted with permission from Thesleff.33)

undergoes programmed cell death or apoptosis after cuspal patterning is completed at the onset of the early bell stage. The dental organ next assumes the shape of a bell as cells continue to divide but at differential rates. A single layer of cuboidal cells called the external or outer dental epithelium lines the periphery of the dental organ, while cells that border the dental papilla and are columnar in appearance form the internal or inner dental epithelium. The latter gives rise to the ameloblasts, cells responsible for enamel formation. Cells located in the center of the dental organ produce high levels of glycosaminoglycans that are able to sequester fluids as well as growth factors that lead to its expansion. This network of star-shaped cells is named the stellate reticulum. Interposed between the stellate reticulum and the internal dental epithelium is a narrow layer of flattened cells, termed the stratum intermedium, that express high levels of alkaline phosphatase. The stratum intermedium is believed to influence the biomineralization of enamel. In the region of the apical end of the tooth organ, the internal and external dental epithelial layers meet at a junction called the cervical loop. At the early bell stage, each layer of the dental organ has assumed special functions and exchanges molecular information that leads to cell differentiation at the late bell stage. The dental lamina that connects the tooth organ to the oral epithelium gradually disintegrates at the late bell stage. At the future cusp tips, cells of the internal dental epithelium stop dividing and assume a columnar shape. The most peripheral cells of the dental papilla organize along the basement membrane and differentiate into odontoblasts, the

dentin-forming cells. At this time, the dental papilla is termed the dental pulp. After the first layer of predentin matrix is deposited, cells of the internal dental epithelium differentiate into ameloblasts or enamel-producing cells. As enamel is deposited over dentin matrix, ameloblasts retreat to the external surface of the crown and are believed to undergo programmed cell death. In contrast, odontoblasts line the inner surface of dentin and remain metabolically active throughout the life of a tooth. Root formation then proceeds as epithelial cells proliferate apically and influence the differentiation of odontoblasts from the dental papilla as well as cementoblasts from follicle mesenchyme. This leads to the deposition of root dentin and cementum, respectively. In multirooted teeth, certain portions of the root sheath grow more rapidly than the remainder, producing tonguelike extensions. When the extensions (two in two-rooted and three in three-rooted teeth) meet, the position of the root furcation is established. The dental follicle that gives rise to components of the periodontium, namely the periodontal ligament fibroblasts, alveolar bone of the tooth socket, and the cementum, also plays a role during tooth eruption, which marks the end phase of odontogenesis. In summary, tooth development is regulated by temporally and spatially restricted, reciprocal interactions between epithelial and mesenchymal compartments, and the potential to dominate tooth development shifts back and forth between epithelium and mesenchyme. The chronology of human tooth development is summarized in Tables 14-1 A and B.

Teeth

429

Table 14-1A. Developmental chart of deciduous teeth34

Tooth

Initiation (wk in utero)

Calcification Begins (wk in utero)

Crown Formation at Birth (38–42 wk)

Crown Complete (mo)

Eruption (mo)

Exfoliation (yr)

Lower central incisor

6–7

13–16

3/5

1–3

6–10

5–6

Lower lateral incisor

7

14–16

3/5

2–3

10–16

6–7

Upper incisors

7

14–16

5/6 central

2–3

8–13

6–7

2/3 lateral Canines

7.5

1/3

9

16–20

9–10

First molars

8

14.5–17

Cusps united, occlusal surface complete, 1/2–3/4 crown height

6

12–16

10–11

10

16–23

Cusps united, 1/4 crown height

10–12

23–30

12

Second molars

15–18

Table 14-1B. Developmental chart of permanent teeth34

Initiation

Calcification begins

Crown complete (yr)

Eruption (yr)

Mandible

20–22 wk IU

3–4 mo

4–5

6–7

Lateral incisor

21–22 wk IU

3–4 mo

4–5

7–8

Canine

20–26 wk IU

4–5 mo

6–7

9–11

First premolar

38–42 wk IU

1.75–2 yr

5–6

10–12

Second premolar

7.5–8 mo

2.25–2.5 yr

6–7

11–12

Central incisor

First molar

15–17 wk IU

Second molar

8.5–9 mo

Third molar

3.5–4 yr

Central incisor Lateral incisor Canine

Birth 2.5–3 yr

2.5–3

6–7

7–8

11–13

8–10 yr

12–16

17–25

20–22 wk IU

3–4 mo

4–5

7–8

21–22 wk IU

3–4 mo

4–5

8–9

21–26 wk IU

4–5 mo

6–7

11–12

First premolar

38–42 wk IU

1.25–1.75 yr

Second premolar

7.25–8 mo

Maxilla

First molar

3.5–4 wk IU

Second molar

8.5–9 mo

Third molar

3.5–4 yr

2–2.5 yr Birth 2.5–3 yr 7–9 yr

5–6

10–11

6–7

10–12

2.5–3

6–7

7–8

12–13

12–16

17–25

IU ¼ in utero.

In recent years significant advances have been made in understanding the molecular mechanisms that determine the site of tooth initiation.30,31 Fig. 14-3 shows that a number of transcription factors, signaling molecules (i.e., growth factors and their receptors), and extracellular matrix molecules are expressed in the mesenchyme of the first branchial arch. Several lines of evidence indicate that synergistic and antagonistic interactions of signaling molecules are recursively utilized in tooth development.30–32 Clinical Considerations

Congenital malformations of the teeth can be more clearly understood by considering tooth development in stages of initiation and proliferation, morphogenesis, and matrix apposition. The dental lamina initiates tooth development. If the lamina is not formed or its early organization is abnormal, initiation will not occur and teeth will not develop at all (anodontia). If only portions of the lamina are

physically disrupted, initiation is disrupted in focal areas and only teeth in that area will not develop (hypodontia). Of course, some disruptive factors may cause overactivity of the lamina, resulting in hyperdontia (supernumerary teeth). After initiation, the separate tooth buds proliferate at their predetermined paces. Interference with proliferation also leads to hypodontia. Histodifferentiation follows the initial steps of proliferation. Cell types (ameloblasts and odontoblasts, for instance) are established during the histodifferentiation stage. If the inner dental epithelium does not differentiate properly, it cannot stimulate odontoblast formation, and tooth development will be arrested. If odontoblasts fail to differentiate properly, they cannot stimulate ameloblast formation and no enamel will form. Abnormal dental structure, poorly organized and formed, results from abnormal differentiation. Differential growth of parts of the dental organ (morphodifferentiation) accounts for the basic size and shape of teeth.

430

Craniofacial Structures

Abnormal morphodifferentiation leads to microdontia, macrodontia, globodontia, supernumerary cusps, and other abnormalities. Apposition refers to the deposition of the matrix of dentin and enamel. Once the cells of the inner dental epithelium have stimulated the underlying mesenchyme to form odontoblasts, the odontoblasts lay down a layer of predentin. Mineralization begins after sufficient predentin is present. The various types of dentin dysplasia are probably defects of predentin deposition. After a small amount of predentin has formed, ameloblasts begin to secrete the enamel matrix and continue to do so until the predetermined size of the crown has been reached. Too little enamel matrix leads to hypoplastic types of enamel dysplasia. After the enamel matrix is laid down, it is mineralized; disruptions at this stage of development lead to hypocalcified types of enamel dysplasia. Maturation of the hard matrix follows appositional growth. Interference with maturation leads to such manifestations as hypomature forms of enamel dysplasia. Future Challenges and Directions

The molecular basis for malformations of human teeth is beginning to be delineated; however, there remains much to be resolved in the area of genotype-phenotype correlations. How locus-specific mutations affect phenotypic changes as measured by tooth shape, position, size, and number is poorly understood. The availability of improved dental diagnostic and genomic tools along with sophisticated mouse transgenesis will greatly add to our knowledge of how allele-specific alterations influence patterns of inheritable disease. Although tooth malformations compromise emotional wellbeing and impose significant financial burdens on patients and their families, these conditions are not life threatening. Therefore, the identification and diagnosis of multigenerational families segregating disorders affecting dentition offers an exciting avenue for research on the genetic etiology of dental diseases. The legacy of inheritable anomalies of human dentition will continue to provide a unique and powerful system for studying the genetic pathways that control the development of human dentition. Knowledge about normal and abnormal tooth development and eruption is essential in the postgenomic area as emerging technologies of biomimetics and tissue engineering are applied to the field of regenerative dental medicine. The next decade will benefit from these advances as they can be well-applied to the bioengineering of animal and human tooth structures through the use of either embryonic or adult (somatic) stem cells. These multipotential cells can be derived from bone marrow stroma as well as from tissues derived from individual layers of embryonic tooth organs or the intact tooth germ itself.35–37 Stem cell populations existent in deciduous teeth that are shed have also shown the potential to form mineralized tooth structures like dentin and bone and to regenerate nerve tissues as well.38–40 References 1. Thesleff I, Pispa J: The teeth as models for studies on the molecular basis of the development and evolution of organs. In: Molecular Basis of Epithelial Appendage Morphogenesis. Chuong CM, ed. International Thomson Publishing Services Ltd, London, 1998, p 157. 2. Weiss K, Stock D, Zhao Z, et al.: Perspectives on genetic aspects of dental patterning. Eur J Oral Sci 106(suppl 1):55, 1998. 3. Kronmiller JE, Beeman CS: Spatial distribution of endogenous retinoids in the murine embryonic mandible. Arch Oral Biol 39:1071, 1994. 4. Osborn JW: Morphogenetic gradients: fields versus clones. In: Development, Function and Evolution of the Teeth. Butler PM, Joysey KA, eds. Academic Press, NY, 1978, p 171.

5. Hunt P, Krumlauf R: Hox codes and positional specification in vertebrate embryonic axes. Annu Rev Cell Biol 8:227, 1992. 6. Imai H, Osumi-Yamashita N, Ninomiya Y, et al.: Contribution of earlyemigrating midbrain crest cells to the dental mesenchyme of mandibular molar teeth in rat embryos. Dev Biol 176:151, 1996. 7. Boyde A: Enamel. In: Handbook of Microscopic Anatomy, vol 6, Teeth. Oksche A, Vollrath L, eds. Springer-Verlag, Berlin, 1989. 8. Fincham AG, Moradian-Oldak J, Simmer JP: The structural biology of the developing dental enamel matrix. J Struct Biol 126:270, 1999. 9. Hubbard MJ: Enamel cell biology. Towards a comprehensive biochemical understanding. Connect Tissue Res 38:17, 1998; discussion 35. 10. Simmer JP, Fincham AG: Molecular mechanisms of dental enamel formation. Crit Rev Oral Biol Med 6:84, 1995. 11. Smith CE, Nanci A: Overview of morphological changes in enamel organ cells associated with major events in amelogenesis. Int J Dev Biol 39:153, 1995. 12. Warshawsky H, Nanci A: Stereo electron microscopy of enamel crystallites. J Dent Res Spec No:1504, 1982. 13. Fujisawa R, Kuboki Y: Preferential adsorption of dentin and bone acidic proteins on the (100) face of Hydroxyapatite crystals. Biochem Biophys Acta 1075:56, 1991. 14. Butler WT, Bhown M, Brunn JC, et al.: Isolation, characterization and immunolocalization of a 53-kDal dentin sialoprotein (DSP). Matrix 12: 343, 1992. 15. Butler WT: Dentin matrix proteins and dentinogenesis. Connect Tissue Res 33:59, 1995. 16. Linde A, Goldberg M: Dentinogenesis. Crit Rev Oral Biol Med 4:679, 1993. 17. Butler WT, Ritchie H: The nature and functional significance of dentin extracellular matrix proteins. Int J Dev Biol 39:169, 1995. 18. MacDougall M, Simmons D, Luan X, et al.: Dentin phosphoprotein and dentin sialoprotein are cleavage products expressed from a single transcript coded by a gene on human chromosome 4. Dentin phosphoprotein DNA sequence determination. J Biol Chem 272:835, 1997. 19. Zhang X, Zhao J, Li C, et al.: DSPP mutation in dentinogenesis imperfecta Shields type II. Nat Genet 27:151, 2001. 20. Xiao S, Yu C, Chou X, et al.: Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP. Nat Genet 27:201, 2001. 21. George A, Sabsay B, Simonian PA, et al.: Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization. J Biol Chem 268:12624, 1993. 22. D’Souza RN, Cavender A, Sunavala G, et al.: Gene expression patterns of murine dentin matrix protein 1 (Dmp1) and dentin sialophosphoprotein (DSPP) suggest distinct developmental functions in vivo. J Bone Miner Res 12:2040, 1997. 23. Hirst KL, Simmons D, Feng J, et al.: Elucidation of the sequence and the genomic organization of the human dentin matrix acidic phosphoprotein 1 (DMP1) gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II. Genomics 42:38, 1997. 24. Smith AJ, Lesot H: Induction and regulation of crown dentinogenesis: embryonic events as a template for dental tissue repair? Crit Rev Oral Biol Med 12:425, 2001. 25. Ten Cate AR: Oral Histology: Development, Structure, and Function, ed 5. Mosby, St. Louis, 1998. 26. Avery JK: Oral Development and Histology. Mosby Year Book, St. Louis, 1987. 27. Mina M, Kollar EJ: The induction of odontogenesis in non-dental mesenchyme combined with early murine mandibular arch epithelium. Arch Oral Biol 32:123, 1987. 28. Jernvall J, Kettunen P, Karavanova I, et al.: Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. Int J Dev Biol 38:463, 1994. 29. Jernvall J, Aberg T, Kettunen P, et al.: The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Development 125:161, 1998.

Teeth 30. Peters H, Balling R: Teeth. Where and how to make them. Trends Genet 15:59, 1999. 31. Jernvall J, Thesleff I: Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 92:19, 2000. 32. Thesleff I: The genetic basis of normal and abnormal craniofacial development. Acta Odontol Scand 56:321, 1998. 33. Thesleff I: Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Science 116:1647, 2003. 34. Cameron AC, Widmer RP: Handbook of Paediatric Dentistry, ed 2. Mosby, London, 1998, p 355–356. 35. Young CS, Terada S, Vacanti JP, et al.: Tissue engineering of complex tooth structures on biodegradable polymer scaffolds. J Dent Res 81:695, 2002. 36. Duailibi MT, Duailibi SE, Young CS, et al.: Bioengineered teeth from cultured rat tooth bud cells. J Dent Res 83:523, 2004. 37. Ohazama A, Modino SA, Miletich I, et al.: Stem-cell-based tissue engineering of murine teeth. J Dent Res 83:518, 2004. 38. Gronthos S, Mankani M, Brahim J, et al.: Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA 97:13625, 2000. 39. Gronthos S, Brahim J, Li W, et al.: Stem cell properties of human dental pulp stem cells. J Dent Res 81:531, 2002. 40. Miura M, Gronthos S, Zhao M, et al.: SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA 100:5807, 2003.

14.1 Tooth Agenesis Definition

Tooth agenesis is the congenital lack of one or more of the deciduous or permanent teeth. It is classified as a clinically and genetically heterogenous condition that affects specific groups of teeth. It is the most common developmental anomaly in humans. The third molars, for instance, are congenitally absent so commonly that surveys of tooth agenesis frequently exclude this tooth type for consideration. The literature uses several terms to describe tooth agenesis that are based on the number of teeth involved. Oligodontia is the agenesis of six or more permanent teeth, whereas absence of less than

431

six teeth is referred as hypodontia. Anodontia refers to the absence of all deciduous and permanent teeth (Fig. 14-4). Diagnosis

A tooth is considered congenitally absent when it is not present clinically (erupted) or radiographically (unerupted) at an age when it is expected to be present. The extent to which tooth agenesis is manifested varies widely and can be presented as the only phenotypic feature (isolated) or associated with other anomalies or as part of a syndrome. Among the several developmental anomalies involving human dentition, the field of tooth agenesis has shown the most progress. The genetic etiology of tooth agenesis has received much attention in recent years, and as Tables 14-2 to 14-5 describe, several genes and underlying mutations have been reported to cause tooth agenesis. Many of these discoveries have been guided by knowledge about the genes involved in murine tooth development, in particular those that are important for the initiation of odontogenesis. Etiology and Distribution

Tooth agenesis occurs more frequently among a few specific teeth (lateral incisors, second premolars, and third molars), with 10– 25% of the population affected. Familial tooth agenesis is transmitted as autosomal dominant, autosomal recessive, and X-linked conditions but can also show no clear segregation pattern. Affected members within a family often exhibit significant variability with regard to the location, symmetry, and number of teeth involved. Residual teeth can vary in size, shape, or rate of development. The permanent dentition is more affected than the primary dentition. Animal models suggest that specific genetic factors might be involved with specific types of teeth during development. Mice with targeted null mutations of both Dlx-1 and Dlx-2 homeobox genes do not develop maxillary molar teeth, but the incisors and mandibular molars are normal. In contrast, among mice with mutant activin ßA (a member of the transforming growth factor (TGF) ß superfamily), incisors and mandibular molar teeth fail to develop

Fig. 14-4. Congenitally missing teeth. Intraoral photographs and panoramic radiographs from a normal 11-year-old male individual (A,B,C) and his 19-year-old affected brother, (D,E,F). A,B,C. Normal mixed primary and permanent dentition. Note the impacted maxillary central incisor and the presence of permanent first and second molars (arrows). Crowns shown in B were placed on the primary molars after the radiograph was taken. D,E,F. Affected individual with the following anomalies: peg-shaped lateral incisors; reduced mesiodistal widths and conical shape of permanent teeth; overretained primary second molars and mandibular central incisors. Notably, permanent mandibular central incisors and all permanent teeth distal to the first premolars are congenitally missing (solid arrows).

432

Craniofacial Structures Table 14-2. Isolated tooth agenesis Phenotype

Causation Gene/Locus

Hypodontia1

Polygenic Possibly MSX1, PAX9, TGFA, others

Hypodontia with anomalous shape of pulp chambers and pulp canals2

AR (602639) 16q12.1

Oligodontia with preferential agenesis of second premolars and third molars3

Sporadic (106600) PAX9, 14q12–q13

Oligodontia with preferential agenesis of second premolars and third molars4,5

AD (106600) MSX1, 4p16.1

Oligodontia with preferential molar agenesis6–13

AD (106600) PAX9, 14q12–q13

Oligodontia with preferential molar agenesis14

AD (106600) MSX1, 4p16.1

Severe oligodontia including deciduous and permanent molar agenesis8

AD (106600) PAX9, 14q12–q13

Table 14-3. Tooth agenesis associated with other defects or diseases Phenotype

Causation Locus/Genes

Anodontia and strabismus15

AD, Unknown

Asphyxiating thoracic dystrophy and oligodontia16

Chromosomal (208500) Deletion, 12p11.21–p12.2

Cleft lip and palate and hypo-dontia outside the cleft area17

Polygenic Possibly MSX1, TGFB3, others

Coloboma of macula with type B brachydactyly and oligodontia18

Sporadic (120400)

Hypodontia and Dupuytren contracture19

AD (126900) with incomplete penetrance

Leukodystrophy and oligodontia20

AR (607694)

Medullary sponge kidney and anodontia of permanent dentition21

AR

Oligodontia and colorectal cancer22

AD AXIN2

Oligodontia and congenital sensorineural hearing loss23,24

AR (221740)

Oligodontia and polycystic ovaries25

AR

beyond a rudimentary bud, whereas maxillary molar teeth develop normally. The mice lack whiskers and have defects in the secondary palates, including cleft palate. In humans, mutations in MSX1 and PAX9 have been associated with tooth agenesis, but those mutations probably cause only a very few cases. However, the pattern of tooth agenesis from these mutations is remarkable, with PAX9 causing preferential agenesis of molars and MSX1 causing preferential agenesis of second premolars and third molars. The majority of the tooth agenesis cases are probably multifactorial with many genes involved.206 Epidemiologic characteristics of tooth agenesis are listed in Table 14-6. Prognosis, Treatment, and Prevention

Unless agenesis of one or more teeth is associated with a syndrome, prognosis is good. The unavoidable dental consequences of tooth agenesis include malocclusion due to improper position of the

teeth, deficient growth of the alveolar processes associated with the missing teeth, and excess space within the dental arches. The availability of space results in drifting, tipping, and supraeruption of the adjacent or opposing teeth. In molar oligodontia, the functional atrophy in alveolar ridge height is easily recognizable. Syndromic and nonsyndromic forms of tooth agenesis that involve multiple teeth result in significant aesthetic, emotional, and financial burdens placed on families faced with the ordeal and costs associated with restoring the dentitions of several affected family members. The average cost for the restoration of dentition in patients affected with severe forms of tooth agenesis approximates $50,000 to $60,000 per individual. Although clinicians have long observed hypodontia and oligodontia, the early diagnosis, preventive or interceptive dental measures, and treatment options for this condition have been extremely limited. The number and type of missing teeth as well as individual skeletal proportions and aesthetic considerations generally dictate treatment regimens. Therapy is phasic, complicated, and lengthy, involving at least two dental specialists. Orthodontic appliances are ideal for the repositioning of existing teeth and the consolidation of space for either a fixed or removable prosthesis. However, when several teeth are missing, as seen in molar oligodontia, orthodontic correction is followed by bone augmentation procedures to increase the bone mass prior to the placement of implants. With the exception of syndromic cases of anodontia, molar oligodontia presents with the most severe of dental complications. There are no useful preventive measures for tooth agenesis, and prenatal diagnosis is impossible or considered by many to be unwarranted. In theory, anodontia can be detected prenatally by ultrasound examination. It is doubtful that a couple would choose to modify the course of a pregnancy for isolated anodontia, making prevention a moot point. References (Tooth Agenesis) 1. Vieira AR, Meira R, Modesto A, et al.: MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res 83:723, 2004. 2. Ahmad W, Brancolini V, Ul Faiyaz MF, et al.: A locus for autosomal recessive hypodontia with associated dental anomalies maps to chromosome 16q12.1. Am J Hum Genet 26:987, 1998. 3. Mostowska A, Kobielak A, Biedziak B, et al.: Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia. Eur J Oral Sci 111:272, 2003.

Table 14-4. Syndromes with tooth agenesis as a component Syndrome

Prominent Features

Causation Locus/Gene

Autosomal Dominant Conditions

Acrofacial dysostosis, type Nager26,27

Limb deformities, severe micrognathia and malar hypoplasia (can also be autosomal recessive)

(154400) 9q32, 1q12–q21

Acrofacial dysostosis, type Palagonia28

Oligodontia, short stature, frizzy hair with aplasia cutis verticis, hand anomalies, unilateral cleft lip, some vertebral anomalies (can also be X-linked dominant)

(601829)

Adenomatous polyposis of the colon29,30

Adenomatous polyps of the colon and rectum, congenital hypertrophy of the retinal pigment epithelium, dental anomalies

(175100) APC, 5q21-q22

ADULT31–33

Ectrodactyly, syndactyly, nail dysplasia, hypoplastic breasts and nipples, intensive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, loss of permanent teeth

(103295) p63, 3q27

Alagille34,35

Eye anomalies, cardiovascular anomalies, abnormal vertebrae, cognitive problems, typical facies, hypodontia, oral xanthomas

(118450) JAG1, 20p12

Ankyloplepharon-ectodermal defects-cleft lip/palate36,37

Coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; cleft lip/palate

(106260) p63, 3q27

Axenfeld-Rieger38–43

Eye, dental, and umbilical anomalies

(180500) PITX2, 4q25–q26 FOXC1, 6p25 13q14

Book44

Congenitally missing premolars, narrow palate, severe functional hyperhidrosis of the hands and feet, small hands, hypoplastic nails

(112300)

Branchio-oculo-facial45

Branchial clefts with characteristic facies, growth retardation, imperforate nasolacrimal duct, premature aging

(113620)

Choanal atresia with maxillary hypoplasia, prognathism, and hypodontia46

Bilateral choanal atresia, tall forehead, maxillary hypoplasia, prognathism, hypodontia

Ectodermal dysplasia 347,48

Mild hypotrichosis, mild hypodontia, and variable degrees of hypohidrosis (can also be autosomal recessive)

(129490) EDAR, 2q11–q13

Ectrodactyly-ectodermal dysplasia-clefting49–51

Lobster-claw anomalies of hands and feet, lacrimal duct anomalies with ocular complications, cleft lip/palate (most cases are sporadic)

(129900) (EEC1) 7q11.2–q21.3 (EEC2) 19p13–q13 (EEC3) p63, 3q27

Ehlers-Danlos type VI52–54

Ocular, muscular, and skin defects; abnormal maxilla; occasional hypodontia and/or smaller teeth sizes

(225400) PLOD1, 1p36.3–p36.2 (continued)

433

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Hair-nail-skin-teeth dysplasias55

Large number of rare disorders involving binary, ternary, or quaternary combination of hair, nails, skin appendages, and teeth anomalies (can also be autosomal recessive or X-linked)

(125640, 257980, 262020, 272980, 275450)

Hallermann-Streiff56

Birdlike facies with hypoplastic mandible and beaked nose, proportionate dwarfism, hypotrichosis, microphthalmia, dental anomalies, congenital cataract

(234100)

Hypodontia with orofacial clefts57

Cleft lip and palate, cleft palate alone, oligodontia with preferential agenesis of second premolars and third molars

(106600) MSX1, 4p16.1

Kallmann58,59

Hypogonadotropic hypogonadism, anosmia, bimanual synkinesia, cleft lip or palate, multiple dental agenesis

(147950) FGFR1, 8p11.2–p11.1

KBG60

Short stature, characteristic facies, mental retardation, skeletal anomalies, oligodontia, macrodontia

(148050)

LADD61

Aplasia or hypoplasia of the puncta with obstruction of the nasal lacrimal ducts; ear, dental, and hand anomalies

(149730)

Limb-mammary62,63

Severe hand/foot anomalies and hypoplasia/aplasia of the mammary gland and nipple, lacrimal-duct atresia, nail dysplasia, hypohidrosis, hypodontia, cleft palate with or without bifid uvula

(603543) p63, 3q27

Niikawa-Kuroki (Kabuki)64–66

A peculiar face, characterized by eversion of the lower lateral eyelid, arched eyebrows with sparse or dispersed lateral onethird, depressed nasal tip, and prominent ears; skeletal anomalies, dermatoglyphic abnormalities, mild to moderate mental retardation; postnatal growth deficiency, heart defects, dental anomalies

(147920)

Oculodentodigital dysplasia67,68

Bilateral microphthalmos, abnormally small nose, hypotrichosis, dental anomalies, fifth finger camptodactyly, syndactyly of the fourth and fifth fingers, missing toe phalanges

(164200) GJA1, 6q21-q23.2

Oligodontia, microcephaly, short stature, characteristic facies69

Microcephaly, short stature, characteristic facies, oligodontia

Unknown

Otodental dysplasia70

Sensorineural hearing loss, dental anomalies, missing premolars

(166750)

Popliteal pterygium71,72

Cleft lip/palate, paramedian mucous cysts of the lower lip, webbing of the lower limbs, digital and genital anomalies

(119500) IRF6, 1q32-q41

(continued)

434

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Scalp-ear-nipple73

Abnormality of the scalp, ears, nipples, tooth agenesis, and renal anomalies

(181270) Unknown

Shopf-Schulz-Passarge74,75

Keratosis palmoplantaris with cystic eyelids, hypodontia, hypotrichosis (can also be autosomal recessive)

(224750) 17q24

Ulnar-mammary76–78

Posterior (ulnar or postaxial) limb deficiencies and/or duplications, mammary gland hypoplasia, apocrine dysfunction, and dental and genital abnormalities

(181450) TBX3, 12q24.1

Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly79,80

Congenital hypotrichosis, uncombable hair, associated with juvenile cataracts, retinal pigmentary dystrophy, oligodontia, and brachymetacarpy

(191482)

Van der Woude71,72,81–84

Lip pits, cleft of lip/palate, hypodontia

(119300) IRF6, 1p34

Witkop (tooth-and-nail)85

Missing teeth and poorly formed nails

(189500) MSX1, 4p16.1

Agonadism, XY, with mental retardation, short stature, retarded bone age, and multiple extragenital malformations86

Minor anomalies: peculiar face, hypodontia, short neck, inverted nipples, thoracolumbar scoliosis, ‘‘dysplastic’’ hips, partial clinodactyly/syndactyly of the toes

Unknown

Amelogenesis imperfecta and platyspondyly87

Mild growth retardation, platyspondyly, vertebral defects, pectus carinatum, limited extension at the elbows, amelogenesis imperfecta, oligodontia

(601216) Unknown

Bardet-Biedl88–94

Mental retardation, pigmentary retinopathy, polydactyly, obesity, hypogenitalism

Multiple loci

Blepharo-cheilodontic95

Cleft lip and/or palate, ectropion of the lower eyelids with ocular hypertelorism, and dental anomalies

(119580)

Brachymetapody-anodontia-hypotrichosis-albinoidism96

Congenital anodontia, small maxilla, short stature, little hair growth, albinoidism, multiple ocular abnormalities

(211370)

Cerebellar hypoplasia with endosteal sclerosis97

Ataxia and developmental delay, microcephaly, short stature, oligodontia, strabismus, nystagmus, congenital hip dislocation

(213002)

Cleft lip/palate, congenital contractures, ectodermal dysplasia, and psychomotor and growth retardation98

Typical facies, congenital contractures, orofacial clefts, oligodontia and other teeth anomalies (may also be X-linked)

(301815)

Cleft lip/palate-ectodermal dysplasia99,100

Anhidrosis, hypotrichosis, dental anomalies, dysplasia of nails, cleft lip and palate, deformity of the fingers and toes, malformation in the genitourinary system, popliteal perineal pterygium, syndactyly

(225000) PVRL1, 11q23–q24

Autosomal Recessive Conditions

(continued)

435

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Cleft palate, stapes fixation, and oligodontia101

Cleft palate, stapes fixation, oligodontia

(216300)

Cockayne102–104

Dwarfism, precociously senile appearance, pigmentary retinal degeneration, optic atrophy, deafness, disproportionately long limbs with large hands and feet and flexion contractures of joints, marble epiphyses in some digits, photosensitivity, mental retardation

(216400) XPB, XPD, XPG, CSA, CSB

Cranioectodermal dysplasia105

Dolichocephaly; sparse, slow-growing, fine hair; epicanthal folds; hypodontia and/or micro-dontia; brachydactyly; narrow thorax

(218330)

Dermatoosteolysis, Kirghizian type106

Recurrent skin ulceration, arthralgia, fever, fistulous osteolysis around joints, oligodontia, nail dystrophy, keratitis with visual impairment or blindness

(221810)

Dysosteosclerosis107

Anterior fontanel tends to remain open, oligo-dontia, progressive mental retardation, oto-sclerosis, intracerebral calcifications (can also be X-linked)

(224300)

Ectodermal dysplasia, Margarita Island type100,108

Scanty eyebrows and eyelashes; sparse, short, and dry scalp hair; dental anomalies; cleft lip/palate; syndactyly of fingers and toes; onychodysplasia

(225060) PVRL1, 11q23-q24

Ellis-van Creveld109–111

Skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth

(225500) EVC, EVC2

Epidermolysis bullosa112–116

Dystrophy of the nails, nonscarring blistering of skin, mild skin atrophy, hypodontia

(226650) COL17A1, LAMA3, LAMB3, LAMC2, ITGB4

Gorlin-Chaudhry-Moss117

Craniofacial dysostosis, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies, patent ductus arteriosus, normal intelligence

(233500)

Hanhart118–120

Aglossia, adactylia; is often associated with missing mandibular incisors, hypertrophy of salivary glands (most cases are sporadic)

(103300)

Hennekan lymphangiectasia-lymphedema121

Intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia, and face; severe mental retardation; facial anomalies

(235510)

Johanson-Blizzard122

Aplasia or hypoplasia of the nasal alae, congenital deafness, hypothyroidism, postnatal growth retardation, mental retardation, midline ectodermal scalp defects, microdontia or absent permanent teeth

(243800)

Leukomelanoderma, infantilism, mental retardation, hypodontia, hypotrichosis123

Mental retardation, leukomelanoderma, hypotrichosis, hypodontia

(246500)

(continued)

436

Table 14-4. Syndromes with tooth agenesis as a component (continued)

Syndrome

Prominent Features

Causation Locus/Gene

MULIBREY nanism124,125

Anomalies of MUscle, LIver, BRain, and EYe

(253250) TRIM37, 17q32–q23

Odontotrichomelic126

Tetramelic deficiency, ectodermal dysplasia, deformed pinnae

(273400)

Polydactyly, postaxial, with dental and vertebral anomalies127

Postaxial polydactyly and other abnormalities of the hands and feet, hypoplasia and fusion of vertebral bodies, dental anomalies

(263540)

Progeria128,129

Precocious senility of a striking degree; death from coronary artery disease is frequent and may occur before 10 years of age

(176670) LMNA, 1q21.2

Pycnodysostosis130

Deformity of the skull, maxilla, and phalanges; osteosclerosis; fragility of bone; dental anomalies

(265800) CTSK, 1q21

Richieri-Costa and Pereira131

Robin sequence, cleft mandible, limb anomalies

(268305)

Rothmund-Thomson132,133

Atrophy, pigmentation, telangiectasia, juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism, dental anomalies, soft tissue contractures, proportionate short stature, anemia, osteogenic sarcoma

(268400) RECQL4, 8q24.3

Spondyloepimeta-physeal dysplasia with abnormal dentition134

Generalized platyspondyly with epiphyseal and metaphyseal involvement, thin tapering fingers with accentuated palmar creases, abnormal dentition (oligodontia and pointed incisors)

(601668)

Mental retardation with peculiar pugilistic nose, large ears, tapered fingers, drumstick terminal phalanges by radiograph, and pectus carinatum. Other complications: premature death, progressive kyphoscoliosis, spinal stenosis, drop attacks, abnormalities in dentition, hearing loss, ocular abnormalities, excess of psychiatric illness in carrier females

(303600) RSK2, Xp22.2-p22.1

Males: characteristic facies; teeth often missing or misshapen; fine, sparse hair; and skin is thin, glossy, smooth, and dry with hypohidrosis. Females: sparse, thin scalp hair and mosaic patchy distribution of body hair; abnormal teeth; mild hypohidrosis

(305100) ED1, Xq12-q13.1

X-Linked Conditions

Coffin-Lowry135–139

Ectodermal dysplasia 1140–142

Ectodermal dysplasia, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum143

(225040)

(continued)

437

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Faciogenital dysplasia144–148

Ocular hypertelorism, anteverted nostrils, broad upper lip, escrotum anomalies, occasional dental anomalies

(305400) FGD1, Xp11.21

Focal dermal hypoplasia149

Atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, multiple papillomas of the mucous membranes or skin, digital anomalies, oral anomalies, ocular anomalies, mental retardation

(305600)

Frontometaphyseal dysplasia150

Marked frontal hyperostosis, underdeveloped mandible, cryptorchidism, subluxated radial heads, metaphyseal dysplasia

(305620) FLNA, Xq28

Incontinentia pigmenti151

Disturbance of skin pigmentation sometimes associated with a variety of malformations of the eye, teeth, skeleton, and heart

(308300) NEMO, Xq28

Mulvihill-Smith152

Low-birth-weight dwarfism with mild to moderate mental retardation, striking multiple pigmented nevi, lack of facial subcutaneous fat

(176690)

Oculofaciocardio-dental153–155

Cataracts, micro-phthalmia, oligodontia, radiculomegaly, septal heart defects

(300166) BCL6 corepressor (BCOR)

Orofaciodigital, type I156,157

Clefts of the jaw and tongue, other malformations of the face and skull, malformations of the hands and teeth, mental retardation

(311200) CXORF5, Xp22.3-p22.2

Otopalatodigital types I and II150,158

Conduction deafness, cleft palate, characteristic facies, generalized bone dysplasia; type II is more severe

(311300, 304120) FLNA, Xq28

W159

Mental retardation with frontal prominence; anterior cowlick; hypertelorism; antimongoloid orbital slant; broad, flat nasal bridge; midline notch of upper lip and submucous cleft of the hard palate; absent upper central incisors; limited motion at the elbow; pes cavus

(311450)

Short stature, hypotelorism, prognathism, hypodontia

(607095)

Down161–165

Mental retardation, typical facies, heart defects, short stature, dental anomalies

(190685) Trisomy 21

Glossopalatine ankylosis166

Glossopalatine ankylosis, cleft palate, limb anomalies, hypoplastic mandible, incisor hypodontia

Hemimaxillofacial dysplasia167

Unilateral enlargement of maxillary alveolar bone and gingival associated with tooth agenesis, facial asymmetry

Chromosomal and Other Conditions

Anauxetic dysplasia160

(continued)

438

Teeth

439

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Oroacral, Verloes-Koulischer type168

Absence of the medial part of the upper alveolar ridge, including the gingiva, frenulum, and tooth buds for the maxillary incisors and canines

(603446)

Sener169

Frontonasal dysplasia, dilated Virchow-Robin spaces, hypodontia, buccal frenula

(606156)

Unusual facies, oligodontia, and precocious choroid calcifications170

Minor digital anomalies, telecanthus, broad and flattened nasal bridge, mild ocular proptosis, small nose with anteverted nostrils, microretrognathia

(603589)

Williams-Beuren171

Typical facies, mental retardation, growth deficiency, cardio-vascular anomalies, infantile hypercalcemia

(194050) 7q11.23

Wolf-Hirschhorn172

Severe growth retardation and mental defect, microcephaly, typical facies, closure defects (cleft lip or palate, coloboma of the eye, cardiac septal defects)

(194190) Chromosomal Del 4p16.3

Table 14-5. Solitary maxillary central incisor defects Type of Defect Associated

Causation Gene/Locus

Table 14-6. Epidemiologic Characteristics of Tooth Agenesis Characteristic

Summary Information 207

Frequency (primary dentition)

1.4%

Frequency (permanent dentition, excluding third molars)208,209

1.6–10%

Ethnic differences210

Multifactorial (214800)

Frequencies are higher in Asians and lower in African-descent populations compared to Europeans

Gender differences211,212

M/F 2:3

Hypophyseal short stature and cleft lip181

Unknown

Familial patterns1,213,214

Approximately 35% are familial cases

Holoprosencephaly182–194

Heterogeneous (236100) SHH, 7q36 SIX3, 2p21 TGIF, 18p13 ZIC2, 13p32 PTCH, 9q22.3 Other loci and chromosomal causes

Isolated defect173

AD (147250) SHH, 7q36

7q36.1 deletion174

Chromosomal Del 7q36.1

18p deletion or r(18)175–178

Chromosomal Del 18p or ring 18

CHARGE179,180

Sibling recurrence 1–9%

Iris coloboma and hypomelanosis of Ito183

Unknown

Klippel-Feil195–197

AD (148900) 8q22.2

Microphthalmia and hypopituitarism198

Unknown

Precocious puberty and hypothalamic hamartoma199

Unknown

Short stature and choanal atresia200

Unknown

Short stature and ocular coloboma201

Unknown

Unusual forms of ectodermal dysplasia202,203

Unknown

VACTERL179,204

Sporadic (192350)

205

XXX syndrome

Trisomy X

Monozygotic twin concordance 89%

4. Vastardis H, Karimbux N, Guthua SW, et al.: A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet 13:417, 1996. 5. Lidral AC, Reising BC: The role of MSX1 in human tooth agenesis. J Dent Res 81:274, 2002. 6. Stockton DW, Das P, Goldenberg M, et al.: Mutation of PAX9 is associated with oligodontia. Nat Genet 24:18, 2000. 7. Nieminen P, Arte S, Tanner D, et al.: Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Eur J Hum Genet 9:743, 2001. 8. Das P, Stockton DW, Bauer C, et al.: Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Hum Genet 110:371, 2002. 9. Frazier-Bowers SA, Guo DC, Cavender A, et al.: A novel mutation in human PAX9 causes molar oligodontia. J Dent Res 81:129, 2002. 10. Das P, Mehreen H, Elcock C, et al.: Novel missense mutations and 288bp exonic insertion in PAX9 in families with autosomal dominant hypodontia. Am J Med Genet 118A:35, 2003. 11. Lammi L, Halonen K, Pirinen S, et al.: A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. Eur J Hum Genet 11:866, 2003.

440

Craniofacial Structures

12. Jumlongras D, Lin JY, Chapra A, et al.: A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia. Hum Genet 114:242, 2004. 13. D’Souza RN, Frazier-Bowers SA: PAX9 I87F mutation (unpublished data). 14. Frazier-Bowers SA, D’Souza RN: MXS1 E48R mutation (unpublished data). 15. Beierle LE, Jorgenson RJ: Anodontia in a child: report of a case. J Dent Child 45:483, 1978. 16. Nagai T, Nishimura G, Kato R, et al.: Del(12)(p11.21p12.2) associated with an asphyxiating thoracic dystrophy or chondroectodermal dysplasia-like syndrome. Am J Med Genet 55:16, 1995. 17. Slayton RL, Williams L, Murray JC, et al.: Genetic association studies of cleft lip and/or palate with hypodontia outside the cleft region. Cleft Palate Craniofac J 40:274, 2003. 18. Thompson EM, Baraitser M: Sorsby syndrome: a report on further generations of the original family. J Med Genet 25:313, 1988. 19. Ranta H, Knif J, Ranta K: Familial hypodontia associated with Dupuytren’s disease. Scand J Dent Res 98:457, 1990. 20. Atrouni S, Daraze A, Tamraz J, et al.: Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity? Am J Med Genet 118A:76, 2003. 21. Khoury Z, Brezis M, Mogle P: Familial medullary sponge kidney in association with congenital absence of teeth (anodontia). Nephron 48:231, 1988. 22. Lammi L, Arte S, Somer M, et al.: Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 75:1043, 2004. 23. Glass L, Gorlin RJ: Congenital profound sensorineural hearing loss and oligodontia: a new syndrome. Arch Otolaryngol 105:621, 1979. 24. Lee M, Levin LS, Kopstein E: Autosomal recessive sensorineural hearing loss, dizziness, and hypodontia. Arch Otolaryngol 104:292, 1978. 25. Hattah FN, Angmar-Mansson B: Oligodontia of the permanent dentition in two sisters with polycystic ovarian syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:368, 1997. 26. Zori RT, Gray BA, Bent-Williams A, et al.: Preaxial acrofacial dysostosis (Nager syndrome) associated with an inherited and apparently balanced X;9 translocation: prenatal and postnatal late replication studies. Am J Med Genet 46:379, 1993. 27. Waggoner DJ, Ciske DJ, Dowton SB, et al.: Deletion of 1q in a patient with acrofacial dysostosis. Am J Med Genet 82:301, 1999. 28. Sorge G, Pavone L, Polizzi A, et al.: Another ‘new’ form, the Palagonia type of acrofacial dysostosis in a Sicilian family. Am J Med Genet 69: 388, 1997. 29. Joslyn G, Carlson M, Thliveris A, et al.: Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 66:601, 1991. 30. Nishisho I, Nakamura Y, Miyoshi Y, et al.: Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665, 1991. 31. Fader M, Kline SN, Spatz SS, et al.: Gardner’s syndrome (intestinal polyposis, osteomas, sebaceous cysts) and a new dental discovery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 15:153, 1962. 32. Propping P, Zerres K: ADULT-syndrome: an autosomal-dominant disorder with pigment anomalies, ectrodactyly, nail dysplasia, and hypodontia. Am J Med Genet 45:642, 1993. 33. Amiel J, Bougeard G, Francannet C, et al.: TP63 gene mutation in ADULT syndrome. Eur J Hum Genet 9:642, 2001. 34. Ho NC, Lacbawan F, Francomano CA, et al.: Severe hypodontia and oral xanthomas in Alagille syndrome. Am J Med Genet 93:250, 2000. 35. Yuan ZR, Kohsaka T, Ikegaya T, et al.: Mutational analysis of the Jagged 1 gene in Alagille syndrome families. Hum Mol Genet 7:1363, 1998. 36. Hay RJ, Wells RS: The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition. Br J Derm 94:287, 1976.

37. McGrath JA, Duijf PHG, Doetsch V, et al.: Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet 10:221, 2001. 38. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996. 39. Perveen R, Lloyd IC, Clayton-Smith J, et al.: Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Invest Ophthalmol Vis Sci 41:2456, 2000. 40. Nishimura DY, Searby CC, Alward WL, et al.: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 68:364, 2001. 41. Priston M, Kozlowski K, Gill D, et al.: Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome. Hum Mol Genet 10:1631, 2001. 42. Saadi I, Semina EV, Amendt BA, et al.: Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 276:23034, 2001. 43. Borges AS, Susanna Junior R, Carani JCE, et al.: Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil. J Glaucoma 11:51, 2002. 44. Book JA: Clinical and genetical studies of hypodontia. I. Premolar aplasia, hyperhidrosis, and canities prematura. A new hereditary syndrome in man. Am J Hum Genet 2:240, 1950. 45. Lee WK, Root AW, Fenske N: Bilateral branchial cleft sinuses associated with intrauterine and postnatal growth retardation, premature aging, and unusual facial appearance: a new syndrome with dominant transmission. Am J Med Genet 11:345, 1982. 46. Ramos-Arroyo MA, Valiente A, Rodriguez-Toral E, et al.: Familial choanal atresia with maxillary hypoplasia, prognatism, and hypodontia. Am J Med Genet 95:237, 2000. 47. Jorgenson RJ, Dowben JS, Dowben SL: Autosomal dominant ectodermal dysplasia. J Craniofac Genet Dev Biol 7:403, 1987. 48. Monreal AW, Ferguson BM, Headon DJ, et al.: Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 22:366, 1999. 49. Qumsiyeh MB: EEC syndrome (ectrodactyly, ectodermal dysplasia and cleft lip/palate) is on 7p11.2-q21.3. Clin Genet 42:101, 1992. 50. O’Quinn JR, Hennekam RCM, Jorde LB, et al.: Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19. Am J Hum Genet 61(suppl):A289, 1997. 51. Celli J, Duijf P, Hamel BCJ, et al.: Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99:143, 1999. 52. Hyland J, Ala-Kokko L, Royce P, et al.: A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers-Danlos syndrome type VI. Nat Genet 2:228, 1992. 53. Ha VT, Marshall MK, Elsas LJ, et al.: A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene. J Clin Invest 93:1716, 1994. 54. Heikkinen J, Toppinen T, Yeowell H, et al.: Duplication of seven exons in the lysyl hydroxylase gene is associated with longer forms of a repetitive sequence within the gene and is a common cause for the type VI variant of Ehlers-Danlos syndrome. Am J Hum Genet 60:48, 1997. 55. Freire-Maia N: Ectodermal Dysplasia—A Clinical and Genetic Study. Liss, New York, 1984, p 251. 56. Franc¸ois J: A new syndrome: dyscephalia with bird face and dental anomalies, nanism, hypotrichosis, cutaneous atrophy, microphthalmia and congenital cataract. Arch Ophthalmol 60:842, 1958. 57. Van den Boogaard MJH, Dorland M, Beemer FA, et al: MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 24:342, 2000. 58. Dode´ C, Levilliers J, Dupont JM, et al.: Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33:463, 2003. 59. Sato N, Katsumata N, Kagami M, et al.: Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast

Teeth

60.

61. 62.

63.

64.

65. 66.

67. 68.

69.

70. 71.

72.

73. 74.

75.

76.

77.

78.

79.

80.

81.

growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab 89:1079, 2004. Herrmann J, Pallister PD, Tiddy W, et al.: The KBG syndrome—a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. Birth Defects Orig Artic Ser XI(5):7, 1975. Hollister DW, Klein SH, Dejager HJ, et al.: The lacrimo-auriculodento-digital syndrome. J Pediatr 83:438, 1973. Van Bokhoven H, Jung M, Smits APT, et al.: Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other hand/foot anomalies maps to human chromosome 3q27. Am J Hum Genet 64:538, 1999. Van Bokhoven H, Hamel BC, Bamshad M, et al.: p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split handfoot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 69:481, 2001. Niikawa N, Matsuura N, Fukushima Y, et al.: Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 99:565, 1981. Lo IFM, Cheung LYK, Ng AYY, et al.: Interstitial dup(1p) with findings of Kabuki make-up syndrome. Am J Med Genet 78:55, 1998. Milunsky JM, Huang XL: Unmasking Kabuki syndrome: chromosome 8p22-8p23.1 duplication revealed by comparative genomic hybridization and BAC-FISH. Clin Genet 64:509, 2003. Gillespie FD: A hereditary syndrome: ‘dysplasia oculodentodigitalis.’ Arch Ophthal 71:187, 1964. Paznekas WA, Boyadjiev SA, Shapiro RE, et al.: Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408, 2003. Melamed Y, Katznelson MB, Frydman M: Oligodontia, short stature, and small head circumference and normal intelligence. Clin Genet 46:316, 1994. Levin LS, Jorgenson RJ, Cook RA: Otodental dysplasia: a ‘new’ ectodermal dysplasia. Clin Genet 8:136, 1975. Kondo S, Schutte BC, Richardson RJ, et al.: Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 32:285, 2002. Ghassibe M, Revencu N, Bayet B, et al.: Six families with van der Woude and/or popliteal pterygium syndrome: all with a mutation in the IRF6 gene. J Med Genet 41:e15, 2004. Finlay AY, Marks R: An hereditary syndrome of lumpy scalp, odd ears and rudimentary nipples. Br J Dermatol 99:423, 1978. Schopf E, Schulz HJ, Passarge E: Syndrome of cystic eyelids, palmoplantar keratosis, hypodontia and hypotrichosis as a possible autosomal recessive trait. Birth Defects Orig Artic Ser VII(8):219, 1971. Stevens HP, Kelsell DP, Bryant SP, et al.: Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24: literature survey and proposed updated classification of the keratodermas. Arch Dermatol 132:640, 1996. Bamshad M, Lin RC, Law DJ, et al.: Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 16:311, 1997. Sasaki G, Ogata T, Ishii T, et al.: Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: implication for impaired sex development. Am J Med Genet 110:365, 2002. Wollnik B, Kayserili H, Uyguner O, et al.: Haploinsufficiency of TBX3 causes ulnar-mammary syndrome in a large Turkish family. Ann Genet 45:213, 2002. Bork K, Stender E, Schmidt D, et al.: Familiaere kongenitale hypotrichose mit ‘unkaemmbaren haaren,’ retina-pigmentblattdystrophie, juveniler katarakt und brachymetakarpie: eine weitere entitaet aus der gruppe der ektodermalen dysplasien. Hautarzt 38:342, 1987. Silengo M, Lerone M, Romeo G, et al.: Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly: report of a new patient with additional findings. Am J Med Genet 47:931, 1993. Koillinen H, Wong FK, Rautio J, et al.: Mapping of the second locus for the Van der Woude syndrome to chromosome 1p34. Eur J Hum Genet 9:747, 2001.

441

82. Kayano S, Kure S, Suzuki Y, et al.: Novel IRF6 mutations in Japanese patients with Van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion. J Hum Genet 48:622, 2003. 83. Kim Y, Park JY, Lee TJ, et al.: Identification of two novel mutations of IRF6 in Korean families affected with Van der Woude syndrome. Int J Mol Med 12:465, 2003. 84. Gatta V, Scarciolla O, Cupaioli M, et al.: A novel mutation of the IRF6 gene in an Italian family with Van der Woude syndrome. Mutat Res 547:49, 2004. 85. Jumlongras D, Bei M, Stimson JM, et al.: A nonsense mutation in MSX1 causes Witkop Syndrome. Am J Hum Genet 69:67, 2001. 86. Kennerknecht I, von Saurma P, Brenner R, et al.: Agonadism in two sisters with XY gonosomal constitution, mental retardation, short stature, severely retarded bone age, and multiple extragenital malformations: a new autosomal recessive syndrome. Am J Med Genet 59:62, 1995. 87. Verloes A, Jamblin P, Koulischer L, et al.: A new form of skeletal dysplasia with amelogenesis imperfecta and platyspondyly. Clin Genet 49:2, 1996. 88. Beales PL, Warner AM, Hitman GA, et al.: Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families. J Med Genet 34:92, 1997. 89. Young TL, Woods MO, Parfrey PS, et al.: Canadian Bardet-Biedl syndrome family reduces the critical region of BBS3 (3p) and presents with a variable phenotype. Am J Med Genet 78:461, 1998. 90. Young TL, Penney L, Woods MO, et al.: A fifth locus for Bardet-Biedl syndrome maps to chromosome 2q31. Am J Hum Genet 64:901, 1999. 91. Katsanis N, Lewis RA, Stockton DW, et al.: Delineation of the critical interval of Bardet-Biedl syndrome 1 (BBS1) to a small region of 11q13, through linkage and haplotype analysis of 91 pedigrees. Am J Hum Genet 65:1672, 1999. 92. Katsanis N, Beales PL, Woods MO, et al.: Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with BardetBiedl syndrome. Nat Genet 26:67, 2000. 93. Katsanis N, Ansley SJ, Badano JL, et al.: Triallelic inheritance in BardetBiedl syndrome, a mendelian recessive disorder. Science 293:2256, 2001. 94. Katsanis N, Lupski JR, Beales PL: Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 10:2293, 2001. 95. Allanson JE, McGillivray BC: Familial clefting syndrome with ectropion and dental anomaly—without limb anomalies. Clin Genet 27:426, 1985. 96. Tuomaala P, Haapanen E: Three siblings with similar anomalies in the eyes, bones and skin. Acta Ophthalmol 46:365, 1968. 97. Charrow J, Poznanski AK, Unger FM, et al.: Autosomal recessive cerebellar hypoplasia and endosteal sclerosis: a newly recognized syndrome. Am J Med Genet 41:464, 1991. 98. Ladda RL, Zonana V, Ramer JC, et al.: Congenital contractures, ectodermal dysplasia, cleft lip/palate and developmental impairment: a distinct syndrome. Am J Med Genet 47:550, 1993. 99. Rosselli D, Gulienetti R: Ectodermal dysplasia. Br J Plast Surg 14:190, 1961. 100. Suzuki K, Hu D, Bustos T, et al.: Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palateectodermal dysplasia. Nat Genet 25:427, 2000. 101. Gorlin RJ, Schlorf RA, Paparella MM: Cleft palate, stapes fixation and oligodontia. Birth Defects Orig Artic Ser VII(7):87, 1971. 102. Henning KA, Li L, Iyer N, et al.: The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell 82:555, 1995. 103. Habraken Y, Sung P, Prakash S, et al.: Transcription factor TFIIH and DNA endonuclease Rad2 constitute yeast nucleotide excision repair factor 3: implications for nucleotide excision repair and Cockayne syndrome. Proc Natl Acad Sci USA 93:10718, 1996. 104. McDaniel LD, Legerski R, Lehmann AR, et al.: Confirmation of homozygosity for a single nucleotide substitution mutation in a Cockayne syndrome patient using monoallelic mutation analysis in somatic cell hybrids. Hum Mutat 10:317, 1997. 105. Levin LS, Perrin JCS, Ose L, et al.: A heritable syndrome of craniosynostosis, short thin hair, dental abnormalities, and short limbs: cranioectodermal dysplasia. J Pediatr 90:55, 1977.

442

Craniofacial Structures

106. Kozlova SI, Altshuler BA, Kravchenko VL: Self-limited autosomal recessive syndrome of skin ulceration, arthroosteolysis with pseudoacromegaly, keratitis and oligodontia in a Kirghizian family. Am J Med Genet 15:205, 1983. 107. Spranger JW, Albrecht C, Rohwedder HJ, et al.: Die dysosteosklerose: eine sonderform der generalisierten osteosklerose. Fortschr Roentgenstr 109:504, 1968. 108. Bustos T, Simosa V, Pinto-Cisternas J, et al.: Autosomal recessive ectodermal dysplasia. I. An undescribed dysplasia/malformation syndrome. Am J Med Genet 41:398, 1991. 109. McKusick VA, Egeland JA, Eldridge R, et al.: Dwarfism in the Amish. I. The Ellis-van Creveld syndrome. Bull Johns Hopkins Hosp 115:306, 1964. 110. Ruiz-Perez VL, Ide SE, Strom TM, et al.: Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 24:283, 2000. 111. Ruiz-Perez VL, Tompson SWJ, Blair HJ, et al.: Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am J Hum Genet 72:728, 2003. 112. Bircher AJ, Lang-Muritano M, Pfaltz M, et al.: Epidermolysis bullosa junctionalis progressiva in three siblings. Br J Dermatol 128:429, 1993. 113. Pulkkinen L, Christiano AM, Gerecke D, et al.: A homozygous nonsense mutation in the beta-3 chain gene of laminin 5 (LAMB3) in Herlitz junctional epidermolysis bullosa. Genomics 24:357, 1994. 114. McGrath JA, Gatalica B, Christiano AM, et al.: Mutations in the 180-kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa. Nat Genet 11:83, 1995. 115. Vidal F, Baudoin C, Miquel C, et al.: Cloning of the laminin alpha-3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics 30:273, 1995. 116. Nakano A, Pulkkinen L, Murrell D, et al.: Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta-4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res 49:618, 2001. 117. Gorlin RJ, Chaudhry AP, Moss ML: Craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies—a new syndrome? J Pediatr 56:778, 1960. 118. Hanhart E: Ueber die kombination von peromelie mit mikrognathie, ein neues syndrom beim menschen, entsprechend der akroteriasis congenita von wriedt und mohr beim Rind. Arch Klaus Stift Vererbungsforsch 25:531, 1950. 119. Hall BD: Aglossia-adactylia. Birth Defects Orig Artic Ser VII(7):233, 1971. 120. Tunc¸bilek E, Yalcin C, Atasu M: Aglossia-adactylia syndrome (special emphasis on the inheritance pattern). Clin Genet 11:421, 1977. 121. Hennekam RCM, Geerdink RA, Hamel BCJ, et al.: Autosomal recessive intestinal lymphangiectasia and lymphedema with facial anomalies and mental retardation. Am J Med Genet 34:593, 1989. 122. Johanson AJ, Blizzard RM: A syndrome of congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. J Pediatr 79:982, 1971. 123. Berlin CI: Congenital generalized melanoleucoderma associated with hypodontia, hypotrichosis, stunted growth and mental retardation occurring in two brothers and two sisters. Dermatologica 123:227, 1961. 124. Avela K, Lipsanen-Nyman M, Idanheimo N, et al.: Gene encoding a new RING-B-box-coiled-coil protein is mutated in mulibrey nanism. Nat Genet 25:298, 2000. 125. Jagiello P, Hammans C, Wieczorek S, et al.: A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity. Hum Mutat 21:630, 2003. 126. Freire-Maia N: A newly recognized genetic syndrome of tetramelic deficiencies, ectodermal dysplasias, deformed ears and other anomalies. Am J Hum Genet 22:370, 1970. 127. Rogers JG, Levin LS, Dorst JP, et al.: A postaxial polydactyly-dentalvertebral syndrome. J Pediatr 90:230, 1977. 128. Eriksson M, Brown WT, Gordon LB, et al.: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293, 2003.

129. De Sandre-Giovannoli A, Bernard R, Cau P, et al.: Lamin A truncation in Hutchinson-Gilford progeria. Science 300:2055, 2003. 130. Gelb BD, Shi GP, Chapman HA, et al.: Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236, 1996. 131. Richieri-Costa A, Pereira SCS: Short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfoot: a new autosomal recessive syndrome. Am J Med Genet 42:681, 1992. 132. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985. 133. Kitao S, Shimamoto A, Goto M, et al.: Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82, 1999. 134. Rao V, Morton RE, Young ID: Spondyloepimetaphyseal dysplasia and abnormal dentition in siblings: a new autosomal recessive syndrome. Clin Dysmorphol 6:3, 1997. 135. Trivier E, De Cesare D, Jacquot S, et al.: Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384:567, 1996. 136. Jacquot S, Merienne K, De Cesare D, et al.: Mutation analysis of the RSK2 gene in Coffin-Lowry patients: extensive allelic heterogeneity and a high rate of de novo mutations. Am J Hum Genet 63:1631, 1998. 137. Manouvrier-Hanu S, Amiel J, Jacquot S, et al.: Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome. J Med Genet 36:775, 1999. 138. Hunter AGW: Coffin-Lowry syndrome: a 20-year follow-up and review of long-term outcomes. Am J Med Genet 111:345, 2002. 139. Simensen RJ, Abidi F, Collins JS, et al.: Cognitive function in CoffinLowry syndrome. Clin Genet 61:299, 2002. 140. Zonana J, Gault J, Davies KJP, et al.: Detection of a molecular deletion at the DXS732 locus in a patient with X-linked hypohidrotic ectodermal dysplasia (EDA), with the identification of a unique junctional fragment. Am J Hum Genet 52:78, 1993. 141. Kere J, Srivastava AK, Montonen O, et al.: X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 13:409, 1996. 142. Monreal AW, Zonana J, Ferguson B: Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet 63:380, 1998. 143. Fryns JP, Chrzanowska K, van den Berghe H: Hypohidrotic ectodermal dysplasia, primary hypothyroidism, and agenesis of the corpus callosum. J Med Genet 26:520, 1989. 144. Aarskog D: A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J Pediatr 77:856, 1970. 145. Pasteris NG, Cadle A, Logie LJ, et al.: Isolation and analysis of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative, rho/ rac guanine nucleotide exchange factor. Cell 79:669, 1994. 146. Orrico A, Galli L, Falciani M, et al.: A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome). FEBS Lett 478:216, 2000. 147. Schwartz CE, Gillessen-Kaesbach G, May M, et al.: Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome. Eur J Hum Genet 8:869, 2000. 148. Lebel RR, May M, Pouls S, et al.: Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene. Clin Genet 61:139, 2002. 149. Goltz RW, Peterson WC Jr, Gorlin RJ, et al.: Focal dermal hypoplasia. Arch Dermatol 86:708, 1962. 150. Robertson SP, Twigg SRF, Sutherland-Smith AJ, et al.: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 151. The International Incontinentia Pigmenti Consortium: Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti. Nature 405:466, 2000. 152. Shepard MK: An unidentified syndrome with abnormality of skin and hair. Birth Defects Orig Artic Ser VII(8):353, 1971. 153. Hayward JR: Cuspid gigantism. Oral Surg Oral Med Oral Path Oral Radiol Endod 49:500, 1980.

Teeth 154. Gorlin RJ, Marashi AH, Obwegeser HL: Oculo-facio-cardio-dental (OFCD) syndrome. Am J Med Genet 63:290, 1996. 155. Ng D, Thakker N, Corcoran CM, et al.: Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet 36:411, 2004. 156. Fenton OM, Watt-Smith SR: The spectrum of the oro-facial-digital syndrome. Br J Plast Surg 38:532, 1985. 157. Ferrante MI, Giorgio G, Feather SA, et al.: Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 68:569, 2001. 158. Dudding BA, Gorlin RJ, Langer LO Jr: The oto-palato-digital syndrome: a new symptom-complex consisting of deafness, dwarfism, cleft palate, characteristic facies, and a generalized bone dysplasia. Am J Dis Child 113:214, 1967. 159. Pallister PD, Herrmann J, Spranger JW, et al.: The W syndrome. Birth Defects Orig Artic Ser X(7):51, 1974. 160. Menger H, Mundlos S, Becker K, et al.: An unknown spondylometa-epiphyseal dysplasia in sibs with extreme short stature. Am J Med Genet 63:80, 1996. 161. Down JL: Observations on an ethnic classification of idiots. Clin Lect Rep London Hospital 3:249, 1866. 162. Lejeune J, Gautier M, Turpin R: Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci 248:1721, 1959. 163. Mikkelsen M: Down’s syndrome cytogenetic epidemiology. Hereditas 86:45, 1977. 164. Hook EG: Epidemiology of Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 11. 165. Thuline HC, Pueschel SM: Cytogenetics in Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 133. 166. Illera MD: Congenital occlusion of pharynx. Lancet 1:742, 1887. 167. Miles DA, Lovas JL, Cohen MM Jr: Hemimaxillofacial dysplaisa: a newly recognized disorder of facial asymmetry, hypertrichosis of the facial skin, unilateral enlargement of the maxilla, and hypoplastic teeth in two patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 64:445, 1987. 168. Verloes A, Koulischer L: New oral-acral syndrome with partial agenesis of the maxillary bones. Am J Med Genet 44:605, 1992. 169. Sener RN: Polycystic brain (cerebrum polycystica vera) associated with ectodermal dysplasia: a new neurocutaneous syndrome. Pediatr Radiol 24:116, 1994. 170. Palotta R, Fusilli P: Unknown syndrome: peculiar face, severe hypodontia of permanent teeth, and precocious choroids clacifications. J Med Genet 35:435, 1998. 171. Ewart AK, Morris CA, Atkinson D, et al.: Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5:11, 1993. 172. Gusella JF, Tanzi RE, Bader PI, et al.: Deletion of Huntington’s diseaselinked G8 (D4S10) locus in Wolf-Hirschhorn syndrome. Nature 318:75, 1985. 173. Nanni L, Ming JE, Du Y, et al.: SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature. J Med Genet 102:1, 2001. 174. Masuno M, Fukushima Y, Sugio Y, et al.: Two unrelated cases of single maxillary central incisor with 7q terminal deletion. Jpn J Hum Genet 35:311, 1990. 175. Dolan LM, Willson K, Wilson WG: 18p- syndrome with a single central maxillary incisor. J Med Genet 18:396, 1981. 176. Santoro FP, Wesley RK: Clinical evaluation of two patients with a single maxillary central incisor. J Dent Child 50:379, 1983. 177. Aughton DJ, AlSaadi AA, Transue DJ: Single maxillary central incisor in a girl with del(18p) syndrome. J Med Genet 28:530, 1991. 178. Lo FS, Lee YJ, Lin SP, et al.: Solitary maxillary central incisor and congenital nasal pyriform aperture stenosis. Eur J Pediatr 157:39, 1998. 179. Hall RK, Bankier A, Aldred MJ, et al.: Solitary median maxillary central incisor, short stature, choanal atresia/midnasal stenosis (SMMCI)

180.

181. 182. 183. 184.

185.

186.

187.

188.

189. 190.

191.

192. 193.

194.

195. 196. 197.

198. 199.

200.

201.

202.

203.

443 syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84: 651, 1997. Harrison M, Calvert ML, Longhurst P: Solitary maxillary central incisor as a new finding in CHARGE association: a report of two cases. Int J Paediatr Dent 7:185, 1997. France´s JM, Knorr D, Martinez R, et al.: Hypophysa¨rer zwergwuchs bei lippen-kiefer-spalte. Helv Paediatr Acta 21:315, 1966. Holmes LB, Driscoll S, Atkins L: Genetic heterogeneity of cebocephaly. J Med Genet 11:35, 1974. Berry SA, Pierpont ME, Gorlin RJ: Single central incisor in familial holoprosencephaly. J Pediatr 104:877, 1984. Zwetsloot CP, Brouwer OF, Maaswinkel-Mooy PD: Holoprosencephaly: variation of expression in face and brain in three sibs. J Med Genet 26:274, 1989. Corsello G, Buttitta P, Cammarata M, et al.: Holoprosencephaly: examples of clinical variability and etiologic heterogeneity. Am J Med Genet 37:244, 1990. Estabrooks LL, Rao KW, Donahue RP, et al.: Holoprosencephaly in an infant with a minute deletion of chromosome 21(q22.3). Am J Med Genet 36:306, 1990. Lurie IW, Ilyina HG, Podleschuk LV, et al.: Chromosome 7 abnormalities in parents of children with holoprosencephaly and hydronephrosis. Am J Med Genet 35:286, 1990. Collins AL, Lunt PW, Garrett C, et al.: Holoprosencephaly: a family showing dominant inheritance and variable expression. J Med Genet 30:36, 1993. Muenke M: Holoprosencephaly as a genetic model for normal craniofacial development. Dev Biol 5:293, 1994. Muenke M, Bone LJ, Mitchell HF, et al.: Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of chromosome 21 important for Down syndrome. Am J Hum Genet 57:1074, 1995. Nanni L, Ming JE, Bocian M, et al.: The mutational spectrum of the Sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Molec Genet 8:2479, 1999. Wallis D, Muenke M: Mutations in holoprosencephaly. Hum Mutat 16:99, 2000. Lehman NL, Zaleski DH, Sanger WG, et al.: Holoprosencephaly associated with an apparent isolated 2q37.1-2q37.3 deletion. Am J Med Genet 100:179, 2001. Orioli IM, Castilla EE, Ming JE, et al.: Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly. Hum Genet 109:1, 2001. Bauman GI: Absence of the cervical spine: Klippel-Feil syndrome. JAMA 98:129, 1932. Fleming P, Nelson J, Gorlin RJ: Single maxillary central incisor in association with mid-line anomalies. Br Dent J 168:476, 1990. Clarke RA, Singh S, McKenzie H, et al.: Familial Klippel-Feil syndrome and paracentric inversion inv(8)(q22.2q23.3). Am J Hum Genet 57:1364, 1995. Artman HG, Boyden E: Microphthalmia with single central incisor and hypopituitarism. J Med Genet 27:192, 1990. Winter WE, Rosenbloom AL, Maclaren NK, et al.: Solitary central maxillary incisor associated with precocious puberty and hypothalamic hamartoma. Pediatr 101:965, 1982. Arliss H, Ward RF: Congenital nasal pyriform aperture stenosis: isolated anomaly vs. developmental fold defect. Arch Otolaryngol Head Neck Surg 118:989, 1992. Liberfarb RM, Abdo OP, Pruett RC: Ocular coloboma associated with a solitary maxillary central incisor and growth failure: manifestations of holoprosencephaly. Ann Ophthalmol 19:226, 1987. Winter RM, MacDermot KD, Hill FJ: Sparse hair, short stature, hypoplastic thumbs, single upper central incisor and abnormal skin pigmentation: a possible ‘‘new’’ form of ectodermal dysplasia. Am J Med Genet 29:209, 1988. Buntinx I, Baraitser M: A single maxillary incisor as a manifestation of a ectodermal dysplasia. J Med Genet 26:648, 1989.

444

Craniofacial Structures

204. Wesley RK, Hoffman WH, Perrin J, et al.: Solitary maxillary central incisor and normal stature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 46:837, 1978. 205. Miura M, Kato N, Kojima H, et al.: Triple-X syndrome accompanied by single maxillary central incisor: case report. Pediatr Dent 15:214, 1993. 206. Vieira AR: Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res 82:162, 2003. 207. Whittington BR, Durward CS: Survey of anomalies in primary teeth and their correlation with the permanent dentition. N Z Dent J 92:4, 1996. 208. Eidelman E, Chosack A, Rosenzweig KA: Hypodontia prevalence among Jewish populations of different origin. Am J Phys Anthrop 39:129, 1973. 209. Graber LW: Congenital absence of teeth: a review with emphasis on inheritance patterns. J Am Dent Assoc 96:266, 1978. 210. Muller TP, Hill IN, Petersen AC, et al.: A survey of congenitally missing permanent teeth. J Am Dent Assoc 81:101, 1970. 211. Bergstrom K: An orthopantomographic study of hypodontia, supernumeraries and other anomalies in school children between the ages of 8-9 years: an epidemiological study. Swed Dent J 1:145, 1977. 212. Brook AH: A unifying aetiological explanation for anomalies of human tooth number and size. Arch Oral Biol 29:373, 1984. 213. Markovic M: Hypodontia in twins. Swed Dent J Suppl 15:153, 1982. 214. Spoonhower C, Valiathan M, Hans MG, et al.: Familial aggregation of congenital hypodontia. In: International Association for Dental Research 82nd General Session Program Book, 2004, p 149.

14.2 Supernumerary Teeth Definition

Supernumerary teeth is the presence of more than the normal complement of deciduous (20) and permanent teeth (32). Diagnosis

Supernumerary teeth can be diagnosed by the actual count, clinically or radiographically. Teeth in excess of the normal complement are named according to their location: mesiodens are located on the palatal side of the maxillary central incisors; supernumerary canines and premolars are located at the normal sites for such teeth; paramolars are located buccal to the first, second, and third molars; and distomolars (fourth molars) are located distal to the third molar in line with the dental arch. There may also be lingual, intradental, and interradicular supernumerary teeth. Supernumerary teeth may be fused with teeth in the normal complement. Supernumerary teeth can present as the only phenotypic feature (isolated), in association with other anomalies (such as tooth agenesis or orofacial clefts), or as part of a syndrome.1–3 Etiology and Distribution

Syndromes with supernumerary teeth as a component are listed in Table 14-7. There is evidence that related etiologic factors contribute to supernumerary teeth, tooth agenesis, and orofacial clefts.3,33,34 Differences in the mesiodistal width of central incisors depending on unilateral or bilateral occurrence of mesiodens and the report of gemination of a deciduous incisor on the same side of a mesiodens support the theory of the split in the tooth bud inducing the development of supernumerary teeth over that of a local hyperactivity of the dental lamina.33 Single and double supernumeraries occur in 90% of cases, and multiple supernumeraries in 10% of cases.35 Epidemiologic characteristics of supernumerary teeth are listed in Table 14-8.

Prognosis, Treatment, and Prevention

Supernumerary teeth may interfere with the eruption of teeth in the normal complement or may cause their malalignment. Unless they are features of a syndrome, prognosis is good. They are easily extracted, even if they are impacted. There are no preventive measures. References (Supernumerary Teeth) 1. Finn SB: Clinical Pedodontics. WB Saunders Company, Philadelphia, 1967, p 477. 2. Mercuri LG, O’Neill R: Multiple impacted and supernumerary teeth in sisters. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 50:293, 1980. 3. Ranta R: Numeric anomalies of teeth in concomitant hypodontia and hyperodontia. J Craniofac Genet Dev Biol 8:245, 1988. 4. Joslyn G, Carlson M, Thliveris A, et al.: Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 66:601, 1991. 5. Nishisho I, Nakamura Y, Miyoshi Y, et al.: Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665, 1991. 6. Mundlos S, Otto F, Mundlos C, et al.: Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773, 1997. 7. Zhou G, Chen Y, Zhou L, et al.: CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia. Hum Mol Genet 8:2311, 1999. 8. Wynne SE, Aldred MJ, Bartold PM: Hereditary gingival fibromatosis associated with hearing loss and supernumerary teeth—a new syndrome. J Periodontol 66:75, 1995. 9. Franc¸ois J: A new syndrome: Dyscephalia with bird face and dental anomalies, nanism, hypotrichosis, cutaneous atrophy, microphthalmia and congenital cataract. Arch Ophthalmol 60:842, 1958. 10. Gorlin RJ, Anderson RC, Blaw ME: Multiple lentigines syndrome: complex comprising multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness, and autosomal dominant hereditary pattern. Am J Dis Child 117:652, 1969. 11. Munshi A, Munshi AK: Leopard syndrome—report of a variant case. J Indian Soc Pedod Prev Dent 17:5, 1999. 12. Digilio MC, Conti E, Sarkozy A, et al.: Grouping of multiple-lentigines/ LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389, 2002. 13. Giedion A: Das tricho-rhino-phalangeale syndrome. Helv Paediatr Acta 21:475, 1966. 14. Ludecke HJ, Schaper J, Meinecke P, et al.: Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III. Am J Hum Genet 68:81, 2001. 15. Bork K, Stender E, Schmidt D, et al.: Familiaere kongenitale hypotrichose mit ‘unkaemmbaren haaren,’ retina-pigmentblattdystrophie, juveniler katarakt und brachymetakarpie: eine weitere entitaet aus der gruppe der ektodermalen dysplasien. Hautarzt 38:342, 1987. 16. Silengo M, Lerone M, Romeo G, et al.: Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly: report of a new patient with additional findings. Am J Med Genet 47:931, 1993. 17. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck. Oxford University Press, New York, 2001, p 1117. 18. Gurrieri F, Sammito V, Ricci B, et al.: Possible new type of oral-facialdigital syndrome with retinal abnormalities: OFDS type (VIII). Am J Med Genet 42:789, 1992. 19. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985. 20. Kitao S, Shimamoto A, Goto M, et al.: Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82, 1999.

Teeth

445

Table 14-7. Syndromes with supernumerary teeth as a component Syndrome

Prominent Features

Causation Gene/Locus

Adenomatous polyposis of the colon4,5

Adenomatous polyps of the colon and rectum, congenital hypertrophy of the retinal pigment epithelium, dental anomalies

(175100) APC, 5q21–q22

Cleidocranial dysplasia6,7

Persistently open skull sutures with bulging calvaria, hypoplasia or aplasia of the clavicles permitting abnormal facility in apposing the shoulders, wide pubic symphysis, short middle phalanx of the fifth fingers, supernumerary teeth, vertebral malformations

(119600) CBFA1 (RUNX2), 6p21

Gingival fibromatosis, hearing loss, and supernumerary teeth8

Gingival overgrowth at the time of deciduous tooth eruption, hearing loss, supernumerary teeth, hypertelorism

Unknown

Hallermann-Streiff9

Birdlike facies with hypoplastic mandible and beaked nose, proportionate dwarfism, hypotrichosis, microphthalmia, dental anomalies, congenital cataract

(234100)

LEOPARD10–12

Multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, sensorineural deafness, delayed secondary sexual characteristics, supernumerary teeth

(151100) PTPN11, 12q24.1

Trichorhino-phalangeal types I and III13,14

Sparse hair, beaked nose, long upper lip, super-numerary teeth, severe metacarpophalangeal shortening

(190350, 190351) TRPS1 18q24.12

Uncombable hair, retinal pigmentary dystrophy, dental anomalies, brachydactyly15,16

Congenital hypotrichosis and uncombable hair, associated with juvenile cataracts, retinal pigmentary dystrophy, oligodontia, brachymetacarpy

(191482)

Unusual facies, digital anomalies, supernumerary teeth17

Prominent forehead with widow’s peak, supernumerary teeth, subglottic tracheal hypoplasia, brachydactyly, club foot, clinodactyly

AD

Oral-facial-digital with retinal anomalies18

Mild mental retardation; small notch in the upper lip; highly arched palate with bifid tongue; supernumerary lower canine bilaterally; lobulated, hamartomatous tongue; multiple frenula (could also be X-linked)

(258865)

Rothmund-Thomson19,20

Atrophy, pigmentation, telangiectasia, juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism, dental anomalies, soft tissue contractures, proportionate short stature, anemia, osteogenic sarcoma

(268400) RECQL4, 8q24.3

Steroid dehydrogenase deficiency21

Supernumerary teeth, steroid dehydrogenase deficiency

Unknown

Cataract-dental22–28

Dense nuclear cataracts and frequently microcornea with mesiodens and incisor anomalies

(302350) Xp22.13

Focal dermal hypoplasia29

Atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, and multiple papillomas of the mucous membranes or skin, digital anomalies, oral anomalies, ocular anomalies, mental retardation

(305600)

Orofaciodigital, types I, III30–32

Clefts of the jaw and tongue, other malformations of the face and skull, malformation of the hands and teeth, mental retardation

(311200, 258850) CXORF5, Xp22.3–p22.2

Autosomal Dominant Conditions

Autosomal Recessive Conditions

X-Linked Conditions

21. Lyngstadaas SP, Crossner CJ, Nazer H, et al.: Severe dental aberrations in familial steroid dehydrogenase deficiency: a new association. Clin Genet 49:249, 1996. 22. Bixler D, Higgins M, Hartsfield J Jr: The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females. Clin Genet 26:30, 1984. 23. Bergen AAB, ten Brink J, Schuurman EJM, et al.: Nance-Horan syndrome: linkage analysis in a family from the Netherlands. Genomics 21:238, 1994. 24. Stambolian D, Bond A, Lewis RA, et al.: Linkage studies in the Nance Horan syndrome using eight polymorphic DNA probes from the short arm of X chromosome. Cytogenet Cell Genet 51:1085, 1989.

25. Zhu D, Alcorn DM, Antonarakis SE, et al.: Assignment of the NanceHoran syndrome to the distal short arm of the X chromosome. Hum Genet 86:54, 1990. 26. Stambolian D, Favor J, Silvers W, et al.: Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance-Horan syndrome, on the mouse X chromosome. Genomics 22:377, 1994. 27. Toutain A, Dessay B, Ronce N, et al.: Refinement of the NHS locus on chromosome Xp22.13 and analysis of five candidate genes. Eur J Hum Genet 10:516, 2002. 28. Burdon KP, McKay JD, Sale MM, et al.: Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe

446

Craniofacial Structures

Table 14-8. Epidemiologic characteristics of supernumerary teeth Characteristic

Summary Information

Frequency (primary dentition)36

<0.1%

Frequency (permanent dentition)37–39

1–5%

Ethnic differences37–39

No remarkable differences in frequency among populations

Gender differences39–42

M/F 2:1 in Europeans; 4:1 in Africans; 5.5:1 in Japanese; and 6.5:1 in Chinese

Familial patterns33

Approximately 30% are familial cases

29. 30. 31. 32. 33. 34. 35. 36.

37. 38. 39.

40. 41. 42.

congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet 73:1120, 2003. Hall EH, Terezhalmy GT: Focal dermal hypoplasia syndrome. J Am Acad Dermatol 9:443, 1983. Sugarman GI, Katakia M, Menkes JH: See-saw winking in a familial oral-facial-digital syndrome. Clin Genet 2:248, 1971. Fenton OM, Watt-Smith SR: The spectrum of the oro-facial-digital syndrome. Br J Plast Surg 38:532, 1985. Ferrante MI, Giorgio G, Feather SA, et al.: Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 68:569, 2001. Stellzig A, Basdra EK, Komposch G: Mesiodentes: incidence, morphology, etiology. J Orofac Orthop 58:144, 1997. Vieira AR: Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res 82:162, 2003. Scheiner MA, Sampson WJ: Supernumerary teeth: a review of the literature and four case reports. Aust Dent J 42:160, 1997. Whittington BR, Durward CS: Survey of anomalies in primary teeth and their correlation with the permanent dentition. N Z Dent J 92:4, 1996. Clayton JM: Congenital dental anomalies occurring in 3,557 children. J Dent Child 23:206, 1956. Niswander JD, Sajuku C: Congenital anomalies of teeth in Japanese children. Am J Phys Anthropol 21:569, 1963. Primo LG, Wilhelm RS, Bastos EPS: Frequency and characteristics of supernumerary teeth in Brazilian children: consequences and proposed treatments. Rev Odontol Sa˜o Paulo 11:231, 1997. Hogstrum A, Andersson L: Complications related to surgical removal of anterior supernumerary teeth in children. J Dent Child 54:341, 1987. So LLY: Unusual supernumerary teeth. Angle Orthod 60:289, 1990. Umweni AA, Osunbor GE: Non-syndromic multiple supernumerary teeth in Nigerians. Odontostomatol Trop 25:43, 2002.

14.3 Microdontia Definition

Microdontia is a tooth that is much smaller than its contralateral homolog or a tooth of the same group from an opposing arch (mandibular central incisors are exceptions), a tooth that does not ‘‘fill’’ its space in the dental arch, or a tooth that appears small because of absence of expected shape (peg shaped, conical, or tapered). There are anatomic standards, of course, but the criteria stated above are the most useful to the clinician. Diagnosis

Microdontia is diagnosed by simple observation or measurement. Standards for tooth size have been published (Table 14-9), but mi-

crodontia is usually determined subjectively. Microdontia may affect only a few teeth, usually homologous teeth such as the maxillary lateral incisors, or may be generalized. It may be an isolated trait, may be associated with tooth agenesis or orofacial clefts, or may be one feature in syndromes.1–6 Etiology and Distribution

Syndromes with microdontia as a component are listed in Table 1410. It is likely that microdontia is a variable expression of tooth agenesis and therefore is probably multifactorial in etiology. The more severe the tooth agenesis, the smaller the size of the tooth formed.3 Individuals with agenesis of one upper lateral incisor present with a 13-fold increased risk of having microdontia involving the contralateral upper lateral incisor. Also, cases with molar agenesis have a fourfold increased risk of having microdontia involving an upper lateral incisor. The suggestive association between molar agenesis and microdontia of the upper lateral incisor provides evidence that incisors and molars share some developmental genetic mechanisms, which appear to be independent from those that regulate premolar development.85 This is in agreement with the pattern of tooth agenesis seen from the mutations in PAX9 and MSX1 in humans. PAX9 causes oligodontia with preferential agenesis of molars, while MSX1 causes oligodontia with preferential agenesis of second premolars and third molars.86 The reported frequency of pegged teeth in the deciduous dentition is 0.2%, while the frequency in the permanent dentition is 1–2% among those of European descent and 6.2% among Japanese.87–89 Prognosis, Treatment, and Prevention

There are no morbid features associated with isolated microdontia. Malalignment of adjacent teeth and malocclusion may occur, depending on the site and extent of microdontia. Treatment usually consists of reshaping the tooth with composite resin or crowning. There are no useful preventive measures for microdontia. References (Microdontia) 1. Schalk-van der Weide Y, Bosman F: Tooth size in relatives of individuals with oligodontia. Arch Oral Biol 41:469, 1996. 2. Carretero Quezada MGC, Hoeksma JB, van de Velde JP, et al.: Dental anomalies in patients with familial and sporadic cleft lip and palate. J Biol Buccale 16:185, 1988. 3. Brook AH, Elcock C, al-Sharood MH, et al.: Further studies of a model for the etiology of anomalies of tooth number and size in humans. Connect Tissue Res 43:289, 2002. 4. Lidral AC, Reising BC: The role of MSX1 in human tooth agenesis. J Dent Res 81:274, 2002. 5. McKeown HF, Robinson DL, Elcock C, et al.: Tooth dimensions in hypodontia patients, their unaffected relatives and a control group measured by a new image analysis system. Eur J Orthod 24:131, 2002. 6. Lammi L, Halonen K, Pirinen S, et al.: A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. Eur J Hum Genet 11:866, 2003. 7. Renner RP: An Introduction to Dental Anatomy and Esthetics. Quintessence, Chicago, 1985. 8. Hay RJ, Wells RS: The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition. Br J Derm 94:287, 1976. 9. McGrath JA, Duijf PHG, Doetsch V, et al.: Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet 10:221, 2001. 10. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996.

Teeth

447

Table 14-9. Average sizes of permanent and deciduous teeth Permanent Heighta

Widthb

Deciduous Heighta

Widthb

10.5

8.5  7.0

6.0

6.5  5.0

Maxillary

Central incisors

9.0

6.5  6.0

5.6

5.0  4.0

10.0

7.5  8.0

6.5

7.0  7.0

First premolars

8.5

7.0  9.0

—

—

Second premolars

8.5

7.0  9.0

—

—

First molars

7.5

10.0  11.0

5.1

7.3  8.5

Lateral incisors Canines

Second molars

7.0

9.0  11.0

5.7

8.2  10.0

Third molars

6.5

8.5  10.0

—

—

Mandibular

Central incisors

9.0

5.0  6.0

5.0

4.2  4.0

Lateral incisors

9.5

5.5  6.5

5.2

4.1  4.0

11.0

7.0  7.5

6.0

5.0  4.8

First premolars

8.5

7.0  8.0

—

—

Second premolars

8.0

7.0  8.0

—

—

First molars

7.5

11.0  10.5

6.0

7.7  7.0

Second molars

7.0

10.5  10.5

5.5

9.9  8.7

Third molars

7.0

10.0  9.5

—

—

Canines

a

Height of crown in cm. Mesiodistal width  buccolingual (buccopalatal) width in cm. Modified from Renner.7

b

11. Perveen R, Lloyd IC, Clayton-Smith J, et al.: Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Invest Ophthalmol Vis Sci 41:2456, 2000. 12. Nishimura DY, Searby CC, Alward WL, et al.: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 68:364, 2001. 13. Priston M, Kozlowski K, Gill D, et al.: Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome. Hum Mol Genet 10:1631, 2001. 14. Saadi I, Semina EV, Amendt BA, et al.: Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 276:23034, 2001. 15. Borges AS, Susanna R Jr, Carani JCE, et al.: Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil. J Glaucoma 11:51, 2002. 16. Jorgenson RJ, Dowben JS, Dowben SL: Autosomal dominant ectodermal dysplasia. J Craniofac Genet Dev Biol 7:403, 1987. 17. Monreal AW, Ferguson BM, Headon DJ, et al.: Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 22:366, 1999. 18. Hyland J, Ala-Kokko L, Royce P, et al.: A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers-Danlos syndrome type VI. Nature Genet 2:228, 1992. 19. Ha VT, Marshall MK, Elsas LJ, et al.: A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene. J Clin Invest 93:1716, 1994. 20. Heikkinen J, Toppinen T, Yeowell H, et al.: Duplication of seven exons in the lysyl hydroxylase gene is associated with longer forms of a repetitive sequence within the gene and is a common cause for the type VI variant of Ehlers-Danlos syndrome. Am J Hum Genet 60:48, 1997. 21. Freire-Maia N: Ectodermal Dysplasia. A Clinical and Genetic Study. Liss, New York, 1984, p 251.

22. Niikawa N, Matsuura N, Fukushima Y, et al.: Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 99:565, 1981. 23. Lo IFM, Cheung LYK, Ng AYY, et al.: Interstitial dup(1p) with findings of Kabuki make-up syndrome. Am J Med Genet 78:55, 1998. 24. Milunsky JM, Huang XL: Unmasking Kabuki syndrome: chromosome 8p22-8p23.1 duplication revealed by comparative genomic hybridization and BAC-FISH. Clin Genet 64:509, 2003. 25. Gillespie FD: A hereditary syndrome: ‘dysplasia oculodentodigitalis.’ Arch Ophthalmol 71:187, 1964. 26. Paznekas WA, Boyadjiev SA, Shapiro RE, et al.: Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408, 2003. 27. Levin LS, Jorgenson RJ, Cook RA: Otodental dysplasia: a ‘new’ ectodermal dysplasia. Clin Genet 8:136, 1975. 28. Kantaputra PN, Kinoshita A, Limwonges C, et al.: A Thai mother and son with distal symphalangism, hypoplastic carpal bones, microdontia, dental pulp stones, and narrowing of the zygomatic arch: a new distal symphalangism syndrome? Am J Med Genet 109:56, 2002. 29. Bork K, Stender E, Schmidt D, et al.: Familiaere kongenitale hypotrichose mit ‘unkaemmbaren haaren,’ retina-pigmentblattdystrophie, juveniler katarakt und brachymetakarpie: eine weitere entitaet aus der gruppe der ektodermalen dysplasien. Hautarzt 38:342, 1987. 30. Silengo M, Lerone M, Romeo G, et al.: Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly: report of a new patient with additional findings. Am J Med Genet 47:931, 1993. 31. Jumlongras D, Bei M, Stimson JM, et al.: A nonsense mutation in MSX1 causes Witkop Syndrome. Am J Hum Genet 69:67, 2001. 32. Sulisalo T, Makitie O, Sistonen P, et al.: Uniparental disomy in cartilage-hair hypoplasia. Eur J Hum Genet 5:35, 1997. 33. Ridanpaa M, van Eenennaam H, Pelin K, et al.: Mutations in the RNA component of RNase MRP cause a pleitropic human disease, cartilagehair hypoplasia. Cell 104:195, 2001.

Table 14-10. Syndromes with microdontia as a component Syndrome

Prominent Features

Causation Gene/Locus

Autosomal Dominant Conditions

Ankyloblepharon-ectodermal defects-cleft lip/palate8,9

Coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; cleft lip/palate

(106260) p63, 3q27

Axenfeld-Rieger10–15

Eye, dental, and umbilical anomalies

(180500) PITX2, 4q25-q26 FOXC1, 6p25 13q14

Ectodermal dysplasia 316,17

Mild hypotrichosis, mild hypodontia, variable degrees of hypohidrosis (can also be autosomal recessive)

(129490) EDAR, 2q11-q13

Ehlers-Danlos type VI18–20

Ocular, muscular, and skin defects; abnormal maxilla; occasional hypodontia and/or smaller teeth sizes

(225400) PLOD1, 1p36.3–p36.2

Hair-nail-skin-teeth dysplasias21

Large number of rare disorders involving binary, ternary, or quaternary combination of hair, nails, skin appendages, and teeth anomalies (can also be autosomal recessive or X-linked)

(125640, 257980, 262020, 272980, 275450)

Niikawa-Kuroki (Kabuki)22–24

A peculiar face, characterized by eversion of the lower lateral eyelid, arched eyebrows with sparse or dispersed lateral one-third, depressed nasal tip, prominent ears, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate mental retardation, postnatal growth deficiency, heart defects, dental anomalies

(147920)

Oculodento-digital dysplasia25,26

Bilateral microphthalmos, abnormally small nose, hypotrichosis, dental anomalies, fifth finger camptodactyly, syndactyly of the fourth and fifth fingers, missing toe phalanges

(164200) GJA1, 6q21–q23.2

Otodental dysplasia27

Sensorineural hearing loss, dental anomalies, missing premolars

(166750)

Symphalangism, Kantaputra type28

Distal symphalangism, microdontia, dental pulp stones, narrowed zygomatic arch

(606895)

Uncombable hair, retinal pigmentary dystrophy, dental anomalies, brachydactyly29,30

Congenital hypotrichosis and uncombable hair, associated with juvenile cataracts, retinal pigmentary dystrophy, oligodontia, and brachymetacarpy

(191482)

Witkop (tooth-and-nail)31

Missing teeth and poorly formed nails

(189500) MSX1, 4p16.1

Cartilage-hair hypoplasia32–35

Short-limbed dwarfism due to skeletal dysplasia, sparse hair, dental anomalies, lymphopenia, anemia, neutropenia

(250250) RMRP, 9p21–p12

Cleft lip/palate, congenital contractures, ectodermal dysplasia, and psychomotor and growth retardation36

Typical facies, congenital contractures, orofacial clefts, oligodontia and other teeth anomalies (may be X-linked)

(301815)

Cleft lip/palate-ectodermal dysplasia37,38

Anhidrosis, hypotrichosis, dental anomalies, dysplasia of nails, cleft lip and palate, deformity of the fingers and toes, malformation in the genitourinary system, popliteal perineal pterygium, syndactyly

(225000) PVRL1, 11q23–q24

Autosomal Recessive Conditions

(continued)

448

Table 14-10. Syndromes with microdontia as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Cranioectodermal dysplasia39

Dolichocephaly; sparse, slow-growing, fine hair; epicanthal folds; hypodontia and/or microdontia; brachydactyly; narrow thorax

(218330)

Ectodermal dysplasia, Margarita Island type38,40

Scanty eyebrows and eyelashes; sparse, short, and dry scalp hair; dental anomalies; cleft lip/palate; syndactyly of fingers and toes; onychodysplasia

(225060) PVRL1, 11q23–q24

Ellis-van Creveld41–43

Skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth

(225500) EVC, EVC2

Gorlin-Chaudhry-Moss44

Craniofacial dysostosis, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies, patent ductus arteriosus, normal intelligence

(233500)

Immunoosseous dysplasia, Schimke type45–47

Combination of spondyloepiphyseal dysplasia and numerous lentigines; microdontia and other dental abnormalities; slowly progressive immune defect; immune-complex nephritis, which leads to death at about age 8 years

(242900) SMARCAL1

Larsen48,49

Bilateral dislocation of the knees, pes cavus, cylindrically shaped fingers, characteristic facies (can also be autosomal dominant)

(150250) FLNB

Microcephalic osteodysplastic dwarfism, type II50,51

Dwarfism, microcephaly, characteristic facies, bone anomalies, microdontia

(210720)

Odontotrichomelic52

Tetramelic deficiency, ectodermal dysplasia, deformed pinnae

(273400)

Polydactyly, postaxial, with dental and vertebral anomalies53

Postaxial polydactyly and other abnormalities of the hands and feet, hypoplasia and fusion of vertebral bodies, dental anomalies

(263540)

Rothmund-Thomson54,55

Atrophy, pigmentation, telangiectasia, juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism, dental anomalies, soft tissue contractures, proportionate short stature, anemia, osteogenic sarcoma

(268400) RECQL4, 8q24.3

Spondyloepimetaphyseal dysplasia with abnormal dentition56

Generalized platyspondyly with epiphyseal and metaphyseal involvement, thin tapering fingers with accentuated palmar creases, abnormal dentition (oligodontia and pointed incisors)

(601668)

Coffin-Lowry57–61

Mental retardation with peculiar pugilistic nose, large ears, tapered fingers, drumstick terminal phalanges by radiograph, and pectus carinatum Other complications: premature death, progressive kyphoscoliosis, spinal stenosis, drop attacks, abnormalities in dentition, hearing loss, ocular abnormalities, excess of psychiatric illness in carrier females

(303600) RSK2, Xp22.2–p22.1

Ectodermal dysplasia 162–64

Males: characteristic facies; teeth often missing or misshapen; fine, sparse hair; skin is thin, glossy, smooth, and dry with hypohidrosis Females: sparse, thin scalp hair and mosaic patchy distribution of body hair; abnormal teeth and mild hypohidrosis

(305100) ED1, Xq12–q13.1

Ectodermal dysplasia, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum65

Severe mental retardation, macrocephaly, hypertelorism, short and downward slanting eyelids, small nose and mouth, dysplastic and low-set ears, swallowing difficulties, reduced sweating, sparse scalp hair, delayed dentition, small teeth with defective enamel

(225040)

X-Linked Conditions

(continued)

449

450

Craniofacial Structures

Table 14-10. Syndromes with microdontia as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Faciogenital dysplasia66–70

Ocular hypertelorism, anteverted nostrils, broad upper lip, escrotum anomalies, occasional dental anomalies

(305400) FGD1, Xp11.21

Focal dermal hypoplasia71

Atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, multiple papillomas of the mucous membranes or skin, digital anomalies, oral anomalies, ocular anomalies, mental retardation

(305600)

Incontinentia pigmenti72

Disturbance of skin pigmentation sometimes associated with a variety of malformations of the eye, teeth, skeleton, and heart

(308300) NEMO, Xq28

Johanson-Blizzard73

Aplasia or hypoplasia of the nasal alae, congenital deafness, hypothyroidism, postnatal growth retardation, mental retardation, midline ectodermal scalp defects, and microdontia or absent permanent teeth

(243800)

Orofaciodigital, type I74,75

Clefts of the jaw and tongue, other malformations of the face and skull, malformation of the hands and teeth, and mental retardation

(311200) CXORF5, Xp22.3–p22.2

Down76–81

Mental retardation, typical facies, heart defects, short stature, dental anomalies

(190685) Trisomy

Microcephaly, macrotia, and mental retardation82

Microcephaly, mental retardation, huge ears with very large lobules, median frenulum of the upper lip, ptosis, microdontia, bilateral ureterohydronephrosis secondary to vesicoureteral reflux (can be autosomal dominant or X-linked)

(602555)

Microcephalic osteodysplastic primordial dwarfism with tooth abnormalities83

Growth retardation, opalescent and rootless teeth, severe microdontia, hypoplastic alveolar process, unerupted teeth, long second toes

(607561)

Williams-Beuren84

Typical facies, mental retardation, growth deficiency, cardiovascular anomalies, infantile hypercalcemia

(194050) 7q11.23

Chromosomal and Other Conditions

34. Bonafe L, Schmitt K, Eich G, et al.: RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet 61:146, 2002. 35. Rindanpaa M, Ward LM, Rockas S, et al.: Genetic changes in the RNA components of RNase MRP and RNase in Schmid metaphyseal chondrodysplasia. J Med Genet 40:741, 2003. 36. Ladda RL, Zonana V, Ramer JC, et al.: Congenital contractures, ectodermal dysplasia, cleft lip/palate and developmental impairment: a distinct syndrome. Am J Med Genet 47:550, 1993. 37. Rosselli D, Gulienetti R: Ectodermal dysplasia. Br J Plast Surg 14:190, 1961. 38. Suzuki K, Hu D, Bustos T, et al.: Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat Genet 25:427, 2000. 39. Levin LS, Perrin JCS, Ose L, et al.: A heritable syndrome of craniosynostosis, short thin hair, dental abnormalities, and short limbs: cranioectodermal dysplasia. J Pediatr 90:55, 1977. 40. Bustos T, Simosa V, Pinto-Cisternas J, et al.: Autosomal recessive ectodermal dysplasia. I. An undescribed dysplasia/malformation syndrome. Am J Med Genet 41:398, 1991. 41. McKusick VA, Egeland JA, Eldridge R, et al.: Dwarfism in the Amish. I. The Ellis-van Creveld syndrome. Bull Johns Hopkins Hosp 115:306, 1964. 42. Ruiz-Perez VL, Ide SE, Strom TM, et al.: Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 24:283, 2000.

43. Ruiz-Perez VL, Tompson SWJ, Blair HJ, et al.: Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am J Hum Genet 72:728, 2003. 44. Gorlin RJ, Chaudhry AP, Moss ML: Craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies—a new syndrome? J Pediatr 56:778, 1960. 45. Lundman MD, Cole DEC, Crocker JFS, et al.: Schimke immunoosseous dysplasia: case report and review. Am J Med Genet 47:793, 1993. 46. Fonseca MA: Dental findings in the Schimke immuno-osseous dysplasia. Am J Med Genet 93:158, 2000. 47. Boerkoel CF, Takashima H, John J, et al.: Mutant chromatin remodeling protein SMARCAL1 causes Shimke immuno-osseous dysplasia. Nat Genet 30:215, 2002. 48. Larsen LJ, Schottstaedt ER, Bost FC: Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr 37:574, 1950. 49. Krakow D, Robertson SP, King LM, et al.: Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 36:405, 2004. 50. Karasik JB, Garcia DM, Pritzker H, et al.: Deletion of 1q21-q24 in a patient with features of microcephalic osteodysplastic primordial dwarfism, type II (MOPDII). Am J Hum Genet 51(suppl):A82, 1992. 51. Lin HJ, Sue GY, Berkowitz CD, et al.: Microdontia with severe microcephaly and short stature in two brothers: osteodysplastic primordial dwarfism with dental findings. Am J Med Genet 58:136, 1995.

Teeth 52. Freire-Maia N. A newly recognized genetic syndrome of tetramelic deficiencies, ectodermal dysplasias, deformed ears and other anomalies. Am J Hum Genet 22:370, 1970. 53. Rogers JG, Levin LS, Dorst JP, et al.: A postaxial polydactyly-dental-vertebral syndrome. J Pediatr 90:230, 1977. 54. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985. 55. Kitao S, Shimamoto A, Goto M, et al.: Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82, 1999. 56. Rao V, Morton RE, Young ID: Spondyloepimetaphyseal dysplasia and abnormal dentition in siblings: a new autosomal recessive syndrome. Clin Dysmorphol 6:3, 1997. 57. Trivier E, De Cesare D, Jacquot S, et al.: Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384:567, 1996. 58. Jacquot S, Merienne K, De Cesare D, et al.: Mutation analysis of the RSK2 gene in Coffin-Lowry patients: extensive allelic heterogeneity and a high rate of de novo mutations. Am J Hum Genet 63:1631, 1998. 59. Manouvrier-Hanu S, Amiel J, Jacquot S, et al.: Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome. J Med Genet 36:775, 1999. 60. Hunter AGW: Coffin-Lowry syndrome: a 20-year follow-up and review of long-term outcomes. Am J Med Genet 111:345, 2002. 61. Simensen RJ, Abidi F, Collins JS, et al.: Cognitive function in CoffinLowry syndrome. Clin Genet 61:299, 2002. 62. Zonana J, Gault J, Davies KJP, et al.: Detection of a molecular deletion at the DXS732 locus in a patient with X-linked hypohidrotic ectodermal dysplasia (EDA), with the identification of a unique junctional fragment. Am J Hum Genet 52:78, 1993. 63. Kere J, Srivastava AK, Montonen O, et al.: X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 13:409, 1996. 64. Monreal AW, Zonana J, Ferguson B: Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet 63:380, 1998. 65. Fryns JP, Chrzanowska K, van den Berghe H: Hypohidrotic ectodermal dysplasia, primary hypothyroidism, and agenesis of the corpus callosum. J Med Genet 26:520, 1989. 66. Aarskog D: A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J Pediatr 77:856, 1970. 67. Pasteris NG, Cadle A, Logie LJ, et al.: Isolation and analysis of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative, rho/ rac guanine nucleotide exchange factor. Cell 79:669, 1994. 68. Orrico A, Galli L, Falciani M, et al.: A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome). FEBS Lett 478:216, 2000. 69. Schwartz CE, Gillessen-Kaesbach G, May M, et al.: Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome. Eur J Hum Genet 8:869–874, 2000. 70. Lebel RR, May M, Pouls S, et al.: Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene. Clin Genet 61:139, 2002. 71. Goltz RW, Peterson WC Jr, Gorlin RJ, et al.: Focal dermal hypoplasia. Arch Dermatol 86:708, 1962. 72. The International Incontinentia Pigmenti Consortium: Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti. Nature 405:466, 2000. 73. Johanson AJ, Blizzard RM: A syndrome of congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. J Pediatr 79:982, 1971. 74. Fenton OM, Watt-Smith SR: The spectrum of the oro-facial-digital syndrome. Br J Plast Surg 38:532, 1985. 75. Ferrante MI, Giorgio G, Feather SA, et al.: Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 68:569, 2001. 76. Down JL: Observations on an ethnic classification of idiots. Clin Lect Rep London Hospital 3:249, 1866.

451 77. Lejeune J, Gautier M, Turpin R: Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci 248:1721, 1959. 78. Mikkelsen M: Down’s syndrome cytogenetic epidemiology. Hereditas 86:45, 1977. 79. Hook EG: Epidemiology of Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 11. 80. Thuline HC, Pueschel SM: Cytogenetics in Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 133. 81. Shapira J, Chaushu S, Becker A: Prevalence of tooth transposition, third molar agenesis, and maxillary canine impactation in individuals with Down syndrome. Angle Orthod 70:290, 2000. 82. Verloes A, Lesenfants S, Philippet B, et al.: Microcephaly, macrotia, unusual mimics and mental retardation syndrome: new syndrome or variant of de Lange type 2 syndrome. Genet Couns 7:277, 1996. 83. Kantaputra PN: Apparently new osteodysplastic and primordial short stature with severe microdontia, opalescent teeth, and rootless molars in two siblings. Am J Med Genet 111:420, 2002. 84. Ewart AK, Morris CA, Atkinson D, et al.: Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5:11, 1993. 85. Barbosa ARS, Modesto A, Meira R, et al.: Molar agenesis is associated with abnormalities of superior lateral incisors. In: International Association for Dental Research 82nd General Session Program Book, 2004, p 194. 86. Vieira AR: Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res 82:162, 2003. 87. Saito T: A genetic study on the degenerative anomalies of deciduous teeth. Jpn J Hum Genet 4:27, 1959. 88. Schulze C: Developmental abnormalities of the teeth and jaws. In: Thoma’s Oral Pathology. Gorlin RJ, Goldman HM, eds. Mosby, St. Louis, 1970. 89. Sumiya Y: Statistical study on dental anomalies in the Japanense. J Anthropol Soc Nippon 67:171, 1959.

14.4 Macrodontia Definition

Macrodontia is a tooth that is much larger than its contralateral homolog or teeth from the same group from an opposing arch (the maxillary central incisors are exceptions); a tooth that ‘‘overfills’’ its space in the dental arch, crowds out adjacent teeth, or is rotated to accommodate its size; or a tooth that appears large because of exaggerated dimension. Fused teeth (joining of two teeth by the pulp tissue and dentin) and germination (budding of a second tooth from one tooth germ) might fit well into the later category. Diagnosis

Macrodontia is diagnosed by simple observation or measurement and comparison with standards for tooth size (Table 14-9). Even though there are anatomic standards, the criteria stated above are the most useful to the clinician. Macrodontia is usually an isolated trait but can be accompanied by other dental anomalies or occur as part of a syndrome.1–3 Also, patients with supernumerary teeth present significantly larger teeth compared to the general population.4 Etiology and Distribution

Syndromes with macrodontia as a component are listed in Table 14-11. Because of the association with sexual chromosome anomalies, it appears that there are dental growth-promoting factors on both the X and the Y chromosomes. The promoting effect of the Y chromosome on tooth growth seems to be stronger than that of the

452

Craniofacial Structures

Table 14-11. Syndromes with macrodontia as a component Causation Gene/Locus

Syndrome

Prominent features

KBG5

Short stature, characteristic facies, mental retardation, skeletal anomalies, oligodontia, macrodontia

AD (148050)

Polydactyly, postaxial, with dental and vertebral anomalies6

Postaxial polydactyly and other abnormalities of the hands and feet, hypoplasia and fusion of vertebral bodies, dental anomalies

AR (263540)

Oculofaciocardio-dental7–9

Cataracts, microphthalmia, oligodontia, radiculomegaly, septal heart defects

XL (300166) BCL6 corepressor (BCOR)

47, XXY (Klinefelter)10

Tall stature, delayed speech in 50% of the cases, behavior disorders

(314240) Chromosomal

47, XYY11,12

Tall stature, 1/3 of the cases will present with delayed speech or language development, higher risk for criminal behavior

(314240) Chromosomal

Hemihyperplasia13,14

The enlarged area may vary from a single digit, a single limb, or unilateral facial enlargement to involvement of half the body

Sporadic (235000) 11p15

X chromosome.10 Occasionally, exaggerated tooth size is seen in conjunction with absence of an adjacent tooth, suggesting that the large tooth may be fusion of two adjacent teeth. The frequency of macrodontia is unknown; it is certainly rare.

13. Gorlin RJ, Meskin LH: Congenital hemihypertrophy. J Pediatr 61:870, 1962. 14. West PMH, Love DR, Stapleton PM, et al.: Paternal uniparental disomy in monozygotic twins discordant for hemihypertrophy. J Med Genet 40:223, 2003.

Prognosis, Treatment, and Prevention

There are no morbid features associated with isolated macrodontia. Malalignment of adjacent tooth and malocclusion can occur, depending on the site and extent of macrodontia. Treatment may be indicated for aesthetic reasons. There are no useful preventive measures for macrodontia. References (Macrodontia) 1. Ekman-Westborg B, Julin P: Multiple anomalies in dental morphology: macrodontia, multituberculism, central cusps, and pulp invaginations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 38:217, 1974. 2. Ritzau M, Carlsen O, Kreiborg S, et al.: The Ekman-Westborg-Julin syndrome: report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:293, 1997. 3. Yoda T, Ishii Y, Honma Y, et al.: Multiple macrodonts with odontoma in a mother and son—a variant of Ekman-Westborg-Julin syndrome. Report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85:301, 1998. 4. Brook AH, Elcock C, al-Sharood MH, et al.: Further studies of a model for the etiology of anomalies of tooth number and size in humans. Connect Tissue Res 43:289, 2002. 5. Herrmann J, Pallister PD, Tiddy W, et al.: The KBG syndrome—a syndrome of short stature, characteristic facies, mental retardation, macrodontia amd skeletal anomalies. Birth Defects Orig Artic Ser XI(5), 1975. 6. Rogers JG, Levin LS, Dorst JP, et al.: A postaxial polydactyly-dentalvertebral syndrome. J Pediatr 90:230–235, 1977. 7. Shepard MK: An unidentified syndrome with abnormality of skin and hair. Birth Defects Orig Artic Ser VII(8):353, 1971. 8. Hayward JR: Cuspid gigantism. Oral Surg Oral Med Oral Path Oral Radiol Endod 49:500, 1980. 9. Gorlin RJ, Marashi AH, Obwegeser HL: Oculo-facio-cardio-dental (OFCD) syndrome. Am J Med Genet 63:290, 1996. 10. Alvesalo L, Portin P: 47,XXY males: sex chromosomes and tooth size. Am J Hum Genet 32:955, 1980. 11. Alvesalo L, Osborne RH, Kari M: The 47,XYY male, Y chromosome, and tooth size. Am J Hum Genet 27:53, 1975. 12. Alvesalo L, Kari M: Size and deciduous teeth in 47, XYY males. Am J Hum Genet 29:486, 1977.

14.5 Abnormalities of Tooth Shape Definition

Abnormalities of tooth shape occur in the crowns or roots of teeth. Crown form may be entirely distorted with the loss of the usual cusp and groove relationships (globodontia), or the crowns may have abnormal or supernumerary cusps (referred as talon cusps for incisors and canines and supernumerary cusps for premolars and molars) or invaginations (dens invaginatus). Shovel-shaped incisors are yet another variation of crown shape. Roots may be foreshortened or bent (dilacerated), or there may be supernumerary roots. The pulp chambers can be vertically enlarged (taurodontia). Diagnosis

Globodontia, talon cusps, supernumerary cusps, dens invaginatus, shovel-shaped incisors, dilacerations, supernumerary roots, and taurodontia may occur as isolated traits or be associated with tooth agenesis, supernumerary teeth, microdontia, or macrodontia. More than one abnormality of tooth shape can be present in the same case. Abnormalities of tooth shape can be part of various syndromes. Short stature is often described as accompanying abnormalities of tooth shape.1–15 Globodontia can be the only obvious feature in someone with otodental dysplasia, an autosomal dominant trait that presents with sensorineural hearing loss and dental anomalies.16 Abnormalities of crown shape are determined clinically. Dilacerated and supernumerary roots and taurodontia can be determined by radiographs. Etiology and distribution

Syndromes with shovel-shaped and other incisor abnormalities as a component are listed in Table 14-12, and those with globodontia or supernumerary cusps as a component are listed in Table 14-13, and those with taurodontia as a component are listed in Table 14-14. Globodontia is probably not seen as an isolated trait. It is found in otodental dysplasia, an autosomal dominant syn-

Teeth

453

Table 14-12. Syndromes with shovel-shaped and other incisor abnormalities as a component Syndrome

Prominent Features

Causation Gene/Locus

Rubinstein-Taybi17–22

Mental retardation, broad thumbs, and facial abnormalities; 90% of the cases present with talon cusps

AD (180849) CREBBP, 16p13.3

Orofaciodigital type II23,24

Poly-, syn-, and brachydactyly, lobate tongue with papilliform protuberances, angular form of the alveolar process of the mandible, supernumerary sutures in the skull, neuromuscular disturbances, cleft palate, and talon cusps

AR (252100)

Cataract-dental25–31

Dense nuclear cataracts and frequently microcornea with mesiodens and incisors of Hutchinson

XL (302350) Xp22.13

Incontinentia pigmenti32,33

Disturbance of skin pigmentation sometimes associated with a variety of malformations of the eye, teeth, skeleton, and heart

XL (308300) NEMO, Xq28

47, XXY (Klinefelter)34,35

Tall stature, delayed speech in 50% of the cases, behavior disorders, occasional shovel-shaped incisors

(314240) Chromosomal

47, XYY36,37

Tall stature, 1/3 of the cases will present with delayed speech or language development, higher risk for criminal behavior, occasional shoved-shaped incisors

(314240) Chromosomal

Down38–42 (190685)

Mental retardation, typical facies, heart defects, short stature, dental anomalies

Trisomy 21

Congenital syphilis43

Skin ulcers, rashes, fever, weakened or hoarse crying sounds, swollen liver and spleen, yellowish skin, anemia, bone deformities, incisors of Hutchinson

Prenatal infection

Sturge-Weber19,44,45

Nevus flammeus of the face, angioma of the meninges, glaucoma, occasional talon cusps

Sporadic (185300) 4q, chromosome 10

Table 14-13. Syndromes with globodontia or supernumerary cusps as a component Causation Gene/Locus

Syndrome

Prominent Features

Otodental dysplasia16

Sensorineural hearing loss, dental anomalies, missing premolars

AD (166750)

Cartilage-hair hypoplasia46–49

Short-limbed dwarfism due to skeletal dysplasia, sparse hair, dental anomalies (supernumerary cusps), lymphopenia, anemia, neutropenia

AR (250250) RMRP, 9p21–p12

Rothmund-Thomson50,51

Atrophy, pigmentation, telangiectasia, juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism, dental anomalies, soft tissue contractures, proportionate short stature, anemia, osteogenic sarcoma

AR (268400) RECQL4, 8q24.3

drome, and in Rothmund-Thomson syndrome, an autosomal recessive condition.16,50,51 The etiology of supernumerary cusps is unknown, although the differences in the prevalences of such abnormality among males and females suggest a multifactorial trait (male to female ratio is 1:2). Supernumerary cusps have a prevalence in the population as high as 47.6%.15 Dens invaginatus is probably a multifactorial trait with higher frequencies in those of Chinese, Japanese, Native Americans, and Eskimos, compared to European and African descents.15,90–93 Shovel-shaped incisors are more common among Native Americans, Inuit, and Asian populations (60–75%) compared to other ethnic groups, and it is probably a multifactorial trait.94 The cause for dilacerated and supernumerary roots is unknown; however, roots can be dilacerated as a consequence of trauma to erupting teeth. The supernumerary roots may be due to the dis-

turbances of the Hertwig’s epithelial root sheath forming the root.95,96 Taurodontia can be caused by a delay in the formation of horizontal extensions of Hertwig epithelial root sheath, whose invagination determines the position of the pulpal floor. Taurodontia has been reported in 0.5% of those of Japanese descent, 0.57–3.2% of those of European descent, and 4.37% of those of African descent. It is probably a multifactorial trait, although there have been a few reported families in which it appears to be transmitted in an autosomal dominant fashion.97 Prognosis, Treatment, and Prevention

None of the abnormalities discussed above is morbid or progressive. At most, they complicate certain types of dental treatment: endodontics (root canal therapy) and extractions. Prevention is not possible or necessary.

454

Craniofacial Structures

Table 14-14. Syndromes with taurodontia as a component Syndrome

Causation Gene/Locus

Prominent Features

Autosomal Dominant Conditions

Apert52–58

Skull malformation (acrocephaly of brachysphenocephalic type) and syndactyly of the hands and feet of a special type (complete distal fusion with a tendency to fusion also of the bony structures)

(101200) FGFR2, 10q26

Axenfeld-Rieger52,59–64

Eye, dental, and umbilical anomalies

(180500) PITX2, 4q25–26 FOXC1, 6p25 13q14

Basal-cell nevus52,65,66

Basal cell nevi; medulloblastoma; congenital thoracic scoliosis; astrocytoma with severe hydrocephalus; the palms and soles may show pits; bridging of the sella turcica; mild mandibular prognathism; lateral displacement of the inner canthi; frontal and biparietal bossing; odontogenic keratocysts of the jaws; kyphoscoliosis; bifid, missing, fused, and/or splayed ribs; imperfect segmentation of cervical vertebrae; characteristic lamellar calcification of the falx cerebri; ovarian fibromata and lymphomesenteric cysts, which tend to calcify; short fourth metacarpal

(109400) PTCH2, 9q22.3

Ectodermal dysplasias52

Large number of disorders characterized by hair, skin, dental, and nail anomalies (can also be autosomal recessive or X-linked)

Genes for the most common forms have been identified

Otodental dysplasia52

Sensorineural hearing loss, dental anomalies, including missing premolars

(166750)

Trichodentoosseous52,67,68

Enamel hypoplasia and hypocalcification with associated strikingly curly hair

(190320) DLX3

Pyramidal molar roots, taurodontia, fused molar roots, juvenile glaucoma, unusual upper lip

(200970)

Dyskeratosis congenita52,70–74

Cutaneous pigmentation, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in most cases

(305000) DKC1, Xq28

Fragile X52,75–78

Moderate to severe mental retardation, macroorchidism, large ears, prominent jaw, high-pitched and jocular speech

(309550) FMR1, Xq27.3

Orofaciodigital, type I52,79,80

Clefts of the jaw and tongue, other malformations of the face and skull, malformation of the hands and teeth, mental retardation

(311200) CXORF5, Xp22.3–p22.2

47, XXY (Klinefelter)81

Tall stature, delayed speech in 50% of the cases, behavior disorders

(314240) Chromosomal

49, XXXXY81

Mild microbrachycephaly, ocular hypertelorism, up-slanting palpebral fissures, epicanthic folds, strabismus, myopia, low broad nasal bridge, poorly modeled ears, short neck, taurodontia

Chromosomal

Down52,82–86 (190685)

Mental retardation, typical facies, heart defects, short stature, dental anomalies

Trisomy 21

Dyschondrosteosis52,87–89

Typical deformity of the distal radius and ulna and proximal carpal bones, mesomelic dwarfism

Pseudo-autosomal genes SHOX or SHOXY

Autosomal Recessive Conditions

Ackerman69

X-Linked Conditions

Chromosomal and Other Conditions

References (Abnormalities of Tooth Shape) 1. Stoy PJ: Taurodontism associated with other dental abnormalities. Dent Pract Dent Rec 10:202, 1960. 2. Haunfelder D: Ein beitrag zu den molaren mit prismatischen wurzeln (sog. taurodontismus). Dtsch Zahnarztbl 21:419, 1967. 3. Stenvik A, Zachrisson BU, Svatun B: Taurodontism and concomitant hypodontia in siblings. Oral Surg Oral Med Oral Path Oral Radiol Endod 33:841, 1972. 4. Moller KT, Gorlin RJ, Wedge B: Oligodontia, taurodontia and sparse hair—a syndrome. J Speech Hear Disord 38:268, 1973.

5. Saulk JJ Jr, Delaney JR: Taurodontism, diminished root formation and microcephalic dwarfism. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 36:231, 1973. 6. Gorlin RJ, Cervenka J, Moller K, et al.: Malformation syndromes: a selected miscellany. Birth Defects Orig Artic Ser XI(2):39, 1975. 7. Garner DG, Girgis SS: Taurodontism, short roots and external resorption associated with short stature and small head. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 44:271, 1977. 8. Casamassimo PS, Nowak AJ, Ettinger RL, et al.: An unusual triad: microdontia, taurodontia, and dens invaginatus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 45:107, 1978.

Teeth 9. Witkop CP Jr, Jaspers MT: Teeth with short thin dilacerated roots in patient with short stature. A dominantly inherited trait. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 54:553, 1982. 10. Davidson LE, Woolass KF: Severe hypodontia in an eight-year-old child. Br Dent J 158:215, 1985. 11. Ireland EJ, Black JP, Scures CC: Short roots, taurodontia, and multiple dens invaginatus. J Pedodontics 11:164, 1987. 12. Bazopoulou-Kyrkanidou E, Dacou-Voutetakis C, Nassi H, et al.: Microdontia, hypodontia, shortbulbous roots and root canals with strabismus, short stature, and borderline mentality. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 74:93, 1992. 13. Kantaputra PN, Gorlin RJ: Double dens invaginatus of molarized maxillary central incisors, premolarization of maxillary lateral incisors, multituberculism of mandibular incisors, canines and first molar, and sensorineural hearing loss. Clin Dysmorphol 1:128, 1992. 14. Shaw L: Short root anomaly in a patient with severe short-limbed dwarfism. Int J Paediatr Dent 5:249, 1995. 15. Kocsis GS, Marcsik A, Ko´tai EL, et al.: Supernumerary occlusal cusps on permanent human teeth. Acta Biol Szeged 46:71, 2002. 16. Levin LS, Jorgenson RJ, Cook RA: Otodental dysplasia: a ‘new’ ectodermal dysplasia. Clin Genet 8:136, 1975. 17. Rubinstein JH, Taybi H: broad thumbs and toes and facial abnormalities. Am J Dis Child 105:588, 1963. 18. Gardner DG, Girgis SS: Talon cusps: a dental anomaly in the Rubinstein-Taybi syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 47:519, 1979. 19. Davies PJ, Brook AH: The presentation of talon cusp: diagnosis, clinical features, associations and possible aetiology. Br Dent J 160:84, 1986. 20. Petrij F, Giles RH, Dauwerse HG, et al.: Rubinstein-Taibi syndrome caused by mutations in the transcriptional coactivator CBP. Nature 376:348, 1995. 21. Murata T, Kurokawa R, Krones A, et al.: Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in RubinsteinTaybi syndrome. Hum Mol Genet 10:1071, 2001. 22. Bartsch O, Locher K, Meinecke P, et al.: Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. J Med Genet 39:496, 2002. 23. Mohr OL: A hereditary lethal syndrome in man. Avh Norske Videnskad Oslo 14:1, 1941. 24. Goldstein E, Medina JL: Mohr syndrome or oral-facial-digital II: report of two cases. J Am Dent Assoc 89:377, 1974. 25. Bixler D, Higgins M, Hartsfield J Jr: The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females. Clin Genet 26:30, 1984. 26. Bergen AAB, ten Brink J, Schuurman EJM, et al.: Nance-Horan syndrome: linkage analysis in a family from the Netherlands. Genomics 21:238, 1994. 27. Stambolian D, Bond A, Lewis RA, et al.: Linkage studies in the Nance Horan syndrome using eight polymorphic DNA probes from the short arm of X chromosome. Cytogenet Cell Genet 51:1085, 1989. 28. Zhu D, Alcorn DM, Antonarakis SE, et al.: Assignment of the NanceHoran syndrome to the distal short arm of the X chromosome. Hum Genet 86:54, 1990. 29. Stambolian D, Favor J, Silvers W, et al.: Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance-Horan syndrome, on the mouse X chromosome. Genomics 22:377, 1994. 30. Toutain A, Dessay B, Ronce N, et al.: Refinement of the NHS locus on chromosome Xp22.13 and analysis of five candidate genes. Eur J Hum Genet 10:516, 2002. 31. Burdon KP, McKay JD, Sale MM, et al.: Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet 73:1120, 2003. 32. Tsutsumi T, Oguchi H: Labial talon cusp in a child with incontinentia pigmenti achromians: case report. Pediatr Dent 13:236, 1991. 33. The International Incontinentia Pigmenti Consortium: Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti. Nature 405:466, 2000.

455 34. Alvesalo L, Portin P: 47,XXY males: sex chromosomes and tooth size. Am J Hum Genet 32:955, 1980. 35. Kirveskari P, Alvesalo L: Shovel shape of maxillary incisors in 47,XXY males. Proc Finn Dent Soc 77:79, 1981. 36. Alvesalo L, Osborne RH, Kari M: The 47,XYY male, Y chromosome, and tooth size. Am J Hum Genet 27:53, 1975. 37. Alvesalo L, Kari M: Size and deciduous teeth in 47, XYY males. Am J Hum Genet 29:486, 1977. 38. Down JL: Observations on an ethnic classification of idiots. Clin Lect Rep London Hospital 3:249, 1866. 39. Lejeune J, Gautier M, Turpin R: Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci 248:1721, 1959. 40. Mikkelsen M: Down’s syndrome cytogenetic epidemiology. Hereditas 86:45, 1977. 41. Hook EG: Epidemiology of Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 11. 42. Thuline HC, Pueschel SM: Cytogenetics in Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 133. 43. Modesto A, Portella W, Souza IPR: Sı´filis congeˆnita: relato de um caso na FO.UFRJ. Rev Odontopediatr 1:209, 1992. 44. Debicka A, Adamczak P: Przypadek dziedziczenia zespolu Sturge’aWebera. Klin Oczna 81:541, 1979. 45. Huq AHMM, Chugani DC, Hukku B, et al.: Evidence of somatic mosaicism in Sturge-Weber syndrome. Neurology 59:780, 2002. 46. Sulisalo T, Makitie O, Sistonen P, et al.: Uniparental disomy in cartilage-hair hypoplasia. Eur J Hum Genet 5:35, 1997. 47. Ridanpaa M, van Eenennaam H, Pelin K, et al.: Mutations in the RNA component of RNase MRP cause a pleitropic human disease, cartilagehair hypoplasia. Cell 104:195, 2001. 48. Bonafe L, Schmitt K, Eich G, et al.: RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet 61:146, 2002. 49. Rindanpaa M, Ward LM, Rockas S, et al.: Genetic changes in the RNA components of RNase MRP and RNase in Schmid metaphyseal chondrodysplasia. J Med Genet 40:741, 2003. 50. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985. 51. Kitao S, Shimamoto A, Goto M, et al.: Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82, 1999. 52. Jorgenson RJ: The conditions manifesting taurodontism. Am J Med Genet 11:435, 1982. 53. Slaney SF, Oldridge M, Hurst JA, et al.: Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am J Hum Genet 58:923, 1996. 54. Oldridge M, Lunt PW, Zackai EH, et al.: Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. Hum Mol Genet 6:137, 1997. 55. Passo-Buenos MR, Richieri-Costa A, Sertie AL, et al.: Presence of the Apert canonical S252W FGFR2 mutation in a patient without severe syndactyly. J Med Genet 35:677, 1998. 56. Lajeunie E, Cameron R, El Ghouzzi V, et al.: Clinical variability in patients with Apert’s syndrome. J Neurosurg 90:443, 1999. 57. Oldridge M, Zackai EH, McDonald-McGinn DM, et al.: De novo Aluelement insertions in FGFR2 identify a distinct pathological basis for Apert syndrome. Am J Hum Genet 64:446, 1999. 58. Wilkie AOM, Slaney SF, Oldridge M, et al.: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165, 1995. 59. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996.

456

Craniofacial Structures

60. Perveen R, Lloyd IC, Clayton-Smith J, et al.: Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Invest Ophthalmol Vis Sci 41:2456, 2000. 61. Nishimura DY, Searby CC, Alward WL, et al.: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 68:364, 2001. 62. Priston M, Kozlowski K, Gill D, et al.: Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome. Hum Mol Genet 10:1631, 2001. 63. Saadi I, Semina EV, Amendt BA, et al.: Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 276:23034, 2001. 64. Borges AS, Susanna Junior R, Carani JCE, et al.: Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil. J Glaucoma 11:51, 2002. 65. Gorlin RJ, Goltz RW: Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib: a syndrome. New Eng J Med 262:908, 1960. 66. Smyth I, Narang MA, Evans T, et al.: Isolation and characterization of human Patched 2 (PTCH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Hum Mol Genet 8:291, 1999. 67. Price JA, Bowden DW, Wright JT, et al.: Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Hum Mol Genet 7:563, 1998. 68. Price JA, Wright JT, Kula K, et al.: A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families. J Med Genet 35:825, 1998. 69. Ackerman JL, Ackerman AL, Ackerman AB: Taurodont, pyramidal and fused molar roots associated with other anomalies in a kindred. Am J Phys Anthropol 38:681, 1973. 70. Heiss NS, Knight SW, Vulliamy TJ, et al.: X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 19:32, 1998. 71. Knight SW, Heiss NS, Vulliamy TJ, et al.: X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am J Hum Genet 65:50, 1999. 72. Vulliamy TJ, Knight SW, Heiss NS, et al.: Dyskeratosis congenita caused by a 3-prime deletion: germline and somatic mosaicism in a female carrier. Blood 94:1254, 1999. 73. Heiss NS, Megarbane A, Klauck SM, et al.: One novel and two recurrent missense DKC1 mutations in patients with dyskeratosis congenita (DKC). Genet Couns 12:129, 2001. 74. Knight SW, Vulliamy TJ, Morgan B, et al.: Identification of novel DKC1 mutations in patients with dyskeratosis congenita: implications for pathophysiology and diagnosis. Hum Genet 108:299, 2001. 75. Kremer EJ, Pritchard M, Lynch M, et al.: Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252:1711, 1991. 76. De Boulle K, Verkerk AJMH, Reyniers E, et al.: A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet 3:31, 1993. 77. Lugenbeel KA, Peier AM, Carson NL, et al.: Intragenic loss of function mutations demonstrate the primary role of FMR1 in fragile X syndrome. Nat Genet 10:483, 1995. 78. Wang YC, Lin ML, Lin SJ, et al.: Novel point mutation within intron 10 of FMR-1 gene causing fragile X syndrome. Hum Mutat 10:393, 1997. 79. Fenton OM, Watt-Smith SR: The spectrum of the oro-facial-digital syndrome. Br J Plast Surg 38:532, 1985. 80. Ferrante MI, Giorgio G, Feather SA, et al.: Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 68:569, 2001. 81. Komatz Y, Tomoyoshi T, Yoshida O, et al.: Taurodontism and Klinefelter’s syndrome. J Med Genet 15:452, 1978. 82. Down JL: Observations on an ethnic classification of idiots. Clin Lect Rep London Hospital 3:249, 1866. 83. Lejeune J, Gautier M, Turpin R: Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci 248:1721, 1959. 84. Mikkelsen M: Down’s syndrome cytogenetic epidemiology. Hereditas 86:45, 1977.

85. Hook EG: Epidemiology of Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 11. 86. Thuline HC, Pueschel SM: Cytogenetics in Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 133. 87. Shears DJ, Vassal HJ, Goodman FR, et al.: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet 19:70, 1998. 88. Grigelioniene G, Eklof O, Ivarsson SA, et al.: Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia. Hum Genet 107:145, 2000. 89. Huber C, Cusin V, Merrer M, et al.: SHOX point mutations in dyschondrosteosis. J Med Genet 38:323, 2001. 90. Sumiya Y: Statistic study on dental anomalies in the Japanese. J Anthropol Soc Nippon 67:215, 1959. 91. Merril RG: Occlusal anomalous tubercles on premolars of Alaskan Eskimos and Indians. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 17:484, 1964. 92. Yip WK: The prevalence of dens invaginatus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 38:80, 1974. 93. Lin LC, Roan RT: Incidence of dens evaginatus investigated from three junior middle schools at Kaohsiung City. Formosan Sci 34:113, 1980. 94. Hrdlicka A: Shovel-shaped teeth. Am J Phys Anthropol 3:429, 1920. 95. Kannan SK, Suganya, Santharam H: Supernumerary roots. Indian J Dent Res 13:116, 2002. 96. Kamat SS, Kumar GS, Raghunath V, et al.: Permanent maxillary central incisor impaction: report of two cases. Quintessence Int 34:50, 2003. 97. Jorgenson RJ, Salinas CF, Shapiro SD: The prevalence of taurodontism in a select population. J Craniofac Genet Dev Biol 2:125, 1982.

14.6 Dental Malocclusion Definition

Dental malocclusion consists of teeth that are not properly aligned in the arch for a reason other than skeletal discrepancy. Malocclusion results from abnormal relationships of the different components of the maxillofacial complex. Malocclusion can be of dental origin or due to skeletal discrepancy. Skeletal malocclusions occur when the maxilla and/or the mandible are not properly aligned in relation to the skull or when the maxilla and mandible are misaligned relative to each other. Some malocclusions involve a dental and skeletal component. Diagnosis

Dental malocclusion can be diagnosed clinically. It can be associated with trauma, caries, oral habits (thumb finger, pacifier), tooth agenesis, supernumerary teeth, microdontia, macrodontia, and abnormalities of tooth shape. Dental malocclusion can also have no apparent cause. Some syndromes with malocclusion have no other dental anomalies. Etiology and Distribution

Syndromes with malocclusion as a component are listed in Table 14-15. Dental malocclusion may be caused by genetic and environmental factors. In pure ethnic stocks, such as Melanesians of the Philippine islands, malocclusion is almost nonexistent. However, in heterogeneous populations, the incidence of jaw discrepancies and occlusal disharmonies is significantly greater.21 Highest rates of normal occlusion are reported in British (67.3%), followed by European descent North-Americans (51%), Lebanese (40.3%), NorthAmerican Indians (34.5%), Egyptians (34.33%), and Swedish (10%).

Teeth

457

Table 14-15. Syndromes with malocclusion as a component Syndrome

Causation Gene/Locus

Prominent Features

Autosomal Dominant Conditions

Brachydactyly type B11

Involvement of the distal phalanges, nail aplasia, coloboma of the macula, characteristic facies, renal agenesis, double uterus and vagina, mixed hearing loss, high-arched palate, crowed teeth, supernumerary ribs

(113000) ROR2, 9q22

Marfan2–10

Increased height; disproportionately long limbs and digits; anterior chest deformity; mild to moderate joint laxity; vertebral column deformity (scoliosis and thoracic lordosis); narrow, highly arched palate with crowding of the teeth

(154700) FBN1, 15q21.1

Prader-Willi11–17

Diminished fetal activity, profound poor muscle tone, feeding problems in infancy, underdeveloped sex organs, short stature and retarded bone age, small hands and feet, delayed developmental milestones, characteristic facies, cognitive impairment, onset of gross obesity in early childhood due to insatiable hunger, tendency to develop diabetes in adolescence and adulthood when weight was not controlled

(176270) Pat del 15q11-q13 Mat UPD 15

Susceptibility to infection, vomiting, coarse features, macroglossia, flat nose, large clumsy ears, widely spaced teeth, large head, big hands and feet, tall stature, slight hepatosplenomegaly, muscular hypotonia, lumbar gibbus, radiographic skeletal abnormalities, dilated cerebral ventricles, lenticular opacities, hypogammaglobulinemia, ‘‘storage cells’’ in the bone marrow, vacuolated lymphocytes in the bone marrow and blood

(248500) MANB

Autosomal Recessive Conditions

Mannosidosis, Alpha, lysosomal18–20

However, dental malocclusion rates are higher in Swedish (83%), followed by North-American Indians (53%), Lebanese (35.5%), Egyptians (33.3%), European-descent North-Americans (26%), and British (13.7%). Skeletal discrepancy, which is more influenced by population mix, is higher in Egyptians (31.6%), followed by Lebanese (24.2%), European-descent North-Americans (23%), British (19%), North-American Indians (10.5%), and Swedish (7%).22–27 No differences between males and females have been noted for dental malocclusion.27 A relationship exists between certain discrete malpositions of the permanent canine and tooth agenesis. Studies indicate significantly elevated prevalence rates for tooth agenesis in association with palatally displaced canine, mandibular lateral incisor–canine transposition, and maxillary canine–first premolar transposition. Like tooth agenesis, these three positional anomalies involving the canine have been reported in families and appear to be under strong genetic control.28–41 Palatally displaced canine occurs in 1–3% of the population, mandibular lateral incisor–canine transposition in 0.03%, and maxillary canine–first premolar transposition in 0.25%.42–48 Maxillary canine–first premolar transposition has a higher frequency in Down syndrome.49 Dental transposition is indicative of faulty field gene function, which would explain why there is an increased occurrence of tooth agenesis on either side of transposed teeth. This may also explain the fact that teeth in the critical marginal areas of dental lamina, lateral incisors, second premolars, and third molars are the most vulnerable for tooth agenesis.21 MSX1 and PAX9, which have been associated with preferential agenesis of posterior teeth, might be involved in the genetic control of positional anomalies involving the canine.41,50 Prognosis, Treatment, and Prevention

Dental malocclusion is not a morbid trait. It may pose aesthetic problems that might lead to lower self-esteem. Other possible con-

sequences are periodontal disease and temporomandibular joint problems. Orthodontic treatment is recommended and usually successful. Preventive and interceptive orthodontics is possible and desirable. Prevention through other techniques is not possible. References (Dental Malocclusion) 1. Oldridge M, Fortuna AM, Maringa M, et al.: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet 24:375, 2000. 2. Dietz HC, Cutting GR, Pyeritz RE, et al.: Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337, 1991. 3. Hayward C, Keston M, Brock DJH, et al.: Fibrillin (FBN1) mutations in Marfan syndrome. Hum Mutat 1:79, 1992. 4. Dietz HC, McIntosh I, Sakai LY, et al.: Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics 17:468, 1993. 5. Hewett DR, Lynch JR, Smith R, et al.: A novel fibrillin mutation in the Marfan syndrome which could disrupt calcium binding of the epidermal growth factor-like module. Hum Mol Genet 2:475, 1993. 6. Hayward C, Porteous MEM, Brock DJH: Identification of a novel nonsense mutation in the fibrillin gene (FBN1) using nonisotopic techniques. Hum Mutat 3:159, 1994. 7. Dietz HC, Pyeritz RE: Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet 4:1799, 1995. 8. Hayward C, Brock DJH: Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. Hum Mutat 10:415, 1997. 9. Hayward C, Porteous ME, Brock DJH: Mutation screening of all 65 exons of the fibrillin-1 gene in 60 patients with Marfan syndrome: report of 12 novel mutations. Hum Mutat 10:280, 1997. 10. Silva DB, Freitas FCN, Vieira AR, et al.: Sı´ndrome de Marfan: caracterı´sticas clı´nicas, implicac¸o˜es dentais e relato de caso. J Bras Odontoped Odonto Bebeˆ 2:230, 1999.

458

Craniofacial Structures

11. Prader A, Labhart A, Willi H: Ein syndrom von adipositas, kleinwuchs, kryptorchismus und oligophrenie nach myatonieartigem zustand im neugeborenenalter. Schweiz Med Wschr 86:1260, 1956. 12. Buiting K, Greger V, Brownstein BH, et al.: A putative gene family in 15q11-13 and 16p11.2: possible implications for Prader-Willi and Angelman syndromes. Proc Nat Acad Sci 89:5457, 1992. 13. Buiting K, Dittrich B, Gross S, et al.: Molecular definition of the Prader-Willi syndrome chromosome region and orientation of the SNRPN gene. Hum Mol Genet 2:1991, 1993. 14. Buiting K, Dittrich B, Gross S, et al.: Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am J Hum Genet 63:170, 1998. 15. Ohta T, Gray TA, Rogan PK, et al.: Imprinting-mutation mechanisms in Prader-Willi syndrome. Am J Hum Genet 64:397, 1999. 16. Ming JE, Blagowidow N, Knoll JHM, et al.: Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting. Am J Med Genet 92:19, 2000. 17. Buiting K, Gross S, Lich C, et al.: Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet 72:571, 2003. 18. Nilssen O, Berg T, Riise HMF, et al.: Alpha-mannosidosis: functional cloning of the lysosomal alpha-mannosidase cDNA and identification of a mutation in two affected siblings. Hum Mol Genet 6:717, 1997. 19. Gotoda Y, Wakamatsu N, Kawai H, et al.: Missense and nonsense mutations in the lysosomal alpha-mannosidase gene (MANB) in severe and mild forms of alpha-mannosidosis. Am J Hum Genet 63:1015, 1998. 20. Berg T, Riise HMF, Hansen GM, et al.: Spectrum of mutations in alpha-mannosidosis. Am J Hum Genet 64:77, 1999. 21. Mossey PA: The heritability of malocclusion: part 2. The influence of genetics in malocclusion. Br J Orthod 26:195, 1999. 22. Goose DH, Thomson DG, Winter FC: Malocclusion in schoolchildren of the west Midlands. Br Dent J 102:174, 1957. 23. Grewe JM, Cervenka J, Shapiro BL, et al.: Prevalence of malocclusion in Cheppewa Indian children. J Dent Res 47:302, 1968. 24. Ingervall B: Prevalence of dental and occlusal anomalies in Swedish conscripts. Acta Odontol Scand 32:83, 1974. 25. El-Mangoury NH, Mostafa YA: Epidemiologic panorama of dental occlusion. Angle Orthod 60:207, 1990. 26. Tipton RT, Rinchuse DJ: The relationship between static occlusion and functional occlusion in a dental school population. Angle Orthod 16:57, 1991. 27. Saleh FK: Prevalence of malocclusion in a sample of Lebanese schoolchildren: an epidemiological study. East Mediterr Health J 5:337, 1999. 28. Racek J, Sottner L: Contribution to the heredity of retention of canine teeth. Cesk Stomatol 77:209, 1977. 29. Peck L, Peck S, Attia Y: Maxillary canine-first premolar transposition, associated dental anomalies and genetic basis. Angle Orthod 63:99, 1993. 30. Peck S, Peck L, Kataja M: The palatally displaced canine as a dental anomaly of genetic origin. Angle Orthod 64:249, 1994. 31. Peck S, Peck L: Classification of maxillary tooth transpositions. Am J Orthod Dentofacial Orthop 107:505, 1995. 32. Peck S, Peck L, Kataja M: Prevalence of tooth agenesis and peg-shaped maxillary lateral incisor associated with palatally displaced canine (PDC) anomaly. Am J Orthod Dentofacial Orthop 110:441, 1996. 33. Peck S, Peck L, Kataja M: Site-specificity of tooth agenesis in subjects with maxillary canine malpositions. Angle Orthod 66:473, 1996. 34. Pirinen S, Arte S, Apajalahti S: Palatal displacement of canine is genetic and related to congenital absence of teeth. J Dent Res 75:1346, 1996. 35. Peck S, Peck L: Palatal displacement of canine is genetic and related to congenital absence of teeth. J Dent Res 76:728, 1997. 36. Peck S, Peck L, Hirsh G: Mandibular lateral incisor-canine transposition in monozygotic twins. J Dent Child 64:409, 1997. 37. Sottner L: Our concept of inheritance of tooth retention from the aspect of molecular biology and genetics. Cesk Stomatol 97:43, 1997.

38. Peck S, Peck L, Kataja M: Mandibular lateral incisor-canine transposition, concomitant dental anomalies and genetic control. Angle Orthod 68:455, 1998. 39. Plunkett DJ, Dysart PS, Kardos TB, et al.: A study of transposed canines in a sample of orthodontic patients. Br J Orthod 25:303, 1998. 40. Shapira Y, Kuftinec MM: Maxillary tooth transpositions: characteristic features and accompanying dental anomalies. Am J Orthod Dentofacial Orthop 119:127, 2001. 41. Peck S, Peck L, Kataja M: Concomitant occurrence of canine malposition and tooth agenesis: evidence of orofacial genetic fields. Am J Orthod Dentofacial Orthop 122:657, 2002. 42. Ro¨hrer A: Displaced and impacted canines. Int J Orthod Oral Surg Radiogr 15:1003, 1929. 43. Dachi SF, Howell FV: A survey of 3874 routine full-mouth radiographs. II. A study of impacted teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 14:1165, 1961. 44. Niczky E, Mu¨ller K, Slavik J: Transposition. Cesk Stomatol 67:227, 1967. 45. Shah RM, Boyd MA, Vakil TF: Studies of permanent tooth anomalies in 7,886 Canadian individuals. I: impacted teeth. J Can Dent Assoc 44:262, 1978. 46. Ja¨rvinen S: Mandibular incisor-cuspid transposition: a survey. J Pedod 6:159, 1982. 47. Sandham A, Harvie H: Ectopic eruption of the maxillary canine resulting in transposition with adjacent teeth. Tandlaegebladet 89:9, 1985. 48. Hirschfelder U, Petschelt A: Impaction of teeth from an orthodontic point of view. Dtsch Zahna¨rztl Z 41:164, 1986. 49. Shapira J, Chaushu S, Becker A: Prevalence of tooth transposition, third molar agenesis, and maxillary canine impactation in individuals with Down syndrome. Angle Orthod 70:290, 2000. 50. Vieira AR: Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res 82:162, 2003.

14.7 Enamel Dysplasia Definition

Enamel dysplasia is any abnormality of enamel formation. These defects affect the quality or quantity of enamel and can be divided into those that are influenced by environmental factors and those that are idiopathic or genetic in origin. Many environmentally related factors can contribute to alterations of enamel. These are listed in Table 14-16.1 Amelogenesis imperfecta (AI) collectively refers to the group of hereditary enamel malformations that occur in the absence of a systemic disorder. Diagnosis

Environmental defects affecting enamel typically manifest as hypoplasia, diffuse opacities, or demarcated opacities.1 Since environmental factors affect only the teeth that are developing at the time of the insult, few teeth or only one dentition may be involved. The affected enamel may be localized or present on many teeth, with varying degrees of involvement on each affected tooth. Hereditary dysplasias typically affect all the teeth of both dentitions, though there are exceptions. A common pattern seen in environmental dysplasias with an insult of short duration is dysplastic, horizontal bands of enamel. The location of the bands can be correlated to the stage of tooth development at the time of the insult and the width to the time interval of the insult. In instances where genetic dysplasias localize, the resulting defect is in a vertical direction because of the manner in which amelogenesis occurs (apex to occlusal direction).2

Teeth Table 14-16. Environmental factors associated with enamel dysplasias1

459

Systemic

enamel dysplasia similar to that of other debilitative diseases or may cause a general discoloration of the enamel as a consequence of pigment deposition during amelogenesis.3

Birth-related trauma

Turner Hypoplasia

Chemicals

Trauma to deciduous teeth or periapical inflammation of an overlying primary tooth may interfere with amelogenesis of succedaneous teeth. The interference leads to hypoplasia or hypocalcification of the enamel of the permanent teeth in a distribution dependent on the extent of the trauma or infection or on the stage of development of the permanent tooth. Traumatic dysplasia affects the permanent incisors more often than other teeth, because injuries to the deciduous incisors are common during childhood. Infectious dysplasia affects premolars more often than other teeth because of the frequency of abscesses under deciduous molars. Permanent molars are least likely to be affected by overlying periapical inflammatory processes since they do not replace a deciduous tooth.3

Chromosomal abnormalities Infections Inherited diseases Malnutrition Metabolic disorders Neurologic disorders Local

Local acute mechanical trauma Electric burn Irradiation Local infection

Etiology and Distribution Natal dysplasia

Horizontal bands of enamel hypocalcification, hypomaturation, or hypoplasia may be seen across the surfaces of teeth that are developing at the time of birth: the middle third of the deciduous incisors and cuspids and the tips of the canines and molars. The trauma of birth or the physiologic changes that occur at birth are responsible for these lines. They are most often found in the deciduous dentition and their presentation is not easily visible. A similar pattern of enamel defects involving the cuspids, bicuspids, and second molars is seen when the traumatic insult occurs around the age of 4 to 5 years.1,3 Ingestional Dysplasia

Severe vitamin D deficiency can cause enamel dysplasia in the typical horizontal distribution. Ingestion of more than 1.8 parts per million (ppm) of fluoride in water also causes enamel hypoplasia. While only 10% of those ingesting 1.8 ppm are affected, 90% of those ingesting 6 ppm or more are affected. The dysplasia varies from mottling of the enamel to hypocalcification and hypoplasia. Even when an entire tooth surface is mottled because of long-term ingestion of fluoride, there are superimposed horizontal lines across the surface that demarcate periods of high and low ingestion.3 Debilitative Dysplasia

Prolonged debilitative disorders are capable of causing a pattern of enamel dysplasia that is also known as fever hypoplasia. While the eruptive diseases of childhood most commonly cause debilitative dysplasia, any serious illness, with or without fever, during the period of tooth development may do so. The extent of the dysplasia (width of the dysplastic horizontal line) reflects the duration of the disease, and the pattern of the dysplasia (number and type of teeth affected) reflects the approximate age at the time of the disease. The dysplasia is usually bilateral, as homologous teeth on the left and right sides are affected equally. Debilitative diseases with prenatal effect on enamel development include congenital syphilis and rubella. Rh incompatibility, when severe enough to cause erythroblastosis fetalis, may cause

Hypoplasia Caused by Antineoplastic Therapy

An emerging cause of enamel dysplasia is therapeutic radiation or chemotherapy used in the treatment for pediatric cancer. The extent of dysplasia is directly related to the age of the individual at treatment, the type of therapy administered, and the dose and field of radiation, if used.1 Amelogenesis imperfecta

AI is a collective term used to describe a group of conditions that demonstrate developmental alterations in enamel structure without systemic involvement. Though a number of classification systems currently exist, the most widely accepted was proposed by Witkop and Sauk and is based predominantly on the observed phenotype.4 Four major types of AI have been identified based on clinical and histologic characteristics of enamel: 1) hypoplastic, 2) hypomaturation, 3) hypocalcified, and 4) hypomaturation-hypoplastic (Fig. 14-5). This organization scheme is correlated to a disturbance in one of the phases of amelogenesis: 1) secretion of an organic matrix, 2) mineralization of the matrix, and 3) maturation of enamel. The four major groups are subsequently subdivided into 15 subtypes based primarily on phenotype and, secondarily, by mode of inheritance (Table 14-17).5 The complexity of the diagnosis for amelogenesis imperfecta implies genetic heterogeneity. There are currently two genes implicated in the pathogenesis of AI. The first genetic association was the discovery of the amelogenin gene in the p21.1-22.3 region of the X chromosome. The second defect was found in the enamelin gene on chromosome 4q21. Both of these genes encode proteins that contribute to the formation of the enamel matrix during amelogenesis. As advances are made in determining the genetic etiology of the various forms of AI, a classification system based on the specific molecular defect rather than the observed phenotype may emerge.6 To date, seven types of hypoplastic AI have been described.1 They are all characterized by an inadequate deposition of enamel matrix. Smooth hypoplastic AI may be inherited as an autosomal dominant trait or as an X-linked dominant one. In autosomal dominant AI, the enamel is thin, smooth, and white and contrasts with the dentin on radiographs. The teeth are small and somewhat conical. In the X-linked dominant type, the enamel in males is thin, smooth, and brown and contrasts with the dentin on X-rays, while the enamel in females shows alternate vertical bands of normal and abnormal enamel.

460

Craniofacial Structures

Fig. 14-5. Amelogenesis imperfecta. A. Intraoral photograph of patient afflicted with amelogenesis imperfecta. Note the small crown size of the permanent teeth (arrow) and consequent open contacts (*). B. Radiograph of the affected teeth, revealing generalized enamel agenesis on erupted as well as unerupted teeth.

Rough hypoplastic AI is inherited in an autosomal dominant manner. The enamel is thin, rough, and yellow-brown and contrasts with dentin on radiographs. There are two types of pitted hypoplastic AI. In one type, the pitting is inherited in an autosomal dominant manner and is generalized, although vertical orientation of the pits may be seen and the labial surfaces are more frequently pitted than the lingual surfaces. In the other type, the pitting is limited to the middle third of the crown and is distributed horizontally. This pattern of localized pitting has been characterized in cases inherited in both

an autosomal dominant and recessive fashion.3 In the autosomal recessive enamel agenesis pattern, there is a total lack of enamel formation. The surface of the dentin is rough and an anterior open bite is occasionally seen.1 In hypomaturation AI, the deposition and initial mineralization of the enamel matrix is normal. There is, however, a defect in the maturation of the enamel structure.1 To date, four types of hypomaturation AI have been described. Pigmented hypomature AI may be inherited as an autosomal recessive or an X-linked recessive trait. The enamel in males with either type is normally thick, yellowbrown, and soft and does not contrast with the dentin on radiographs. The enamel in females with the autosomal recessive form is identical to that in males. By contrast, X-linked recessive form in females shows alternate vertical bands of normal and hypomature enamel. Localized hypomature AI, typically inherited as an autosomal dominant trait, is believed to also occur as an X-linked trait.1 It is characterized by white, opaque enamel over the incisal and occlusal two-thirds of the teeth. The distribution of the defect is horizontal, contrary to the normal vertical distribution observed in other genetic dysplasias, leading to the descriptive term snow-capped teeth.3 In the hypocalcified form of AI, the enamel matrix is deposited normally but fails to mineralize to any significant extent.1 Two types of hypocalcified AI have been identified. One is inherited as an autosomal dominant trait, and the other as autosomal recessive. The enamel of both types is normally thick, yellow-brown and friable and appears moth-eaten on radiographs.3 The hypomaturation/hypoplastic form of AI demonstrates both enamel hypoplasia and hypomaturation. Though the two identified patterns are similar, they are differentiated by the thickness of enamel and the overall tooth size. The hypomaturation/hypoplastic pattern is characterized by enamel hypomaturation, where the enamel appears mottled yellow-white to yellow-brown. This is accompanied by varying degrees of taurodontism. The hypoplastic/hypomaturation form of AI has thin enamel as a hallmark feature and also demonstrates hypomaturation.1 AI affects approximately one in 1500 Americans of Caucasian background, with autosomal dominant hypocalcified AI accounting for 40% of all cases. While the frequency of AI among Americans of other racial backgrounds has not been reported, there is no

Table 14-17. Classification of amelogenesis imperfecta5 Type

Pattern

Specific Features

Inheritance

Genetic Defect

IA

Hypoplastic

Generalized pitted

AD

Unknown

IB

Hypoplastic

Localized pitted

AD (104500)

Enamelin (ENAM)

IC

Hypoplastic

Localized pitted

AR (204650)

Unknown

ID

Hypoplastic

Diffuse smooth

AD (104500)

Enamelin (ENAM)

IE

Hypoplastic

Diffuse smooth

XLD (300391)

Amelogenin(AMELX)

IF

Hypoplastic

Diffuse rough

AD

Unknown

IG

Hypoplastic

Enamel agenesis

AR

Unknown

IIA

Hypomaturation

Diffuse pigmented

AR (204700)

Unknown

IIB

Hypomaturation

Diffuse

XLR (301100)

Amelogenin (AMELX)

IIC

Hypomaturation

Snow capped

X-linked

Unknown

IID

Hypomaturation

Snow capped

AD

Unknown

IIIA

Hypocalcified

Diffuse

AD

Unknown

IIIB

Hypocalcified

Diffuse

AR

Unknown

IVA

Hypomaturation-hypoplastic

Taurodontism

AD (104510)

Unknown

IVB

Hypoplastic-hypomaturation

Taurodontism

AD

Unknown

Teeth Table 14-18. Syndromes with enamel dysplasia as a feature3

461

Dysplasia Type

14.8 Dentin Dysplasia

Amelo-onycho-hypohidrotic

Hypocalcification/hypoplasia

Definition

Oculodentoosseous dysplasia

Hypoplasia

Trichodentoosseous

Hypocalcification/hypoplasia

Tuberous sclerosis

Pitted hypoplasia

EEC

Hypoplasia

Ectodermal dysplasia, Basan type

Hypocalcification

Dentin dysplasia is an abnormal formation of dentin. The dysplasia may manifest in the absence of a systemic disorder or in conjunction with other anomalies and have either an environmental or genetic origin. Environmentally induced dentin dysplasias include pigmentary and physiologic dysplasia. Dentinogenesis imperfecta (DI) refers to one of the inherited dentin dysplasias that presents without a systemic component. This includes types I and II dentin dysplasia; DI types I, II, and III; pulpal dysplasia; and fibrous dysplasia of the dentin.

Syndrome

Autosomal Dominant Conditions

Autosomal Recessive Conditions

Morquio syndrome (MPS-IV)

Hypoplasia

Vitamin D–dependent rickets

Rough hypoplasia

Kohlschutter

Hypoplasia

Pigmentary Dysplasia

McGibbon

Aplasia

Epidermolysis bullosa (AR type)

Pitted hypoplasia

Pigmentary dysplasia can be seen clinically because of the translucent nature of the overlying enamel. Erythropoietic porphyria causes red-brown discoloration of the teeth; in primary teeth the pigmentation (porphyrin deposition) may involve all layers, whereas in permanent teeth the pigmentation is predominantly in the dentin and cementum. Erythroblastosis fetalis (hemolytic disease of the newborn) causes yellow-green pigmentation; again, the enamel may be affected, but the heaviest pigmentation (deposition of hemolyzed fetal blood products) is in the dentin. Tetracycline causes a yellow to yellow-brown discoloration of dentin. Agents and compounds that may discolor fully formed teeth include silver amalgam (black), copper (blue-green), nickel and chromium (green), lead (brown), bismuth (gray-blue), oil of cloves (brownblack), bilirubin (green), hemin and hematin (blue-black), methemoglobin (red-brown), and hematoidin (orange). Physiologic processes through which fully formed teeth may become discolored include internal resorption (pink), pulp disease (gray-black), and dental caries (color dependent on staining agent to which dentin is exposed).

X-Linked Conditions

Amelocerebrohypohidrotic

Hypoplasia

Pseudohypoparathryoidism

Pitted hypoplasia

Focal dermal hypoplasia

Hypoplasia

evidence that it differs greatly from that among Caucasians. Enamel dysplasia is also seen as a component of many syndromes of genetic and environmental origin. These are summarized in Table 14-18.3 Prognosis, Treatment, and Prevention

Enamel dysplasia, while not inconsequential, has a generally good prognosis. Other tooth layers are not affected, and the teeth can be maintained for a lifetime. Whether it is environmental or genetic in etiology, enamel dysplasia is easily and successfully treated, albeit the necessary restorative dentistry may be expensive. Sealants, composite restorations, crowns, and other restorative techniques work well and are used interchangeably, depending on the site and extent of the dysplasia.3 Enamel dysplasia of environmental origin can be prevented by avoiding the known cause. Enamel dysplasia of genetic origin can be dealt with through genetic counseling. While most couples may not modify family planning because of a risk for AI, some will; those who do not can be alerted through counseling of the risks so that prognosis is improved by early diagnosis and treatment.3 References (Enamel Dysplasia) 1. Neville BW, Damm DD, Allen CM, et al.: In: Oral and Maxillofacial Pathology, ed 2. WB Saunders Company, Philadelphia, 2002, p 49. 2. Jorgensen RJ, Yost C: Etiology of enamel dysplasias. J Pedodontol 6:315, 1982. 3. Jorgenson RJ: Teeth. In: Human Malformations and Related Anomalies, ed 1. Stevenson RE, Hall JG, Goodman RM, eds. Oxford University Press, New York, 1993, p 383. 4. Witkop CJ, Sauk JJ: Heritable defect of enamel. In: Oral Facial Genetics. RE Stewart, GH Prescott, eds. CV Mosby, St. Louis, 1976, p 151. 5. Witkop CJ: Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification. J Oral Pathol 17:547, 1988. 6. Aldred MJ, Savariarayan R, Crawford PJM: Amelogenesis imperfecta: a classification and catalogue for the 21st century. Oral Dis 9:19, 2003.

Physiologic Dysplasia

Most physiologic dysplasias are seen as exaggerated developmental lines on histologic sections. Dentinogenesis Imperfecta

The types of DI (Table 14-19) can be differentiated by clinical and radiographic features (Fig. 14-6). In classical DI (DI-IA), the teeth are yellow-brown to blue-gray in color and appear translucent. The crowns are bulbous because of an exaggerated constriction at the cementoenamel junction. The pulp chambers of some primary teeth and all secondary teeth are obliterated by atypical dentin. The obliteration is progressive, beginning before eruption and continuing afterwards. The roots are excessively tapered and foreshortened. Histopathologic studies reveal (1) absence of extensions of dentinal tubules into the enamel, (2) smooth (not scalloped) dentin-enamel junctions, and (3) abnormal dentinal tubules. In DI-IB, the teeth are also yellow-brown to blue-gray in color and appear translucent. Crown shape is like that of DI-IA, but the pulp chambers of primary teeth, rather than being obliterated, are excessively large. There is very little dentin, with most of the pulplike inner portion of the teeth consisting of coarse collagen bundles. In DI-II, also called radicular dentin dysplasia or rootless teeth, the crowns are normal in color and shape. The pulp chambers are virtually obliterated, but there are crescent-shaped radiolucencies in

462

Craniofacial Structures

Table 14-19. Classification of dentinogenesis imperfecta (DI)1–3 Type

Features

Alternative Classification

Genetic Defect

IA

Obliterated appearance, obliterated pulps, exaggerated coronal constriction

Shields II (125420)

Dentin sialo-phosphoprotein (DSPP)

IB

Similar to IA, but pulp chambers of deciduous teeth are enlarged

DI Brandywine type, Shields III (125500)

Likely dentin matrix acidic phospho-protein-1 (DMP1)

II

Obliterated pulp (crescent-shaped radiolucencies), foreshortened roots, premature loss of teeth

Dentin dysplasia I (125400)

Unknown

III

Opalescence of deciduous teeth, thistle-tube pulp chambers

Dentin dysplasia II, pulpal dysplasia (125420)

Dentin sialo-phosphoprotein (DSPP)

IV

Obliterated pulps, fibrous dentin

Fibrous dysplasia of dentin

Unknown

the central portions of the teeth. The roots are virtually absent, leading to premature ‘‘loosening’’ and loss of teeth. There are also multiple periapical radiolucencies around most roots. Histopathologic studies reveal that, in fact, the pulp is absent, having been replaced by regularly formed, eumorphous concretions. In DI-III, also termed coronal dentin dysplasia, the color of the crowns of the primary teeth resembles that of DI-I, but the crowns of the secondary teeth are normal in color and shape. On radiographs the pulp chambers of affected teeth resemble the

Fig. 14-6. Dentinogenesis imperfecta (DGI). A. Intraoral photograph of patient afflicted with DGI. Note the discoloration and extensive loss of tooth structure. B. Radiograph of the affected teeth, revealing bulbous crowns, obliterated pulp chambers, and narrowed root canals. (Courtesy of Dr. Nadarajah Vigneswaran, University of Texas Health Science Center, Houston, TX.)

thistle-tube glassware used in chemistry laboratories. Roots are well formed, and there is seldom premature tooth loss. In DI-IV, the crowns of teeth are also normal in size and shape, as are the pulp chambers, but pulpal tissue is obliterated by atypical dentin, and the dentin itself is abnormal in histopathologic study. Etiology and Distribution

DI-I is a relatively common disorder, affecting approximately one in 8000 individuals. It has recently been linked to mutations in the dentin sialophosphoprotein (DSPP) gene on chromosome 4q21.4 The gene product is cleaved into two dentin-specific matrix proteins, dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). DPP, a highly acidic protein, is the major noncollagenous component of dentin, being solely expressed by the ectomesenchymal-derived odontoblast cells of the tooth. Unique to all of the reported cases of DI-I, all patients have a positive family history (have affected progenitors), and all patients whose ancestry can be traced are descended from the population in a particular province in France. DI-IA is inherited as an autosomal dominant trait, with virtually complete penetrance and remarkably little variation in expression. Variation is so minimal, in fact, that its occurrence (e.g., enlarged pulp chambers of primary teeth) is evidence that favors the existence of DI-IB. DI-IB is largely limited to a triracial isolate in the United States, although it has recently been reported among Ashkenazi Jews. Linkage analysis revealed the most likely candidate gene for DI-IB in a branch of the Brandywine kindred was dentin matrix acidic phosphoprotein-1.5 These results again were consistent with the hypothesis that DI-I and DGI-III are allelic or the result of mutations in two tightly linked genes, DSPP and DMP1. DI-II is more rare than DI-I, occurring in only one in 100,000 persons. The mutation rate for the DI-II gene seems low and clinical variation is minimal. While the primary defect is unknown, it has been suggested that the epithelial component of the root sheath invaginates too early in development and causes root aplasia. DI-III is less common than the other dentin dysplasias, having been reported in only a few families. It is an autosomal dominant disorder in which mineralization of the dentin of the primary teeth is abnormal. On the basis of the phenotypic overlap and shared chromosomal location with dentinogenesis imperfecta type I, it has been proposed that the two conditions are allelic. A missense mutation (encoding an aspartic acid to tyrosine change) was reported in DSPP in a family with dentin dysplasia type II.6 The substitution in the hydrophobic signal peptide domain caused a failure of translocation of the encoded proteins into the

Teeth

endoplasmic reticulum. It is hypothesized that this would likely lead to a loss of function of both DSP and DPP. DI-IV is the rarest of the dentin dysplasias, having been reported in a single family as an autosomal dominant trait. The primary defect underlying this disorder is unknown. Prognosis, Treatment, and Prevention

Individuals affected by DI-I are prone to lose teeth because the inherent weakness at the dentin-enamel junction causes the enamel to fracture, thereby exposing the more delicate, underlying dentin to occlusal forces and cariogenic agents. Any treatment that protects the dentin should prove effective. Stainless steel crowns and other types of full crown coverage are adequate. Dental restorations, such as amalgam fillings and gold inlays, are likely to fail. Individuals with DIII lose their teeth because excessive mobility leads to periodontal disease or exfoliation. Short of extractions and prostheses, treatment is not effective. DI-III and DI-IV do not predicate the loss of teeth. Prevention is possible only through family planning by affected individuals. References (Dentin Dysplasia) 1. Shields ED, Bixler D, EI-Kafrawy AM: A proposed classification for heritable human dentine defects with a description of a new entity. Arch Oral Biol 18:543, 1973. 2. Jorgenson RJ: Problems in nomenclature of craniofacial disorders. J Craniofac Genet Dev Biol 9:7, 1989. 3. Jorgenson RJ: Teeth. In: Human Malformations and Related Anomalies. Stevenson RE, Hall JG, Goodman RM, eds. Oxford University Press, New York, 1993, p 383. 4. Patel PI: Soundbites. Nat Genet 27:129, 2001. 5. MacDougall M, Jeffords LG, Gu TT, et al.: Genetic linkage of the dentinogenesis imperfecta type III locus to chromosome 4q. J Dent Res 78:1277, 1999. 6. Rajpar MH, Koch MJ, Davies RM, et al.: Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization. Hum Mol Genet 11:2559, 2002.

14.9 Cementum Dysplasia Cementum dysplasia is a neoplastic disease that is described here because it is relatively common and its neoplastic nature is not always recognized at discovery. At the time of discovery, cementum dysplasia often resembles hypercementosis or fibrous dysplasia of the adjacent alveolar bone. Cementum is the most poorly understood layer of the teeth. Nonetheless, three entities should be mentioned here: concrescence, familial cementoma, and cementum dysplasia. Concrescence is simply the fusion of adjacent teeth by cementum only. Concrescence is probably caused by nothing more than close approximation of the roots of developing teeth. Its frequency in the population has not been well-established. Familial cementomas are neoplastic lesions that appear in all four quadrants, a combination that is thought to be inherited as an autosomal dominant trait. Only a few families have been reported. Cementum dysplasia is a neoplastic process that is found in two to three individuals per 1000 in the general population. Females are more commonly affected than males and blacks more commonly than whites. Mandibular anterior teeth are more commonly affected than other teeth.

463

Each of these disorders is benign, requires no treatment, and cannot be prevented. Each may complicate extraction of affected teeth that have to be removed for other reasons.1 Reference (Cementum Dysplasia) 1. Jorgenson RJ: Teeth. In: Human Malformations and Related Anomalies. Stevenson RE, Hall JG, Goodman RM, eds. Oxford University Press, New York, 1993, p 383.

14.10 Abnormalities of Tooth Eruption Definition

Abnormalities of tooth eruption can be early, delayed, or a lack of tooth eruption. All of these conditions can manifest independently or as a component of an underlying disorder. The normal eruption sequence for each tooth is shown in Tables 14-1A and 14-1B. Ordinarily, the deciduous teeth erupt between ages 6 months and 2 years in the following sequence: incisors, 6 to 9 months; first molars, 12 to 14 months; canines, 16 to 18 months; and second molars, 20 to 24 months. The permanent teeth ordinarily erupt between ages 6 and 21 years in the following sequence: first molars and lower central incisors, 6 to 7 years; lower lateral incisors, 7 to 8 years; upper lateral incisors, 8 to 9 years; lower canines, 9 to 10 years; premolars, 10 to 12 years; upper canines, 11 to 12 years; second molars, 12 to 13 years; and third molars, 17-21 years. Small variations from these eruption patterns are common and may even be familial. Teeth in females generally erupt earlier than those in males. Natal Teeth

Natal teeth are those that are present at birth or erupt within the first month. While natal teeth are most commonly lower central incisors, other teeth may erupt early or the natal teeth may be supernumerary (predeciduous). Natal teeth may be inherited in an autosomal dominant fashion.1 They occur in roughly one in 3000 newborns.2 Natal teeth are found in cyclopia, Ellis-van Creveld syndrome, Hallermann-Streiff syndrome, pachyonychia congenita, PallisterHall syndrome, short rib-polydactyly type II, and WiedemannRautenstrauch syndrome. Eruption Delays or Impaction

Developmental delays in tooth eruption are most commonly attributed to mechanical interferences caused by supernumerary teeth, crowding, soft tissue impaction, or odontogenic tumors and cysts. Ankylosis typically occurs after partial eruption of the tooth into the oral cavity; it is defined as the fusion of cementum or dentin to alveolar bone due to cellular changes in the periodontal ligament caused by trauma and other pathologies. When the tooth becomes ankylosed, it appears to submerge in relation to adjacent teeth that continue to erupt. Eruption failure and delayed eruption are conditions that do not naturally involve ankylosis and are associated with craniofacial dysostosis, hypothyroidism, hypopituitarism and several genetic and medical syndromes.3–6 Eruption defects can also present as a component of various syndromic conditions and are summarized in Table 14-20. Primary failure of eruption (PFE) is characterized by a localized failure of eruption of permanent posterior teeth and lacks any systemic involvement. The affected teeth are nonimpacted,

464

Craniofacial Structures

nonankylosed, and fully formed, but are unable to reach the occlusal plane presumably due to a primary defect in the eruption mechanism itself. Attempts to close the resultant ‘‘open bite’’ orthodontically often result in ankylosis of PFE-affected teeth.7 (Fig. 14-7)

Prognosis, Treatment, and Prevention

Most natal teeth are firmly imbedded and pose no risk to the neonate. Those that are loose should be extracted to avoid aspiration. Delayed eruption can have considerable consequence on ultimate

Table 14-20. Syndromes with tooth eruption defects as a feature6 Causation Gene/Locus

Syndrome

Eruption Phenotype

Cleidocranial dysplasia

Delayed eruption

AD (600211) RUNX2/CBFA1, 6p21

Osteopetrosis

Failure of eruption

AR and AD TRAF6

GAPO

Failure of eruption

AR

Osteopathia striata with cranial sclerosis

Failure of eruption in some cases

AD

Osteoglophonic dysplasia

Failure of eruption of 28 teeth

AD

Singleton-Merten

Dysplastic development with delayed eruption of 28 teeth

AD possibly

Aarskog

Delayed eruption

XLR (305400) FGDY1, Xp21.1

Acrodysostosis

Delayed tooth eruption (23% of cases)

AD (101800)

Albright hereditary osteodystrophy

Delayed eruption

AD (103580) GNAS, 20q13.2

Apert

Delayed and ectopic eruption

AD (101200) FGFR2

Chondroectodermal dysplasia (Ellis–van Creveld)

Delayed eruption and partial anodontia

AR (225500) Several mutations in the EVC gene

Cockayne

Delayed eruption

AR CSB (ERCC6) gene (helicase)

De Lange

Delayed eruption

AD NIPBL, 5p13.1

Dubowitz

Delayed eruption and hypodontia

AR possibly

Frontometaphyseal dysplasia (Gorlin-Cohen)

Delayed eruption and retained deciduous teeth

AD (304120) FLNA, Xq28

Goltz (Focal dermal hypoplasia)

Delayed eruption and hypodontia with hypoplastic teeth

XLD, lethality in hemizygous males

Hunter

Delayed eruption

XL (309900) IDS, Xq28

Incontinentia pigmenti

Delayed eruption and hypodontia in 80%

XLD, lethality in males NEMO, Xq28 heterogeneous

Killian/Teschler-Nicola

Delayed eruption

Mosaic tetrasomy 12p in skin fibroblasts

Levy-Hollister

Delayed eruption of 18 teeth

AD

Maroteaux-Lamy mucopolysaccharoidosis (MPS VI)

Delayed eruption with small teeth

AR (253200) ASB, 5q11–q13

Osteogenesis imperfecta, type I

Delayed eruption and dysplastic teeth

AD COL1A1, COL1A2

Progeria (Hutchinson-Gilford)

Delayed eruption of 18 and 28 teeth and hypodontia of 28 teeth

AR (176670) LMNA, 1q21.2

Pyknodysostosis

Delayed eruption and occasional anodontia

AR (265800) CTSK, 1q21

Primary failure of eruption*

Failure of 28 teeth to erupt partially or completely

*Not associated with overt systemic disease.

Teeth

465

occlusion. The choices of treatment for impacted teeth include longterm observation, orthodontically assisted eruption, transplantation, or surgical removal. The presence of infection, nonrestorable carious lesions, cysts, tumors, or destruction of adjacent teeth necessitates surgical removal of the affected teeth.8 None of the conditions affecting tooth eruption is preventable. References (Abnormalities of Tooth Eruption) 1. Bodenhoff J, Gorlin RJ: Natal and neonatal teeth; folklore and fact. Pediatrics 32:1087, 1963. 2. Jorgenson RJ, Shapiro SD, Salinas CF, et al.: Intraoral findings and anomalies in neonates. Pediatrics 69:577, 1982. 3. Sauk JJ: Genetic disorders involving tooth eruption anomalies. In: The Biological Mechanisms of Tooth Eruption and Root Resorption. Davidovitch Z, ed. EBSCO Media, Birmingham, 1988, p 171. 4. Gorlin RJ, Cohen MM, Levin LS: Syndromes of the Head and Neck, ed 3. Oxford University Press, New York, 1990. 5. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 6. Wise GE, Frazier-Bowers S, D’Souza RN: Cellular, molecular, and genetic determinants of tooth eruption. Crit Rev Oral Biol Med 13:323, 2002. 7. Proffit WR, Vig KW: Primary failure of eruption: a possible cause of posterior open-bite. Am J Orthod 80:173, 1981. 8. Neville BW, Damm DD, Allen CM, et al.: Oral and Maxillofacial Pathology, ed 2. WB Saunders Company, Philadelphia, 2001, p 49.

Fig. 14-7. Primary failure of eruption. Intraoral photograph (A), dental models (B), and panoramic radiograph (C) showing nonankylosed, submerged upper left posterior quadrant and resulting posterior lateral open bite (arrows).

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Part IV Neuromuscular Systems

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15 Brain Alasdair G.W. Hunter

T

he anatomy of the developing central nervous system (CNS) dominates embryonic topography in much the same way that function of the mature CNS dominates postnatal actions and behavior. The CNS is represented initially as an ectodermal plate, stretching the length of the dorsum of the embryonic disc.1–4 The margins of the plate become elevated during developmental stages 8–9 (days 18–20) and eventually roll into a tube during developmental stages 10–12 (days 22–26). Closure of the tube begins at the level of the third somite and progresses bidirectionally from that point. The brain develops from the neural tube rostral to somite 4 and the spinal cord caudal to this level. The segmental nature of the brain is superficially obscured by three major flexures and the markedly discordant growth of its different parts. Three anatomical regions may be identified. The forebrain (prosencephalon) differentiates into the midline diencephalon (thalamus and hypothalamus) and the telencephalon (cerebral hemispheres). The midbrain (mesencephalon) forms the rostral part of the brain stem and the colliculi. The hindbrain (rhombencephalon) forms the caudal portion of the brain stem, the pons, and the cerebellum. Cranial nerves I and II derive from the forebrain; III and IV, from the midbrain; and V–XII, from the hindbrain. It is easier to envision the segmental nature of the spinal cord because of the egress and entrance of spinal nerves at the level of each somite. Complex interrelationships exist through which the CNS influences the development of other organ systems during embryogenesis. Perhaps only the hematopoietic system and the kidneys are exempt from major CNS influence during development. So extensive are the developmental interrelationships that it is tempting to assign to the central nervous system a place of preeminence among the body systems. With the exception of its dependence on the cardiovascular system, the developing CNS is influenced by other systems in only a limited way. This is primarily because many vital functions (nutrition, oxygenation, waste disposal, production of growth factors, protection against mechanical injury), which will become the major responsibility of

Acknowledgements: The author thanks Doctors C. Jiminez, V. Briggs, S. Grahavoc, L. Auruch, W. Blackburn, and Mr. N.R. Cooley Jr. for providing and helping to select illustrations for chapters 15–17.

different systems, are carried out during embryogenesis by the maternal host and placenta. The developing CNS is subject to all of the processes that lead to anomalies.2–8 The presence of anomalies may be obvious at birth or may become evident later because of developmental impairment or neurologic dysfunction. Virtually all visible chromosome aberrations alter mental capability and may cause specific malformations. Exempted from this generalization are most structural and numerical aberrations of the sex chromosomes. It is likely that each chromosome contains numerous genes that participate in brain formation and maintenance of its structure and function. Likewise, environmental insults of a wide variety can affect brain development or damage the brain after development is essentially complete. Radiation, certain infections, metabolic derangements, and a number of drugs and chemicals are the best known of these environmental influences. Vascular insults, placento-amniotic disruptions, the process of twinning, and mechanical forces contribute further to the number of CNS anomalies. As with all developing systems, the CNS becomes progressively resistant to influences from the environment. Defects of neural tube closure are the most common CNS malformations and are among the most common of all major anomalies.3–10 Neural tube defects are usually obvious at birth or present in early infancy. This is not the case with many CNS malformations whose presence are not suspected until seizures, developmental impairment, obstruction of CSF flow, or mass effect prompts imaging of the central nervous system. Malformations are the leading cause of death in infancy and lethal anomalies of the CNS are among the most common of these.11 Disturbances of individual genes and molecular pathways that account for a number of malformations of the CNS have been identified during the past decade. Considerable progress has been made in delineating the molecular causes of holoprosencephaly and lissencephaly, and some progress has been made as well in understanding hydrocephaly, agenesis of the corpus callosum, cerebellar dysgenesis, and other CNS anomalies.12–20 As notable as these advances are, more remains to be learned than we know at present. Most disappointing has been the failure to identify major genes that predispose to neural tube defects. The cranium and vertebral column prevent casual inspection of the CNS. To be sure, certain anomalies of the CNS can be predicted with some accuracy from associated clinical 469

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Neuromuscular Systems

features—for example, holoprosencephaly can be predicted from abnormal midface development, small brain size from cranial measurement, some cases of lissencephaly from facial features, and so forth.21–23 Until recently, however, detailed observations on the anatomy of the CNS could only be made at autopsy, although a limited view could be obtained through invasive tests such as arteriography and pneumoencephalography. Most CNS structures can now be visualized by ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). Ultrasound is most useful prenatally and during the early months of life when the anterior fontanel is open. MRI has become the procedure of choice for imaging brain and spinal cord anatomy and has revolutionized our thinking about several classes of CNS malformation. References 1. O’Rahilly R, Mu¨ller F: Developmental Stages in Human Embryos. Carnegie Institution of Washington, Publication 637, 1987. 2. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott, Williams and Wilkins, Baltimore, 2004, pp 90, 433. 3. O’Rahilly R, Mu¨ller F: Human Embryology and Teratology, ed 3. Wiley-Liss, New York, 2001, p 395. 4. Lemire RJ, Loeser JD, Leech RW, et al: Normal and Abnormal Development of the Human Nervous System. Harper and Row, Hagerstown, 1975. 5. Norman MG, McGillivray BC, Kalousek DK, et al.: Congenital Malformations of the Brain. Oxford Univ Press, New York, 1995. 6. Warkany J, Lemire RJ, Cohen MM, Jr: Mental Retardation and Congenital Malformations of the Central Nervous System. Year Book Medical Publishers, Chicago, 1981. 7. Melnick M: Current concepts of the etiology of central nervous system malformations. BDOAS XV(3):19, 1979. 8. Myrianthopoulos NC: Our load of central nervous system malformation. BDOAS XV(3):1, 1979. 9. Hall JG, Friedman JM, Kenna BA, et al.: Clinical, genetic and epidemiological factors in neural tube defects. Am J Hum Genet 43:827, 1988. 10. National Birth Defects Prevention Network: 2004 Congenital Malformations Surveillance Report. Birth Defects Res (Part A) 70:553, 2004. 11. Centers for Disease Control and Prevention: Infant mortality statistics from the 2001 period linked birth/infant death data set. Nat Vital Stat Rep 52:1, 2003. 12. Roessler E, Belloni E, Gaudenz K, et al.: Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357, 1996. 13. Muenke M, Cohen MM Jr.: Genetic approaches to understanding brain development: holoprosencephaly as a model. Ment Retard Dev Disabil Res Rev 6:15, 2000. 14. Kato M, Dobyns WB: Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 12:R89, 2003. 15. des Portes V, Francis F, Pinard J-M, et al.: Doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). Hum Mol Genet 7:1063, 1998. 16. Hong SE, Shugart YY, Huang DT, et al.: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26:93, 2000. 17. Kitamura K, Yanazawa M, Sugiyama N, et al.: Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 32:359, 2002. 18. Jouet M, Rosenthal A, Armstrong G, et al.: X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 7:402, 1994. 19. Jackson AP, McHale DP, Campbell DA, et al.: Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet 63:541, 1998.

20. des Portes V, Boddaert N, Sacco S, et al.: Specific clinical and brain MRI features in mentally retarded patients with mutations in the Oligophrenin-1 gene. Am J Med Genet 124A:364, 2004. 21. Croen LA, Shaw GM, Lammer EJ: Holoprosencephaly: epidemiologic and clinical characteristics of a California population. Am J Med Genet 64:465, 1996. 22. Aicardi J: Diseases of the Nervous System in Childhood, ed 2. Mac Keith Press, London, 1998, p 90. 23. Jones KL, Gilbert EF, Kaveggia EG, et al.: The Miller-Dieker syndrome. Pediatrics 66:277, 1980.

15.1 Microcephaly Definition

Microcephaly is a cranial vault that is smaller than normal. Since growth of the cranium depends on the forces of an expanding brain, microcephaly is an indicator of an undersized brain. Thus, in defining microcephaly one is in reality attempting to define a lower limit for normal brain size. Although a number of parameters, including the use of cranial height, width, and length, may more accurately reflect brain volume, in clinical practice microcephaly is defined in terms of age- and sex-appropriate curves of occipitofrontal circumference (OFC). There is some difference of opinion about whether the lower limit should be defined as 2 or 3 SD below the mean.1,2 The more liberal 2 SD is used in this discussion because it is consistent with usual clinical practice and it shows good correlation with symptomatology. OFC is a dynamic measure, and it is not uncommon for the centile to fall over time from normal to 2 SD and below. However, the use of such a definition, which by its nature includes 2.5% of the population, requires a cautious approach when assessing its significance. Some authors use the term micrencephaly when small brain size is due to a primarily developmental abnormality and the term true micrencephaly when the small brain is the only pathology.3 That distinction is not made in this discussion. Diagnosis

To identify microcephaly requires an accurate measurement of maximum head circumference, which is then compared with appropriate age- and sex-matched controls4 (Fig. 15-1). There may also be some argument for using ethnically matched data. Adult head size centiles should be used after age 18 years.5 Measurement of OFC is best obtained by using a tape that does not stretch and by placing the tape around the cranium at a level just above the supraorbital ridges and at the opisthocranion. However, the tape should be adjusted up and down to ensure that maximum circumference of the skull is obtained, while at the same time excluding ears, braids, and the like from the measurement.4 Any marked deviation from normal skull shape can affect the measurement. For example, dolichocephaly will increase the head circumference. When there is doubt, length, width, and cranial height measurements6 and cranial radiographic studies may substitute (Fig. 15-2).7 A study of neonates showed a correlation between OFC and brain volume estimated by computed tomography (CT) of 0.55 (p < 0.003) and demonstrated that below an OFC of 33.5 cm a lower OFC strongly predicted a reduced brain volume.8 Microcephaly differs from most of the topics in this chapter in that it is not a primary malformation but rather a sign of a small

Brain

Fig. 15-1. Four-month-old infant with microcephaly, pancytopenia, intracranial calcifications and seizures. This X-linked condition closely mimics the disorder caused by prenatal cytomegalovirus infection.

brain (Fig. 15-3). The underlying pathogenesis may reflect the normal population variation of brain volume or a broad spectrum of genetic or acquired insults that may act prenatally, perinatally, or postnatally to inhibit brain development and, ultimately, size. The traditional approach to the classification of microcephaly has separated genetic from non-genetic causes. The latter are often referred to as acquired or secondary. However, these terms have

Fig. 15-2. Cranial radiograph of 14-year-old male with microcephaly of unknown cause. Note the marked craniofacial disproportion.

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also been used to describe post-natal onset microcephaly, that is, to contrast with congenital microcephaly. Although primary is usually used to define isolated genetic microcephaly, it has been used to contrast acquired or secondary microcephaly. These terms are avoided in this section. We are on the threshold of a new understanding of microcephaly, and the driving forces are careful application of neuroimaging9–11 and the mapping and cloning of genes related to the development of the brain.12,13 Some of the most exciting progress has been in the area of isolated microcephaly without evident acquired cause. In 1998 Barkovich et al.9 reported that most children with the isolated finding of an OFC  3 SD at birth had fewer than the normal number of gyri, sulci about one-half the normal depth, absent tertiary sulci, and a normal or decreased cortical thickness. At first, this was called microlissencephaly; but Hanefeld10 pointed out that this was an inappropriate term and suggested oligogyric microcephaly, which is now used interchangeably with microcephaly with simplified gyral pattern (MSG).11 Barkovich et al.9 distinguished a subset of patients (group 1) who, despite their severe microcephaly and MSG, had a relatively mild clinical course with a normal newborn examination, normal tone or mild corticospinal tract signs, and uncommon and readily controlled seizures. Difficulties with feeding and weight gain were frequent but early milestones were mildly delayed and many walked by 24 months and developed some language ability. Other children with MSG (originally groups 2–5; now group 211) have a much more severe clinical course and their magnetic resonance imaging (MRI) scan may show delayed myelination, hypoplasia of the brainstem or cerebellum, or increased extra-axial spaces. These children present as newborns with abnormal neonatal reflexes, spasticity, poor feeding and failure to thrive. The subsequent course is one of severe spastic quadriplegia, intractable seizures, and profound mental retardation. Agenesis of the corpus callosum may occur in both groups. Based on his personal review of unpublished ‘‘data on several of the families studied’’ Dobyns11 believes that the families mapped with autosomal recessive isolated microcephaly (traditionally primary microcephaly) correspond to his Group-1-MSG. Furthermore, he considers that the time has come to make this a diagnosis of inclusion, rather than exclusion, and proposes a birth OFC of  3 SD, a low sloping forehead, MSG brain pattern, and lack of extracranial malformations as diagnostic criteria. He suggests that parents of these children be counseled that there is a 25% recurrence risk. Although this conclusion may be correct, and there are families with clear autosomal recessive inheritance,9,14,15 not all authors would go that far, and this author does not consider the current published data adequate to draw any conclusion. In the original paper9 there were 17 patients from 14 families and no data were provided that would allow for a segregation analysis. Three cases were from one highly inbred family and another two were siblings. Mochida and Walsh12 distinguished what they called microcephaly vera, in which the brain is the only affected organ and it is small but with normal architecture. On pathologic study the architecture may be normal or show depletion of cortical layers II and III and of the germinal zone near the ventricles. The clinical course is really not distinct from Group-1 MSG, and the overlap between the two conditions and their respective relationship to the mapped and cloned microcephaly genes13,16,17 remains to be clarified. Microcephaly vera has also been used to describe patients whose MRI is compatible with MSG.18 In the interim it is unlikely that any classification of microcephaly will withstand the test of time, but Fig. 15-4 provides

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Neuromuscular Systems

Fig. 15-3. Vertical and lateral views of opened cranium of a microcephalic fetus showing severe brain hypoplasia and external hydrocephaly. Note the absence of olfactory nerves and a central cleavage line on the cerebral surface in the vertical view. The incised falx is retracted posteriorly. The absence of gyral development is noted in both views (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

a framework on which to approach the diagnosis of microcephaly. By considering these categorical items individually, one is unlikely to overlook important details of history and physical examination. And, as molecular information becomes more directly applicable, the approach will allow appropriate selection of cases for study. To determine the precise etiology of a case of microcephaly remains one of the most challenging tasks in medicine. The patient is often not seen until some time after birth, when microcephaly is recognized during an investigation of an associated developmental delay and by which time much important historical information has been lost and some laboratory tests are no longer appropriate. The need for a detailed family history is axiomatic. The history includes a careful search for consanguinity and measurement of the head size of the parents and siblings.

Standard inquiries with respect to the specific pregnancy should include its planning; any attempts to terminate; the timing and quantity of the consumption of alcohol, medications, and other drugs; chronic and acute maternal illnesses, fevers and rashes; and any other intervention or treatment. Information about the activity of the fetus and any complications of labor and delivery may also be useful. The timing of the onset of microcephaly is an important detail. While routine obstetric ultrasound more and more provides prenatal information about head growth, it is ironic that the simple measurement of birth OFC is often missing from the newborn examination. The simple fact that the head was small at birth can eliminate perinatal and postnatal etiologies. However, it must be stressed that the converse does not hold; a normal birth

Fig. 15-4. A categorical pathway that may aid the diagnosis/classification of patients with microcephaly. Solid line could be an example of isolated (pure microcephaly) with affected sibs. Dotted line might represent an infection such as rubella.

Brain

OFC does not eliminate either genetic microcephaly or a prenatally acquired cause. Careful examination of the patient may uncover minor anomalies (such as disturbed hair patterning) that could be evidence of an early prenatal disturbance; or a particular appearance with associated anomalies may suggest a specific syndrome. The details of further investigations will depend on the presence or absence of historical clues and/or associated malformations. Further investigation may include laboratory testing for maternal phenylketonuria, prenatal infection, and chromosome aberrations. Neuroimaging is important, both to detect major intracranial malformations and to better determine the nature of the small brain. In one recent study of non-syndromic microcephaly, 62% of the patients had an abnormal neuroimaging study, and the presence of a detectable abnormality correlated with the severity of the developmental delay.19 When the OFC was between 2 and 2.99 SD, 43% of patients had an abnormality demonstrated on scanning, as compared with 80% when the OFC was  3 SD. It has long been known that an important proportion of isolated, unexplained microcephaly is genetic, most often autosomal recessively inherited. Several authors have attempted to identify clues that will help to pinpoint genetic microcephaly cases, and this information will remain germane until genetic testing becomes available to clinical practice, and even then may help to select appropriate cases for study. Penrose20 noted decreased skull height and width, short stature, prominent ears, a normal face, stooped posture, furtive movements, and a lack of associated sensory or motor signs. Baraitser21 stressed that the microcephaly was usually congenital, confirmed the clinical characteristics, and noted some sparing of personality. Qazi and Reed22 emphasized that consanguinity, increased pregnancy wastage, negative history, presence at birth (50%), lack of significant neurologic problems, relatively normal early milestones, and a higher rate of subnormal intellect in first-degree relatives were associated with the familial cases. Sujatha et al.23 used segregation analysis to support the validity of these criteria, although their study suggested that not all patients thus defined have autosomal recessive microcephaly. Certainly isolated genetic microcephaly occurs in the absence of a characteristic appearance and in the absence of any specific personality.22,24 Equally important, patients whose clinical features include paresis, seizures, visual disturbances, and lack of speech and ambulation may have a genetic basis for their condition. Brandon et al.24 documented a high rate of spastic diplegia in genetic microcephaly. Tolmie et al.25 found spastic quadriplegia, seizures, and profound retardation in five of nine families with isolated genetic microcephaly. Thus, while craniofacial appearance, lack of neurologic signs, negative history for etiologic events, and microcephaly at birth may suggest a genetic etiology, they are not proof of such a cause. Furthermore, a significant neurologic impairment or a normal OFC at birth does not rule out a genetic cause. This heterogeneity extends to autosomal dominant isolated microcephaly. Haslam and Smith26 first reported four families with normal stature, indistinct phenotype, and borderline to mild retardation. Since then similar families, as well as those with more severe retardation and with normal intellect, have been reported27–29; they serve to emphasize the need to examine family members and to be cautious when discussing prognosis. It is probable that moderate and more severe retardation occur on an autosomal dominant basis but are genetically lethal. The prenatal diagnosis of microcephaly is subject to the ability to accurately measure and define a small brain when

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present, and the gestational timing at which the microcephaly occurs. Cervenak et al.30 in a study of 24 pregnancies found a very poor correlation between a biparietal diameter of  3 SD, measured a few days before term, and the presence of postnatal microcephaly. However, there were no false-positive predictions when the OFC was less than 4 SD, the head perimeter (HP) less than 5 SD, the HP/abdominal perimeter less than 3 SD, or the femur length to HP greater than þ3 SD. Errors in gestational dating or the occurrence of intrauterine growth retardation (IUGR) can also compromise diagnosis. A careful search should be made for additional morphologic anomalies of the brain, and the finding of large subarachnoid spaces, a rudimentary ventricular shape,31 or shortness of the frontal lobe32 may predate measurable microcephaly. A discrepancy of signal size generated from vertebral versus carotid branches on transvaginal sonography with power Doppler was reported in two cases31 but not confirmed in two others,33 perhaps reflecting etiologic heterogeneity. Fetal MRI may add further definition where ultrasound has raised an initial concern.34 The major difficulty with the prenatal diagnosis of microcephaly is that often it does not become apparent until after the second trimester and thus cannot be detected until well into the third trimester.35,36 The distribution of causes of microcephaly that is detected prenatally is likely to vary with gestation and family history, and to be different from that ascertained at birth. Indeed, den Hollander et al.37 found that 25 of 30 prenatal cases were part of a complex problem, thus pointing to the need for a careful wholebody fetal examination. Table 15-1 lists a large number of conditions with microcephaly and associated malformations. Conditions in which there is usually a significant associated brain malformation (e.g., cerebellar hypoplasia, lissencephaly) are included under the specific malformation entry and not under microcephaly. Similarly, conditions in which there is a clear postnatal abiotrophy or metabolic disease are excluded. For most syndromes little is known about the underlying structure of the brain. Etiology and Distribution

Anything that impairs growth and integrity of the brain from the time of its early development to the end of the rapid postnatal growth period may lead to microcephaly. The causes are myriad, and the same agent may act in different ways at different times to cause microcephaly. For example alcohol can act to cause both neuronal migrational abnormalities and excess apoptosis. Developmental and degenerative causes of microcephaly can be both genetic and environmental (extrinsic); but, it can be generally assumed that evidence of the destruction of a normally developed brain is not genetic. However, if fetal inherited thrombophilias are proven to cause vascular disruptive changes, then even this rule will have its exception.528 Developmental problems may be suspected if there are associated extracranial malformations, or if the brain shows an associated primary anomaly such as holoprosencephaly, MSG, or is simply small with a normal appearing architecture. Microcephaly with extracranial anomalies may lead to the recognition of a known or unknown genesis syndrome (Table 15-1). Developmental microcephaly may be intrinsic (in most cases genetic) to the embryo or be extrinsic resulting from a variety of potential agents. At this time it is not clear whether all cases of MSG and microcephaly vera are genetic or whether there are non-genetic phenocopies. Twelve of the 14 families with MSG reported by Barkovich et al.9 had no positive family history, but the number of

Table 15-1. Syndromes in which microcephaly has been reported Syndrome

Prominent Features

Causation Gene/Locus

Abidi: X-linked mental retardation38

Variable short stature, prominent ears, cleft lip/palate, small testes, moderate to severe mental retardation

XLR Xq12-q21

Ablepharon-macrostomia39

Virtual to complete absence of upper and lower lids, failed lip fusion, abnormal nasal alae, corneal damage, absent lanugo, hypoplastic nipples, some cases with cryptophthalmos, absent zygomatic arch, abnormal genitalia

AR (200110) One father with minor signs

Absent abdominal musclesmicrophthalmia40

Wide sutures and fontanel, telecanthus, epicanthus, flat nose, low-set small ears, cleft palate, narrow chest, bifid sternum, low umbilicus, hypoplastic genitalia, joint laxity

AR

Acanthosis nigricans-short stature41

IUGR, prominent long nose with high bridge, small mandible and ears, hearing loss, small hands and feet, cryptorchidism, dislocated radial heads

AR or XLR

Achalasia-adrenocorticalalacrima42

In addition to this known association, brothers displayed microcephaly, ataxia, delayed development, and optic atrophy

AR (231550) 12q13

Achalasia-microcephaly43

Moderate to severe mental retardation, achalasia leading to pulmonary complications that respond to treatment

AR (200450)

Acrocraniofacial-Kaplan type44

Telecanthus, downslanting palpebrae, ptosis, ear anomalies and pits, high nasal bridge, cleft palate, micrognathia, broad tips to digits, proximal thumb, developmental delay. One of two sibs microcephalic.

AR (201050)

Acrofacial dysostosis-Catania type45

IUGR, postnatal growth and mild developmental retardation, malar hypoplasia, tall forehead, widow’s peak, carious teeth, short 1st and 5th fingers, interdigital webbing

AD (101805)

Acrofacial dysostosisPalomeque type46

IUGR, postnatal growth and severe mental retardation, severe maxillary and mandibular hypoplasia, downslanting palpebrae, colobomata, abnormal ears, significant four-limb anomalies with pedunculated thumbs

Unknown

Acrometageria47

Single patient with short stature, beaked nose, skin atrophy on limbs and poor subcutaneous fat, fine thin hair, hyperextensible joints. No excess chromosome breakage. Stated as microcephalic but no measurements reported.

Unknown

Acro-renal-ocular-thumb48

Variable eye anomalies including colobomata; thumb changes ranging from limited flexion and hypoplastic tip to preaxial polydactyly/severe hypoplasia; mild renal anomalies; OFC inconsistently recorded; one of three measured at 3rd centile

AD (102490)

ACTH deficiency-face dysmorphia565

Prenatal and postnatal growth failure, moderate mental retardation, severe micrognathia, cleft palate, atrial septal defect, hypospadias, hearing loss

Unknown

Adducted thumbsmyopathic face49

Craniosynostosis, mental retardation, myopathy, swallowing problems, palatal anomalies, downslanting palpebrae, ophthalmoplegia, limited movement of large joints, early death

AR (201550)

Adrenal hypoplasia-growth hormone deficiency-skeletal anomalies50

Developmental delay, partial androgen resistance, early dental eruption, flat nasal bridge, abnormal helices, high palate, short limbs, delayed bone age, hip dysplasia

Unknown

Albinism-digital anomalies51

Sloped forehead, oculocutaneous albinism, deficient/hypoplastic distal fingers and great toe

AR (203340)

Albinism-immunodeficiencymicrocephaly52

Tyrosine positive oculocutaneous albinism, granulocytopenia, intermittent thrombocytopenia, protruding midface, unusual hair, mild mental retardation

AR (203285)

Alcohol, prenatal53

IUGR, postnatal growth failure, developmental delay, fine motor dysfunction, short palpebrae, maxillary hypoplasia, short nose, thin and smooth upper lip, small distal phalanges

In utero exposure to alcohol

Al-Gazali-leprechaun-like54

Insulin resistance, hypoglycemia, variable growth pattern, some microcephalic, hyperteloric, low nasal bridge, thick lips, prominent nipples, large genitalia, large extremities, brachydactyly

AR (246200)

Alopecia-congenital seizures55

Intractable neonatal seizures, hypertonia, hyperreflexia, profound psychomotor delay, sparse hair follicles, mild hyperkeratosis, gyral changes, reduced cortical neurons

AR

Alopecia-keratosis follicularis-dwarfism56

Square face, micrognathia, long philtrum, delayed teeth, severe psychomotor delay, seizures

XLR

Alopecia-mental retardationMoynahan57

Universal atrichia, any hair at birth soon lost, short stature, delayed puberty, severe retardation

AR

Alopecia-shawl scrotum58

Postnatal onset sparse scalp hair, eyebrows, and lashes; protruding ears; hair follicles containing hair remnants with surrounding fibrosis

AR

Alopecia-skeletal anomalies59

IUGR, growth failure, turricephaly, prominent nose, large ears, contractures, clinodactyly, short middle phalanges, vertebral and other bone fusions, mental retardation

AR (203550)

(continued)

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Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Upswept hair, bitemporal narrowness, hypoplastic supraorbital ridges, eyebrow flare, hypertelorism, high/cleft palate, micrognathia, low and rotated ears, short stature, delayed development

AR? (600325)

Amish-lethal microcephaly17

Congenital microcephaly, possible MSG type, and lethal within a year. Isolated marked elevation of 2-ketoglutaric acid when well. 1/500 Amish births

AR (607196) SLC25A19, 17q25.3

Anemia-abnormal appearance-short stature61

Growth and developmental delay, ptosis, epicanthus, mid-face hypoplasia, small jaw, cupped ears, small penis, delayed puberty

AR?

Angelman62

Broad-based gait, arms abducted, unprovoked laughter, seizures, vertical skull base, occipital groove, macrostomia, prognathia, tongue protrusion, moderate to severe developmental delay

Mat del 15q11-q13 (75%) Pat UPD (5%) UBE3A (<5%)

Anophthalmia-postnatal growth failure63

IUGR, FTT, anophthalmia or related eye anomalies, large fontanels, abnormal ears, hypertelorism, over-riding digits, hypotonia, small genitalia, developmental delay, consanguinity

AR

Anonychia congenitamicrocephaly64

Normal intelligence and appearance; absent to very hypoplastic nails; variable wide-spaced teeth. Single family.

AR?

Anterior chamber cleavagecerebellar hypoplasia65

Postnatal microcephaly, dense hair, broad nose with low bridge, wide cupid-bow mouth, shield chest, tracheostenosis, congenital hypothyroidism, cerebellar hypoplasia, anterior chamber eye anomalies

Unknown (601427)

Apple peel atresia-ocular anomalies-microcephaly66

Marked microcephaly, developmental delay, variable eye anomalies include anterior chamber and microphthalmia, apple peel jejunal atresia

AR (243605)

Armendares: retinitis pigmentosacraniosynostosis67

Postnatal growth delay, craniostenosis, atypical retinitis pigmentosa, micrognathia, ptosis, epicanthus, telecanthus, short nose, clinodactyly

Unknown

Arthrogryposis-jaw and finger contractures68

Microstomia, micrognathia, groove above chin, high palate, large ears, hand contractures, metacarpophalangeal subluxation, talipes equinovarus, dislocated hip

AD (121070)

Asphyxiating thoracic dysplasia variant69

Thoracic and pelvic changes like Jeune asphyxiating thoracic dysplasia, asymmetric cupped ribs, some bony changes cleared, mental retardation (possibly chance concurrence of microcephaly/MR with Jeune)

AR

Asymmetric crying face70

Developmental delay and postnatal growth failure in a child whose mother and maternal grandmother were also microcephalic with asymmetric crying face, and whose maternal aunt had microcephaly, asymmetric crying face, mental retardation, and cleft palate

AD (125520)

Ataxia-ocular telangiectasiachromosome instability71

Onset of psychomotor regression in infancy; ataxia, dysarthria; increased sporadic chromosomal breaks, especially chromosome 7; timing of onset of microcephaly unclear

Unknown

ATR-1672

Alpha-thalassemia, macro- or microcephaly, broad forehead, hyperteloric, low nasal bridge, irregular teeth, genital anomalies

AD (141750) 16p13.3

ATR-X73

Flat face with low nasal bridge, hypertelorism, epicanthus, inverted ‘‘V’’ upper lip, large mouth, small teeth, everted lower lip, short stature, genital anomalies, hemoglobin H disease with HbH bodies

XLR (300032) XNP, Xq13

Ataxia-short stature-DNA repair74

Microcephaly and growth failure from infancy; moderate mental retardation; initially clumsy, later onset of dysarthria, nystagmus, and ataxia. Decreased DNA excision repair.

Unknown

Baller-Gerold-RothmanThompson-like75

IUGR infant with overlapping features of the syndromes; parents cousins; unusual appearance, short forearms, obesity, hypoplastic thumbs, craniostenosis

AR?

Bartsocas-Papas: popliteal pterygium76

Ankyloblepharon, corneal ulcers, syngnathia, cleft lip/palate, nasal hypoplasia, absence/syndactyly of hands and feet, pterygia, genital anomalies, highly lethal

AR (263650)

Battaglia: coarse face-joint laxity-seizures77

Severe developmental delay, somewhat coarse face, full lips, everted lower lip, initial hypotonia, abnormal posture, hip and knee flexion, lax joints, delayed bone age and thin diaphyses

AR?

Bavinck: eye anomalies-short stature78

Short stature, mild retardation, prominent and narrow forehead, epicanthus, cataract, other eye anomalies, abnormal external ears, short nose with thick alae, small hands

AD

Bawle-Horton: microcephaly27

A number of families have autosomal dominant microcephaly, sometimes with additional findings of unknown specificity; variable mental retardation, soft facial signs, short stature

AD

Aminopterin-like

60

(continued)

475

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Benzodiazepine, prenatal

Low nasal bridge, short nose, short palpebral fissures, epicanthus, small mandible, flat upper and full lower lips, cleft/high palate, developmental delay, mild cortical dysplasia

In utero exposure to benzodiazepine

Bindewald: Fallot spectrummild dysmorphia80

Tetralogy of Fallot/double outlet RV, severe growth and mental retardation, hirsute forehead, large ears, micrognathia, mild 2-4 toe syndactyly, plantar creases

AR (601127)

Blepharophimosis-epicanthus inversus-microcephaly81

Blepharophimosis, ptosis, epicanthus inversus; the BPES syndrome (types I and II) are due to FOX2 mutations. Cases with microcephaly may be a contiguous gene syndrome.

Del 3q23

Blepharophimosis-radial hypoplasia-cardiac82

Hypertelorism, blepharophimosis, micrognathia, hypoplastic left heart, camptodactyly, radial hypoplasia, developmental delay

Unknown

Blepharophimosis-radioulnar synostosis83

Microcephaly, blepharophimosis, ptosis and radioulnar synostosis in two unrelated patients

Unknown

Bo¨rjeson-ForssmanLehmann84

Central obesity, narrow palpebrae, large ears, short stature, moderate to severe retardation, kyphosis, short neck, post-pubertal hypogonadism

XLR (301900) PHF6, Xq26-q27

Bowen-conradi85

Lethal syndrome with IUGR, micrognathia, prominent nose, rocker-bottom feet, joint restriction, clouded cornea, most cases reported in Hutterites

AR (211180)

Brachy/camptodactyly-short stature86

Short stature, hypotelorism, maxillary hypoplasia, micrognathia, hamate-capitate and semilunar-pyramidal fusion, 2-5 distal metacarpal hypoplasia, proximal phalanges very underdeveloped

Unknown

Brachycephalosyndactylycataract87

Postnatal onset microcephaly, normal IQ, hypertelorism, ptosis, microcornea, coloboma, downslanting palpebrae, malar flatness, retrognathia, low and rotated ears, linear skin depigmentation, duplicated hallucal nails

Unknown

Brachydactyly A2-diabetes88

Hypoplastic thumbs and halluces, short index fingers with absent middle phalanges, learning problems, small genitalia, delayed puberty

AR (211369)

Brachydactyly-nail dysplasia89

Type B brachydactyly, coarse face with synophrys and hirsutism, crowded teeth, abnormal helices, kyphosis, variable syndactyly of toes and fingers, mental retardation

XLD probable (603396)

Brachyphalangy-tibial aplasia-polydactyly90

Scalp defect, short palpebrae, blocked nasolacrimal ducts, small nose, small jaw, cleft ear lobules, preauricular tags, abnormal fingers, postaxial polydactyly of feet

Unknown

Braeger: ischiadic hypoplasiapolydactyly91

IUGR, developmental delay, hypertelorism, epicanthus, short nose, hypospadias, four-limb postaxial polydactyly, hypogammaglobulinemia, small ischia. Single case, consanguinity

Unknown

Branchio-oculo-facial92

Microcephaly and delayed development inconsistent, prominent philtral pillars, broad nose and nasal tip, ocular coloboma, branchial clefts, post auricular linear scar

AD (113620)

BRESHECK93

Microhydrocephaly with fused thalami, growth and mental retardation, alopecia, scaling skin, Hirschsprung, cleft palate, renal anomalies, microphthalmia

AR or XLR

Brittle cornea-joint hyperextensibilty94

Similar to ED VI. Blue sclera, keratoglobus with risk of globe rupture, lax joints, normal lysyl-hydroxylase. Sister in a sib-pair with consanguineous parents was microcephalic

AR (229200)

Buntix: microbrachycephalyradioulnar synostosis95

Short stature, short philtrum, pigmentary retinopathy, radioulnar synostosis. Consanguinity

AR

Burton: microcephaly-short stature96

Normal to borderline intelligence, simple protruding ears, nystagmus/esotropia, stature 3 to 6 SD

AD (156580)

Calcified basal gangliamicrophthalmia308

Mild mental retardation, microphthalmia, cataract, peaked nose with prominent root, high palate, micrognathia; single case

Unknown

CAMFAK97

Congenital cataracts and microcephaly, hypertonia, progressive kyphoscoliosis, hip dysplasia, demyelinization similar to Cockayne.

AR?

Camptodactyly-Guadalajara type98

IUGR, restriction at elbows and interphalangeal joints, short stature, wide forehead, epicanthic folds, telecanthus, microphthalmia, short and anteverted nares, abnormal pinnae, frontal and ethmoid sinus agenesis, bony anomalies

AR (211910)

Canescence-joint laxity99

Profound retardation, ligamentous laxity, thin skin, short stature, droopy lower eyelids, prominent eyes, premature graying

AR

Carbamazepine, prenatal100

Generally uncommon mild findings of growth delay, upslanting palpebrae, short nose, and hypoplastic nails; more severe reports of spina bifida, microcephaly, developmental delay; one case of radial microbrain

Prenatal exposure

79

(continued)

476

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Carey-Fineman-Ziter

Robin sequence, Moebius phenotype, muscle hypoplasia, downslanting palpebrae, ptosis, low and rotated ears

AR (254940)

Carpenter-Waziri102

Coarse facial appearance, full eyebrows, depressed nasal bridge, open mouthed, widely spaced teeth, short stature, moderate developmental delay, brachydactyly with wide distal phalanges

XLR (300032) XNP, Xq13

Castriota-Scanderberg: acrodysplasia103

IUGR, proportionate short stature, absent/hypoplastic clavicles, poor pubic ossification, hypoplastic/absent clavicles, brachydactyly

Unknown

Cataracts-aberrant oral frenula104

Growth proportionately <3rd centile, epicanthus, cataracts, ptosis, upslanting palpebrae, small and anteverted nose, multiple oral frenula; borderline to normal intelligence

AD

Cataract-autonomic neuropathy105

Microcephaly, narrow forehead, congenital cataracts, progressive autonomic dysfunction with variable age of onset of gut motility and hypotensive problems, sensory and motor involvement, severe developmental delay

AR

Cataracts-renal tubular necrosis106

Congenital cataracts, early onset seizures, significant developmental delay, spongy breakdown of gray and white matter, cerebellar dysplasia, histiocytic infiltration and necrotic foci in kidneys

AR (218900)

Caudal appendage-short terminal phalanges107

Monozygous twin with ‘‘tail,’’ short stature, short terminal phalanges, mixed deafness, developmental delay, initial normal OFC, arrested hydrocephalus, then microcephaly

Unknown

Cerebellar ataxia-optic atrophy108

Congenital spasticity, ataxia and optic atrophy, severe mental retardation, growth failure, abnormal osmophilic skin EM pattern

AR

Cerebellar hypoplasiaendosteal sclerosis109

Developmental delay, oligodontia, small teeth, congenital hip dislocation, sclerosis of long bones and vertebrae, stenosis of medullary space

AR

Cerebral aneurysmscalcification110

Short stature, delayed development, seizures, symmetric calcification of basal ganglia, thalami, and dentate, pulmonary emphysema, cirrhosis. Three male sibs, two microcephalic

AR or XLR

Cerebro-arthro-digital111

Extreme IUGR, microcephaly or hydrocephaly, fat cheeks, short upturned nose, small and inturned mouth, bud-like digits, hypoplastic to absent nails, sacral agenesis and skeletal anomalies

Unknown

Cerebro-costo-mandibular112

Micrognathia, cleft palate, glossoptosis, rib gaps, absent 12th rib, variable developmental delay and microcephaly (11/28), high mortality; variable inheritance

Variable (117650)

Cerebro-oculo-facioskeletal113

Prominent nasal root, large ears, deep-set eyes, narrow palpebrae, microphthalmia, cataract, camptodactyly, progressive postnatal growth failure, inanition, death in infancy

AR (214150) CKN2, 10q13 XPG, 13q33 EM9, 19q13.2-q13.3

COFS-osteopetrosis114

Congenital contractures, hypotonia, postnatal growth failure, prominent nasal bridge, micrognathia, muscular degeneration, early death

Unknown

Cerebro-oculo-genital115

Microphthalmia, corneal opacity, severe developmental delay, small phallus, hypospadias, marked microcephaly or hydranencephaly, absent corpus callosum

XLR (309800)

Cerebro-oculo-skeletalrenal116

Optic atrophy, absence of retinal vessels, seizures, growth and developmental delay, elongated clavicles, cupped ribs, mild platyspondyly, rhizomelia, schizencephaly, nephritis/nephrosis

Unknown (200995)

Cerebro-renal-digital117

Pterygium coli, postaxial polydactyly hands and feet, dysplastic kidneys, vaginal agenesis, polysplenia (family ‘‘G’’ of report)

AR

Ceroid-lipofuscinosiscongenital118

Rare conatal presentation of microcephaly and neuronal ceroid-lipofuscinosis, seizures, hyperactive reflexes

AR (204200)

Cervical ribs-preaxial polydactyly119

Male proband with urethral obstruction, congenital heart, IUGR, anal atresia, micropenis, spinal defects; female sibs and mother with cervical ribs, missing ribs; one with Sprengel anomaly

XLD? (601389)

Cervical vertebral fusionshort stature120

Mild retardation, sloping forehead, beaked nose, ptosis, prominent eyes, low-set ears, malar hypoplasia, micrognathia, funnel chest; cervical spine fusion, instability, compression; consanguinity

AR (251250) XLR

Choanal stenosis-hypotheliabranchial fistulae121

Bilateral choanal stenosis, broad forehead, prominent nose, branchial fistulae, lacrimal duct stenosis, hypothelia, hearing loss, growth and speech delay; consanguinity

AR?

Choanal stenosis-short stature122

Short nose, epicanthus, long philtrum, thin upper lip, atrial and ventricular septal defects, developmental delay

AR (214800)

101

(continued)

477

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Chondrodysplasia-joint dislocations123

Growth failure, joint dislocations, club feet, kyphoscoliosis, finger flexion, prominent eyes, low nasal bridge, glaucoma, epiphyseal changes

AR (215200)

Chondrodysplasia-pseudohermaphroditism124

IUGR, growth retardation, hypoplastic irides, optic disc colobomas, micromelia, narrow chest, hypoplastic scapulae, trapezoid vertebrae, short hand bones. One case a 46,XY female with cerebellar hypoplasia

AR? (600092)

Chondrodysplasia punctatadel Xp22.32125

Nasal hypoplasia, generalized ichthyosis, mild mental retardation, behavioral difficulties, stippled epiphyses, mixed hearing loss. Described as mildly microcephalic

XLR Xp22.32

Chorioretinopathymicrocephaly-AR126

Microphthalmia, chorioretinopathy, optic atrophy, short stature, cutis marmorata, mental retardation

AR (251270)

Chorioretinopathymicrocephaly-AD127

Microphthalmia, persistent embryonic remnants, chorioretinal dysplasia, myopic astigmatism, developmental delay

AD (156590)

Chromosome abnormalities128

Microcephaly is a nonspecific finding in a large number of chromosome deletion and/ or duplication syndromes

Chromosome imbalance

Chromosome instabilityMaraschio129

Primary amenorrhea, Wolff-Parkinson-White, follicular thyroid adenoma, slightly bulbous nose, small jaw, low IgG subclasses, high level of spontaneous chromosome aberrations

AR?

Chromosome instabilityWegner130

Normal development, small jaw, epicanthus, high palate, areas of depigmentation, anal stenosis/atresia, low IgA level, defective T-cells, cellular hypersensitivity to x-rays and bleomycin

AR (251260)

Chudley: facial-obesityhypogonadism131

One of four patients microcephalic; moderate to severe mental retardation, short stature, bitemporal narrowing, almond-shaped palpebrae, anteverted nares, inverted ‘‘V’’ upper lip, macrostomia, hypogonadism

XLR (309490)

Cleft lip/palate-hypodipsic hyponatremia132

Single case. Bilateral cleft lip/palate, possible hypothalamic defect with hypodipsic hyponatremia, hyperlipemia, microcephaly, growth and developmental delay

Unknown

Cleft mandible-athetosis133

Prominent forehead, small midface, prominent mandible with cleft and absent incisors, preauricular tag, coloboma, hypotonic becoming athetoid

Unknown

Cleft lip/palate congenital megacolon134

Cleft lip and/or palate, mental retardation, variable microcephaly, short stature, other variable minor anomalies

AR

Coffin-Siris135

Growth failure, scalp hypotrichosis, body hypertrichosis, fingernail hypoplasia, absent/hypoplastic terminal phalanx, developmental delay, hindbrain anomalies

AD? (135900)

Coffin-unusual facearthritis136

Growth and developmental delays, small and anteverted nose, long and smooth philtrum, thin upper lip, probable sensorineural deafness, onset arthritis in infancy

AR

Cohen137

Mid-childhood-onset obesity, mental retardation, high nasal bridge, downslanting fissures, prominent nasal root, large ears, chorioretinal dystrophy, narrow hands and feet

AR (216550) COH1, 8q22-q23

Colobomas-clefting-mental retardation138

Microbrachycephaly and short stature, colobomas of iris and retina, ptosis, cleft lip and palate, developmental delay

AR or XLR

Colobomatous microphthalmia-cerebellar hypoplasia139

Microcephalic at birth, microphthalmia, iris coloboma, cataracts, optic nerve hypoplasia, high palate, cerebellar hypoplasia. Single case, parental consanguinity

AR?

Congenital contracturesshort stature314

Severe developmental delay, short stature, severe scoliosis, congenital contractures, myopia, ptosis, beaked nose, dental anomalies

Unknown

Congenital heart defectsskeletal changes140

Growth failure, hypotonia, delayed development, seizures, aortic hypoplasia, atrial and ventricular septal defects, micropenis, redundant forehead and neck skin, postaxial polydactyly

AR or XLR

Congenital heart defectsunusual face141

Delayed growth and development, seizures, prominent ear lobes with pits/creases, anteverted nares, high palate, lacrimal duct stenosis, thyroglossal cyst, tetralogy of Fallot, short thick feet

AR or XSLR

Congenital muscular dystrophy-cataracts142

Mild developmental delay, slowly progressive merosine positive dystrophy, normal neuroimaging, abnormal ERG, hyperpigmented fundus

AR

Congenital myopathy-bullous skin eruption143

Myopathy, bullous skin eruption, secretory diarrhea, zinc deficiency, postnatal growth failure, mild developmental delay, hearing loss, congenital heart defect

AR

Congenital progeria: PettyWiedemann144

IUGR, congenital microcephaly, wide sutures, persistent fontanel, sparse hair, progeroid face, poor subcutaneous fat, lax and wrinkled skin, delayed growth, normal mental development

Unknown

(continued)

478

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Conotruncal heartmicrophthalmia145

Microbrachycephaly reported (case 2) but not documented, minor ear anomalies, unusual appearance (no photos), small mouth, microphthalmia, tetralogy of Fallot or truncus arteriosis

AR

Corneal dystrophy-ichthyosis nigrans146

Annular corneal dystrophy, ichthyosis nigrans, myopia, photophobia

Unknown

Cortada: acromesomelic anomalies-dental arch contraction147

Contracted dental arches, hypodontia, bowed radii, hypoplastic ulnar styloid, acromicria, small feet, hypotelorism, epicanthus, profound retardation

AR

Cranioectodermal dysplasiaSensenbrenner148

Dolichocephaly, frontal bossing, sparse and fine hair, dental anomalies, marked brachydactyly, short narrow thorax, pectus excavatum, one case microcephalic and one macrocephalic of 14

AR (218330)

Craniofacial dysostosisdiaphyseal hyperplasia149

Rhizomelic short stature, brachydactyly, hypoplastic malar region, prominent eyes, small mandible, large fontanel closes early, fractures, thick cortex of long bones, thin skull, Wormian bones

AD (122900)

Craniosynostosis-absent fibula150

Coronal synostosis, lacrimal duct stenosis, intraabdominal testes, short stature, reduced span, microbrachycephaly, hypodontia, normal intelligence

AR (218550) XLR

Craniosynostosis-anal anomaly-porokeratosis151

Coronal synostosis, imperforate/anterior anus, hypospadias; postnatal onset of spreading porokeratosis; no FGFR1, 2 or 3 mutations

AR or XLR (603116)

Craniosynostosis-colobomasplit hand152

Upslanting palpebrae, paranasal folds, high palate, micrognathia, iris colobomata, syndactyly toes 2-5, asymmetric split hand, perineal hypospadias, severe retardation

Unknown

Craniosynostosishumeroradial-aplastic thumbs153

IUGR, marked microcephaly, ridged sutures, prominent eyes with short palpebrae, micrognathia, elbow and knee flexion contractures, absent thumbs, bilateral humeroradial synostosis, hydranencephaly

Unknown

Craniosynostosis-limb reduction-clefting154

Mid facial hypoplasia, cleft lip/palate, auricular anomalies, hypertelorism, radial/ fibular aplasia, short stature (patient looked similar to SC-phocomelia, no chromosome puffing noted)

AR?

Crouzon-marked microcephaly155

U-shaped palate, shallow orbits, posteriorly rotated ears, glaucoma, craniostenosis and growth failure (facial appearance supports primary suture involvement, possibly same as Crouzon)

Unknown

Cutaneous hypo- and hyperpigmentation-spastic paraparesis156

Mental retardation, gray hair as infant, hypopigmented patches, freckles and cafe-aulait spots, progressive spastic paraparesis, muscle wasting, long nose, retrognathia

AR (270680)

Cutis laxa (male lethal)157

Delayed growth and development, lax ligaments, dislocated hips, open fontanel, downslanting palpebral fissures, urinary tract anomalies; all 14 cases so far are female

AR (219200)

Cutis laxa-short umbilical cord158

Initial increased OFC becoming microcephalic, marked cutis laxa and hypertonia at birth diminishing with time, epicanthus, telecanthus, low nasal bridge and anteverted nares. Single case

Unknown

Cutis verticis gyrata-retinitis pigmentosa159

Primary cutis verticis gyrata, prominent supraorbital ridges, hypertelorism, progressive RP, cataracts, sensorineural deafness, kyphoscoliosis, developmental delay

XLR or AR (605685)

Cytomegalovirus, prenatal infection160

Asymptomatic to severe CNS changes. May include IUGR, microcephaly, intracranial calcification, hydrocephaly, chorioretinal changes, deafness

Prenatal infection

Czeizel-Lowry: cataractmicrocephaly161

Mild microcephaly, postnatal nuclear cataract, severe developmental delay, Pertheslike hip changes; CT showed bilateral symmetric hypodensities in pallidum and corpus striatum

AR (212540)

Da Silva: mental retardationmicrocephaly162

Severe mental retardation, postnatal growth failure, preauricular skin tag, camptodactyly, nasal skin tag, club feet, increased tone, pulmonary infections, hypoplastic corpus callosum, lethal

AR

Deafness-male pseudohermaphroditism163

IUGR, hypertelorism, ptosis, small nose, microtia, micrognathia, cleft palate, hypospadias, small penis, shawl scrotum, mental retardation, feeding and respiratory problems

AR

De Barsy164

IUGR, growth failure, progeroid appearance, large ears, clouded cornea, thin lips, cutis laxa and atrophic skin, hypotonia, lax small joints, mental retardation

AR

De Lange165

IUGR, synophrys, short nose, anteverted nares, prominent philtrum, thin upper lip with downward ‘‘V’’ at midpoint, proximal thumbs, ulnar ray defects, severe retardation usual, milder form recognized

AD (122470) NIBPL, 5p13.1 (continued)

479

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Delozier-Blanchet: microcephalyhypogenitalism166

Amphora-shaped face, microcephaly with nystagmus, spasticity, obesity and hypogenitalism, severe mental retardation

AR or XLR

De Moor: frontonasal dysplasia167

Sporadic cases of growth and developmental failure, mild frontonasal dysplasia, congenital heart disease (TOF/aortic stenosis), mild genital anomalies

Unknown

D’ercole: short staturecongenital heart168

IUGR, growth and developmental retardation, congenital heart, oval face with high palate and furrowed tongue, delayed puberty

XLR

Desmosterolosis169

IUGR, downslanting palpebral fissures, low nasal bridge, thick alveolar ridges, gingival nodules, congenital heart defect, ambiguous genitalia, variability includes case with macrocephaly and another with microcephaly, abnormal cholesterol biosynthesis

AR (602398) DHCR24 1p33-p33.1

Digito-renal-cerebral170

Absent distal phalanges of fingers and toes, cystic dysplasia and other renal anomalies

AR (222760)

Disequilibrium171

Adults described with variable microcephaly and mental retardation, broad-based gait, truncal ataxia, intention tremor, athetoid posturing, dysarthria, short stature

AR (224050)

Distal aphalangia-extra metatarsal172

Variable asymmetric distal aphalangia, hand and foot syndactyly, duplication of 4th metacarpal, short stature, borderline intelligence

AR

Distal arthrogryposis-mental retardation173

Postnatal onset microcephaly, frontal and parietal bossing, high narrow forehead, narrow chest, retrognathia, narrow and pointed nose, adducted thumbs, tapered and contracted fingers

AR?

Dolichospondylic dysplasia174

Short stature, beaked nose, epicanthus, rotated ears, scoliosis, thin gracile metacarpals, tall vertebral bodies, mild retardation to borderline IQ, mild microcephaly. Single case, not to be confused with dolichospondyly described in syndromes such as 3-M.

Unknown

DOOR175

Sensorineural deafness, onychodystrophy, osteodystrophy with absent distal phalanges, mental retardation. A severe, often lethal, form may have elevated 2-oxoglutarate

AR (220500)

Duane anomaly-ASDmicrocephaly176

Duane retraction in association with short neck, spastic paraplegia, atrial septal defect and microcephaly; not dysmorphic

Unknown

Dubowitz177

IUGR, short stature, sparse hair, sloped forehead, small palpebral fissures, ptosis, telecanthus, broad nose, palate anomalies, micrognathia, eczematoid skin

AR (223370)

Drayer: microcephalydigital178

Hypertelorism, blepharophimosis, low set ears, brachydactyly 2-5, proximal thumbs, short 3–5 toes, short stature, developmental delay

AR

Dwarfism-bowed femurs179

IUGR, disproportionate short stature, hypotelorism, upslanting palpebrae, prominent clavicles, narrow chest, flexion contractures of major joints and fingers, irregular flared metaphyses, coronal cleft vertebrae

Unknown

Dwarfism-delayed sexual maturation180

Severe mental retardation, proportionate short stature, infantile genitalia, delayed bone age, no specific facial signs; possible parental consanguinity

AR or XLR

Dwarfism-enamel hypoplasia-diabetes181

Congenital microcephaly, growth and mental retardation, onset of diabetes in infancy, small wide-spaced teeth with enamel hypoplasia. The two sisters had elevated alanine, pyruvate, and lactate.

AR

Dwarfism-microcephalyhydrocephaly182

Sloping forehead with marked microcephaly, no developmental progress, short and cupped ribs, mildly flat vertebrae, postmortem hydrocephalus, one sib with absent corpus callosum

AR

Dwarfism-tall vertebrae183

Prenatal proportionate short stature with hypertelorism, prominent supraorbital ridges, triangular face, tall and narrow vertebrae, slender tubular bones

AD (126950)

Dyserythropoiesesmicrocephaly-IUGR325

IUGR, postnatal growth failure with mild liver dysfunction and chronic diarrhea, significant neonatal jaundice, aniso/microcytosis, abnormal iron metabolism with ringed sideroblasts

AR/XLR?

Dyskeratosis congenita184

Unusual case of autosomal recessive form with severe microcephaly, mental retardation, and cerebellar hypoplasia, in addition to usual nail dystrophy, mucosal and skin pigment changes, and bone marrow failure

AR?

Ear-patella-short stature185

Microtia, micrognathia, small mouth with thick lips, developing high narrow nose, high forehead, short stature, absent patella, dislocating elbows, several bony anomalies, and delayed bone age

AR (224690)

Ectodermal dysplasia-ocular: Wallis-Beighton186

Mental and growth retardation, blindness due to microcornea and sclerocornea, narrow nasal bridge, flared nostrils, short upper lip, broad alveolar ridge, prominent ears, fine and sparse hair, barrel-shaped upper incisors (continued)

480

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Ectrodactyly-deafness

Similar to EEC with ectodermal dysplasia, typical ectrodactyly, submucous cleft palate, Mondini anomaly causing sensorineural deafness, vertical talus

AD (220600) 7q21.1-q21.3

Ectrodactyly-ectodermal dysplasia-clefting188

Typical ectrodactyly (central reduction); ectodermal changes may include skin, hair, nails, and teeth; cleft lip/palate, lacrimal duct, and urogenital anomalies; developmental delay in 7% and microcephaly in 2% of cases

AD (129900) p63, 3q27 7p11.2-q21.3, Chr 19

Ellis: microcephaly-heartrenal189

IUGR, severe microcephaly, small ears, pre-auricular pits, short palpebral fissures, hypoplastic alae, cleft palate, redundant neck skin folds, varied congenital heart defects, lung segmentation defects, unilateral renal agenesis, high lethality, brain in one sib small with reduced gyri, hydranencephaly-like in one

AR (601355)

Elmer: anterior chamberlentigenes-marfanoid190

Axenfeld anomaly, Rieger anomaly, posterior embryotoxon, mild mental retardation, lentigines on the back, marfanoid habitus; two males complete situs inversus; parental consanguinity

AR

Epiphyseal dysplasia-retinitis pigmentosa191

Short stature; variable mild retardation; hypertelorism; optic atrophy; limited elbow extension; small, flat, irregular epiphyses; wide lumbar pedicles

AR

Evans: microcephalyhypotelorism192

Normal intelligence, hypotelorism, malar hypoplasia; one of six had Axenfeld anomaly

AD (156580)

Facial anomalies-hypoplastic genitalia193

Prenatal onset, IUGR, severe retardation, low upswept hairline, prominent glabella, large abnormal ears, hydronephrosis, camptodactyly, lethal (prenatal diagnosis possible), consanguinity

AR or ?XLR

Facio-digital-genital-Kuwait type194

Variable short stature with normal development, Aarskog-like face with hypertelorism, anteverted nares, long and deep philtrum, long neck and sloped shoulders, broad hand with mild interdigital webbing and hyperextensibility, microcephaly recorded but frequency not documented

AR (227330)

Fallot complex-mental and growth retardation195

Severe growth and developmental delay, large and protruding ears, slightly upslanting palpebral fissures, high palate, micrognathia, cutaneous toe syndactyly, longitudinal plantar crease

AR

Familial microcephalyTolmie type 2196

Neonatal microcephaly, severe generalized seizures, spasticity, and profound mental retardation

AR

Fanconi pancytopenia197

Short stature, radial ray defects, skin pigment anomalies, variable-onset aplastic anemia/leukemia, urogenital anomalies, increased baseline and clastogen-induced chromosome breakage

AR (227650) FAA, 16q24.3 (60–65%) BRCA2, 13q12.3 FACC, 9q22.3 (8%) FANCD2, 3p25.3 FANCE, 6p22-p21 (13%) FANCF, 11p15 FANCG, 9p13

Feingold: mesobrachyphalangytracheoesophageal fistula198

Grecian nose, telecanthus, prominent occiput, micrognathia, tracheoesophageal fistula, duodenal atresia, 2-3 toe syndactyly, hypoplasia middle phalanges 2nd and 5th fingers, normal development, resembles del (13q22-qter)

AD

Feingold: short stature-cleft palate-ear anomalies199

Similarities to Goldenhar syndrome; facial asymmetry, thin ear helices, broad nasal bridge, cleft palate, gingival hypertrophy, prominent alveolar ridges, short fingers, spina bifida occulta, mild mental retardation; single case

Unknown

Feinstein: partial alopeciapersonality traits200

Sparse scalp, body, eyebrow, and eyelash hair, lighter in color than family; harsh, deep voice; thick, protruding ears; microcornea and marked hypermetropia; hyperkinetic, mischievous, cheerful, self confident, and outgoing

Unknown

Fernhoff: short stature-malar/ mandibular hypoplasia201

Single case, IUGR, significant micrognathia, cleft soft palate, petite face, narrow palpebral fissures, epicanthic folds, small low-set ears, overlapping fingers with bilateral fixed flexion deformities of the 3rd, 4th, and 5th proximal interphalangeal joints, small pituitary, absence of the cerebellar external granular layer

Unknown

Fetal alcohol202

Variable pre- and postnatal growth failure, short palpebral fissures, malar hypoplasia, short nose, smooth philtrum, thin upper lip, small distal phalanges and nails, cardiac malformations, vertebral anomalies, strawberry hemangioma

In utero alcohol exposure

Fetal brain disruption203

Marked microcephaly with overlapping sutures, scalp rugae, and severe mental retardation resulting from a variety of disruptive causes including thromboembolism, infection, and fetal trauma

Disruption

187

(continued)

481

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Fibular deficiency-mental retardation204

IUGR, hypertelorism, downslanting palpebral fissures, high and narrow forehead, anteverted nares, short philtrum, small mouth, mental retardation, fibular remnant, short, bowed tibia; mild, variably short metacarpals, metatarsals, and proximal phalanges of the toes

Unknown

Filippi: unusual faciessyndactyly205

Low birth-weight, growth failure, severe retardation, prominent forehead, prominent nasal root with specific shape to root, syndactyly 3-4 fingers and 2-4 toes, characteristic metacarpophalangeal profile

AR (272440)

Floating-Harbor206

IUGR, speech delay with normal motor development, bulbous nose with wide columella, deep-set eyes, short philtrum, thin lips, triangular face, short neck, brachy/ clinodactyly; microcephaly an inconsistent sign

Sporadic (136140)

Focal dermal hypoplasia207

Coloboma, microphthalmia, dental hypoplasia and abnormal eruption, linear skin hypoplasia with hyperpigmentation, atrophic macules, extruding areas of fat; developmental delay and microcephaly are variable findings

XLD (305600) Xp22.31

Frydman: V-esotropiablepharophimosis208

Short stature, borderline microcephaly, blepharophimosis, ptosis, strabismus, variable telecanthus, short palpebrae, V-esotropia with upward gaze paralysis, 2-3 toe syndactyly

AR (210745)

Fryns-Verresen: IUGRcoloboma-microcephaly209

IUGR, sloping forehead, low-set ears, microphthalmia, iris coloboma, cataracts, corneal clouding, congenital heart; absent left kidney, ureter, and ductus deferens in one male, hypospadias, anal stenosis; female sib had unilateral cleft lip/palate; perinatally lethal

AR

Funduscopic anomalies without retardation210

Variable funduscopic changes as in Gardner syndrome; fine granular pigment with hyperpigmented spots and areas of atrophy, patchy chorioretinal atrophy

AR

German: peculiar face-growth retardation211

Reduced intrauterine movement, dolichocephaly, long face, long and smooth philtrum, downslanting fissures, large nose and ears, mild camptodactyly, cleft palate, mental retardation, lethal

AR

Gillessen-Kaesbach: polycystic kidneysbrachymelia212

Potter type 1 polycystic kidneys, microbrachycephaly, short and full neck, hypertelorism, upslanting palpebral fissures, flat nasal tip, smooth philtrum, fleshy and posteriorly rotated ears, short limbs, rocker-bottom feet, brachydactyly, congenital heart defect, and other intra-abdominal anomalies

AR

Giuffre: microcephalyradioulnar synostosis213

Radio-ulnar synostosis, 5th finger clinodactyly, mild finger cutaneous syndactyly, cubitus valgus. Original cases of normal intelligence; similar sporadic cases since reported with mild delay.

AD

Golabi: short stature-brittle hair214

Postnatal onset microcephaly, growth and developmental retardation, narrow triangular face, upslanting palpebral fissures, epicanthus, telecanthus, prominent ears; seizures, atrial septal defect, brittle hair, and large central incisors variable features

XLR

Goldblatt: genitopatellar215

Hypoplastic/absent patella, contractures of major joints, short stature, cupped ears, flat nasal bridge, mid-face hypoplasia, micrognathia, crossed renal ectopia, scrotal hypoplasia; 4 of 7 cases with absent corpus callosum

Unknown (606170)

GOMBO216

Named for growth retardation, ocular abnormalities, microcephaly, brachydactyly, oligophrenia; has prominent nose, dental anomalies, aged skin, 5th finger, clinodactyly, prognathism. Original cases found to be 46,XY, ish der(3),t(3;22) (p25;q13).

Partial 3p monosomy and 22q trisomy (233270)

Goniodysgenesis-short stature217

Growth and mental retardation, downslanting palpebral fissures, Rieger anomaly, epicanthus, preauricular pits, possible cardiac valve defects

AD? (138770)

GRANDDAD218

IUGR, sparse scalp hair, prematurely aged face, postnatal growth failure, normal development, triangular face, deep-set eyes, hypermetropia, prominent nasal septum, hypoplastic alae, poor fat, 2 of 7 microcephalic

Unknown

Green: anal-renalsyndactyly219

Postnatal growth failure, anal stenosis, unilateral renal agenesis, variable 2-5 toe syndactyly; adult had broad forehead, narrow nose, and ventricular septal defect

AD

Grix: broad thumbshyperostosis220

Large thumbs and halluces, neonatal hyperostosis, puffy eyelids, high nose, bulbous tip, bifid tongue tip, psychomotor delay, hypertonic, postnatal growth failure, hypertrichosis

AR or SLR

Growth failureencephalopathy-endocrine221

Postnatal onset microcephaly and growth failure, high bossed forehead, flat occiput, upslanting palpebral fissures, high palate, small pointed chin, cortical atrophy; one sib with septum pellucidum cyst, stereotypic movements

AR

Growth hormone deficiencyadvanced bone/sexual maturation222

Severe microcephaly, short stature, advanced skeletal and sexual maturation, limited extension at elbows, isolated growth hormone deficiency; one of the two brothers was mentally retarded

XLR or AR

(continued)

482

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Grubben: short-dentaleczema223

Pre- and postnatal growth and developmental delay, hypotonia; small, widely spaced or missing teeth, eczematous skin rash; small, puffy hands and feet with tapering digits; partial agenesis of the corpus callosum or ventriculomegaly; selective IgG2 subclass deficiency a possible marker

AR (233810)

Gurrieri: retardationseizures-skeletal224

IUGR, postnatal growth and developmental delay, deep-set eyes, short philtrum, kyphosis, joint laxity, seizures, cerebral atrophy; 1 of 4 sibs truly microcephalic, minor pelvic and spine anomalies

AR (601187)

Gustavson: blind-deafspasticity225

Generally lethal in first year, severe sensorineural hearing loss, large malformed ears, optic atrophy, restricted movement of the large joints, spasticity, seizures. One severely affected girl

XLR Xq26

Halal: microcephaly cleft palate226

Mild developmental delay, retinal pigment anomaly, hypotelorism, prognathism, variable camptodactyly affecting distal interphalangeal joints of fingers 2-5

AD or XLD

Halal-Silver227

Mild de Lange-like gestalt, short stature, thin build, mild synophrys, long eyelashes, depressed nasal bridge, long philtrum, thin lips, micrognathia, cryptorchidism, metatarsus adductus, dermatoglyphic anomalies

AD (112370)

Hallerman-Streiff228

Short stature, fronto-parietal prominence, microphthalmia, cataracts, thin pointed nose, hypodontia, natal teeth, skin atrophy, hypotrichosis

AD; most are new mutations (234100)

Hall-Riggs: coarse faceskeletal dysplasia229

Progressive metaepiphyseal disorder with severe retardation, flat nasal bridge, large lips, brachydactyly, short arms; microcephaly may be of postnatal onset

AR (234250)

Hamel: X-linked retardationheart defect230

Short stature, long narrow face, sunken eyes, malar hypoplasia, anomalous and protruding ears, broad nasal bridge and bulbous tip, micrognathia becoming prognathic, cleft palate and uvula, Fallot complex, atrial and septal defects, hypospadias

XLD (300463) PQBP1, Xp11.23

Hennekam-RenckensWennen231

Single case with short stature, mental retardation, total alopecia, optic atrophy, severe myopia, full lips, fleshy nose with prominent nasolabial grooves. Subject’s sweating was normal, and she had apparently normal teeth.

Unknown

Hepatic cirrhosis-unusual face232

Growth and mental retardation, triangular face, prominent eyes, hypoplastic alae, pinched nose, skin pigment changes, trident hands, abnormal toes, aminoaciduria

AR

Herpes, prenatal233

About 5% of neonatal herpes is acquired in utero: variable clinical spectrum may include cutaneous, ocular, and CNS lesions; about one-half have an encephalitis that can cause microcephaly or hydranencephaly

Prenatal infection with herpes virus

Herrick: multisystem atrophy234

Perinatally lethal with cerebellar hypoplasia, brainstem atrophy, degeneration of the basal ganglia and the thalamus, sudanophilic staining in macrophages and astrocytes of the white matter, flexion contractures, hypertonia

AR

Hirschsprung-cleft palate235

Mild retardation, hypertelorism, synophys, prominent nose, poor hair growth, hypotonic

AR (235730) SMADIP1, 2q22

Hirschsprung-cleft palatedigital236

Profound growth and developmental failure, myoclonic seizures, short segment Hirschsprung, cleft soft palate, distal digital hypoplasia, 5th finger clinodactyly, 3-4 toe syndactyly

AR

Hirschsprung-microcephalyretardation237

Large nose, prominent ears, deep set and large eyes, infero-nasal coloboma, short philtrum, developmental delay, CT evidence of defective neuronal migration (2 cases with agenesis of corpus callosum)

AD del 2q22-q23

HIV III infection, prenatal238

There is no current evidence to suggest a dysmorphic syndrome associated with HIV III; postnatal growth failure and microcephaly are secondary to chronic illness and CNS infection

Intrauterine or conatal infection

HMC239

Hypertelorism (marked), narrow palpebral fissures, microtia with choanal stenosis, cleft lip/palate, broad bifid nose, mild renal anomalies, ?congenital heart defect

AR (239800)

Holmes-Gang: club footretardation240

Large anterior fontanel, epicanthus, short and anteverted nose, short upper lip, severe equinovarus, propositus had renal hypoplasia; shown to be allelic with ATRX

XLR (301040) XNP, Xq13

Houlston: glomerulonephritismarfanoid habitus241

Mental retardation, marfanoid habitus with joint laxity and arachnodactyly, focal glomerulonephritis; one sister developed acute myeloblastic leukemia at 17 years; parental consanguinity

AR (248760)

Humoral immunodeficiencyface-limb242

Humoral immunodeficiency, arched eyebrows, hypoplastic nares, macrostomia with thin lips, triphalangeal thumbs, hypoplastic thenar eminence, mild delay; single case

Unknown

(continued)

483

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Hunter-McAlpine

Oval face, almond-shaped eyes, ptosis, small nose, downturned mouth, short stature, retardation, brachydactyly with characteristic metacarpo-phalangeal profile, craniostenosis, elbow limitation

dup 5q35-qter

Hurst: craniostenosis-ear anomalies244

Short stature; atretic auditory meati; small abnormal ears; micrognathia; small mouth; short neck; camptodactyly; delayed bone age; dislocated radial heads; abnormal clavicles, patellae, and glenoid fossa

Unknown

Huson: spondyloepiphyseal dysplasia tarda— microcephaly245

Spondyloepiphyseal dysplasia tarda, developmental delay, broad nasal root, short philtrum, full lips, rhizomelic shortness of limbs, broad chest, short sternum, mild radiologic findings of SED

AR (600093)

Hutteroth: absent thumbs246

Developmental delay, congenital heart defect, wide forehead, flat occiput, narrow high palate, absent thumbs, elbow restriction, radio-ulnar synostosis, bowing, 3-4 finger syndactyly, short stature

Unknown

Hyams: cerebral palsyglaucoma247

Sisters with spastic cerebral palsy, later onset glaucoma, mild developmental delay; parental consanguinity

AR

Hydantoin, prenatal248

Soft signs of short nose with broad base, telecanthus, ptosis, short neck, wide mouth, mild IUGR/developmental delay, distal digit hypoplasia; microcephaly not a common finding

In utero exposure to hydantoin

3-hydroxybutaric aciduria249

Poor fetal movement, triangular face, short sloping forehead, bitemporal narrowness, prominent philtrum

AR

Hypogonadism-short stature250

Hypergonadotrophic hypogonadism, narrow forehead, synophrys, abnormal pinnae, early tooth loss

AR (251200)

Hypogonadism-short statureobesity251

Mental retardation, short stature, micropenis, hypotonia, narrow forehead, normal sized hands with ulnar deviation and minor finger anomalies (similar to Bo¨rjeson-Forssman-Lehmann)

XLR

Hypomelanosis of Ito252

Causally nonspecific neurocutaneous disorder with hypopigmented skin, usually in streaks or whorls and following the lines of Blaschko; may be associated with hypertrichosis, eye and CNS malformations

Various mosaic karyotypes

Hypoparathyroiddysmorphism253

Congenital hypoparathyroidism, seizures, growth and developmental retardation, deep-set eyes, beaked nose with low bridge, long philtrum, thin upper lip, micrognathia, medullary stenosis

AR (241410) 1q42-43

Hypoplastic right heartmultiple congenital anomalies254

A cluster of infants with unusual rate of associated malformations included microcephaly (10/14), Pierre Robin (2), low set ears (4), arrhinencephaly (1)

Unknown

Ichthyosis-digital anomalies255

One of two sibs microcephalic, growth and developmental delay, epicanthus, full lateral eyelids, lower lip groove, minor ear anomalies, flexion deformities, hypoplastic toes and nails

AR (258840)

Ichthyosis-microcephalydeafness256

Congenital ichthyosis, spastic quadriplegia, severe developmental delay, myoclonus, deafness, high palate; pair of MZ twins

Unknown

Imaizumi-Kuroki: radial raydwarfism257

IUGR, postnatal growth and developmental delay, triangular face, short palpebrae, prominent eyes, sparse hair, deep philtrum, hypoplastic radii, absent thumbs and first metacarpals. Single case

Unknown

Immunodeficiencychromosome instability258

Growth failure, mental retardation, cafe´-au-lait spots, chromosome instability reflected by 7;14 rearrangements. Cells did not complement some patients of Seemanova et al260 (see Immunodeficiency-normal intelligence) but did complement other reported cases.

AR (251260) Nibrin/p95, 8q21

Immunodeficiencymalformations259

Postnatal growth and developmental delay, large protruding ears, sloping forehead, prominent beaked nose, hypoplastic patellae, eczema, defective hemotaxis, transient hypogammaglobulinemia, hypogonadism

AR or XLR (251240)

Immunodeficiency-normal intelligence260

Congenital microcephaly, receding forehead, upslanting palpebrae, long straight nose, small mandible, short stature, hypogammaglobulinemia, decreased cellular immunity, respiratory infections, and lymphoreticular malignancy

AR (251260)

Inbal: myopathy-lactic acidosis-anemia261

Myopathy with abnormal mitochondrial inclusions, lactic acidosis, sideroblastic anemia, mental retardation, normal face with long philtrum. Age of onset of the microcephaly unclear

AR (600462)

Intermittent hyperpnea-wide mouth262

Profound mental retardation, wide mouth, thick fleshy lips, broad beaked nose, abnormal EEG, intermittent hyperpnea equivalent to Joubert (one of two microcephalic)

Unknown

243

(continued)

484

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Intestinal atresia-ocular anomalies263

Apple peel intestinal atresia, variable microphthalmia, corneal clouding, shallow anterior chamber, irregular dilated pupils, epicanthus, mild delay, microcephaly progressive from birth

AR

Ippel: cataracts-retinitis pigmentosa264

Microcephaly may be postnatal, mild to moderate mental retardation, congenital sutural cataracts, middle or late childhood onset of retinitis pigmentosa

AR

Iris colobomataventriculomegaly265

Pre- and postnatal growth retardation, developmental delay, iris colobomata, dilated ventricles, spasticity, and abnormal immunoglobulin levels

AR

Ives: microcephalymicromelia266

IUGR, perinatal death, fused elbows, forearm shortened with single long bone, two to four digits on hands

AR (251230)

Jaffer: arachnodactyly-chest deformity267

Short stature and developmental delay, hypertelorism, prominent jaw, high arched palate, pectus carinatum, joint laxity, spondylolisthesis, scoliosis, mitral valve prolapse

Unknown

Janssen: cystic hygromarenal-syndactyly268

Early lethal, anterior cystic hygroma, eyelid fusion, hypertelorism, upslanting palpebral fissures, broad nose with depressed bridge, micrognathia, renal dysplasia, bicornuate uterus, clitoromegaly, cutaneous syndactyly of toes 4 and 5

AR

Jejunal atresia-ocular-sex reversal564

Jejunal atresia, aberrant right tracheobronchus, corectopia, iris stromal hypoplasia, peripheral anterior synechia, 46,XY sex reversal

Unknown

Johanson-Blizzard269

Scalp defects, hypoplastic alae nasi, hypodontia, microdontia, deafness, exocrine pancreatic dysfunction, IUGR, short stature, ano-rectal anomalies, normal to retarded intelligence

AR (243800)

Jones: blepharophimosisabnormal ears270

Short stature, mild developmental delay, brachymicrocephaly, small ears with overfolded helix, sparse medial eyebrows, epicanthic folds, small and upslanting palpebral fissures, malar hypoplasia, long philtrum, narrow palate; single case

Unknown

Jorgenson: ptosis blepharophimosis271

Facial asymmetry, ptosis, blepharophimosis, retardation; three unrelated children, variable additional minor digital and arm anomalies

Unknown

Juberg-Hayward272

Cleft lip/palate, hypoplastic columella and alae, hypoplastic and distally placed thumbs, short stature, hypodontia, elbow anomalies, 2-3 toe syndactyly

AR/?AD (216100)

Juberg-Hellman: female limited seizures273

The prevalence of microcephaly and its age of onset is unclear; early development normal to 4–18 months; onset of seizures and developmental delay limited to females

XLD female limited Xp23

Judge: porokeratosiscraniosynostosis274

Microbrachycephaly, postnatal erythematous, reticulate facial rash with poikiloderma and focal crusting of the scalp and ears; symmetrical, demarcated, erythematous, hyperkeratotic plaques with raised, brown hyperkeratotic margins on forearms, dorsum hands, thighs and knees; craniosynostosis, hypospadias, hypotrichosis

AR?

Kabuki275

Variable developmental delay, hypotonia, long palpebral fissures with everted lateral 1/3 of the lower lid, ptosis, broad nasal tip, cleft/high-arched palate, prominent ear lobes, congenital heart and renal anomalies, prominent fetal finger pads, joint hypermobility, patellar dislocation, premature thelarche

Uncertain (147920)

Kapur-Toriello276

Variable growth failure, retardation, microphthalmia, coloboma, bulbous nasal tip with underhanging columella, cleft lip/palate, minor ear anomalies, constipation, gut malrotation, congenital heart defects

AR (244300)

Kaufman: oculocerebrofacial277

Microcornea, strabismus, pale discs, small teeth, minor external ear anomalies, thin fingers, micrognathia, neonatal respiratory problems, mental retardation

AR (244450)

Kawashima: deafness-ear anomalies278

Facial asymmetry, prominent glabella, thick protruding lower lip, micrognathia, low-cupped ears, mild retardation; variable, asymmetric mixed, or sensorineural deafness

AD (156620) XLD

KBG279

Short stature, mental retardation, low hairline, large maxillary central incisors, round face, high nasal bridge and bulbous tip, cervical ribs, vertebral anomalies, finger syndactyly

AD (148050)

Kelly: microcephaly-digital anomalies280

Severe retardation, sloping forehead, prominent nose, small jaw, scoliosis, decreased elbow extension and supination, short 4th and 5th metacarpals, complete syndactyly toes 4-5, and partial syndactyly of toes 2-4

XLR or AR

Kondoh281

Pre- and postnatal growth retardation, sparse hair, widow’s peak, bushy eyebrows, ptosis, pear-shaped nose with narrow alae, long philtrum, thin upper lip, interphalangeal and knee contractures, atopic dermatitis

AR (606242)

Kozlowski: wrinkly skin-hip dislocation282

IUGR, bilateral congenital hip dislocation, thin skin with wrinkling over the hands, umbilical hernia, hypotonia, advanced pneumatization of the paranasal sinuses, and pseudoepiphyses of the 2nd metacarpals

AR

(continued)

485

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Kraus-Rupert

Microcephaly, hypogonadism, obesity, 2-4 toe syndactyly, prominent ears

Probable AR

Labrune-Assathiany: progressive vitiligo284

Growth and developmental delay, beaked nose, high narrow palate, late childhood onset progressive vitiligo, macrogenitosomia, double meatus. Single case, consanguinity.

Unknown

Langer-Giedion285

Mild to severe retardation, large protruding ears, bulbous nose with ‘‘tented’’ alae, long simple philtrum, cone-shaped epiphyses, exostoses of long bones (some clinical correlation with size of chromosome deletion)

(150230) del(8q) TRPS1 and EXT1, 8q24.12-24.13

Lathosterolosis383

Variable Smith-Lemli-Opitz–like signs in two cases published to date but unique intracellular storage of mucopolysaccarides and lipids in liver and non-neuronal cells of CNS

AR (607330) SC5D, 11q23.3

Lenz microphthalmia286

Developmental delay, external ear anomalies, ptosis, cleft lip/palate, sloped shoulders, clavicle hypoplasia, syndactyly, camptodactyly, thumb anomalies, renal anomalies

XLR (309800) Xq27-q28

Leprechaunism287

IUGR, growth failure, adipose deficiency, prominent eyes, thick lips, gingival hyperplasia, large phallus, hirsutism, infections, insulin-binding defect, death

AR (246200) insulin receptor gene, 19p13.3

Lethal multiple pterygium288

Fetal death, cutaneous joint webbing, frequent cystic hygroma and hydrops, growth failure; marked heterogeneity. One case report with hypoplastic cerebellum and immature spinal cord tracts.

AR

Lethal progeroid-osteolysis289

Growth and developmental delay, severe micrognathia, glossoptosis, patchy hyperpigmented skin, still joints, progeroid appearance, high forehead, slightly beaked nose, sparse hair, hypoplastic distal phalanges. Single case.

Unknown

Leukotriene C4-synthesis deficiency290

Progressive developmental delay and hypotonia, hyporeflexia, decreased motor conduction velocities, early death, broad nasal root, epicanthus, absent CSF leukotriene C4 and raised LTB4. Parental consanguinity in the case.

AR

Ligase IV291

Growth and/or developmental delay, Seckel-like face, pancytopenia, variable skin signs can include photosensitivity, hypothyroid; cells show radiosensitivity due to DNA ligase IV deficiency

AR (606593) LIG4, 13q22-q34

Lindstrom: IUGRdwarfism292

Severe retardation, seizures, cleft lip, small pointed chin, lens opacity on slit-lamp examination, simple ear helix, short neck, camptoclinodactyly of fifth fingers, acrocyanosis

AR

Livido reticularis-snub nose293

Profound mental retardation, short stature, livedo reticularis, snub nose, diastasis recti, hypoplastic nails both fifth toes; deletion Yq11-ter found in the father

Unknown

Low birth weight-dwarfismdysgammaglobulinemia294

IUGR, growth and developmental delay, joint hyperextensibility, brachydactyly, single flexion crease fifth fingers, calcaneovalgus, recurrent bacterial infections, elevated IgA

AR

Macroepiphyses-wrinkled skin295

Club feet, long fingers, lax joints, aged appearance, wrinkled hands, dry coarse hair, pectus excavatum, osteopenia, multiple fractures, enlargement of joints, normal development

Unknown (248010)

Macular bullous dystrophyretardation296

IUGR, postnatal growth failure; maculo-papulous skin rash, vesicles filled with clear fluid on sun-exposed areas; short tapering fingers, nail dystrophy; permanent loss of scalp hair in the first year; corneal opacity, glaucoma, cataract; hypogenitalism, diabetes mellitus

XLR (302000) Xq26-qter

Madokoro: short palpebraemicrognathia297

Severe microcephaly, downslanting palpebrae, hypertelorism, epicanthus, delayed development, small mouth, cleft palate

AR

Mandibulofacial dysostosisthoracic deformities507

Growth retardation, mandibulofacial dysostosis, thoracic deformity; one brother with asplenia, the other with gallbladder aplasia

AR/XLR?

Marden-Walker298

Delayed motor development, blepharophimosis, low-set and malformed ears, cleft palate, micrognathia, renal microcysts or cystic dysplastic kidney, joint contractures, arachnodactyly, camptodactyly, kyphoscoliosis, congenital heart malformations; likely heterogeneous

AR (248700)

Marion-Mayers: face dysmorphia-IUGR299

Significant IUGR, hypotonia and delayed development, metopic prominence, high nasal root, low-set ears, downturned mouth, triangular face, phonation anomalies

AR?

Martsolf 300

Brachycephaly, cataracts, malar hypoplasia, prognathism, pouting lower lip, hypogonadism, aged appearance, short palms, broad finger tips, mental retardation

AR (212720)

283

(continued)

486

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Mastocytosis-microtia

Short stature, developmental delay, facial asymmetry, frontal bossing, upslanting palpebrae, broad nasal bridge with hypoplastic alae, microtia, scoliosis; consanguinity

AR? (248910)

Maternal hyperthermia302

Impact varies with timing, must be sustained and
398C; microcephaly in about 10%; heterotopias; microphthalmia, contractures, micrognathia (causal association not proven in prospective studies)

In utero hyperthermia

Maternal hyperphenylalaninemia303

IUGR, mental retardation, seizures, congenital heart defects, cleft palate, cervical vertebral anomalies, strabismus, 80% risk of microcephaly in untreated pregnancies

In utero hyperphenylalaninemia

Matsoukas: oculararticular304

Growth and developmental retardation, multiple joint dislocations, short palpebrae, hypertelorism, high palate, small mouth, microphthalmia, corneal sclerosis

AD

Me´garbane´: elbows-tibiadeafness-cataracts305

Mental retardation, sensorineural deafness, cataracts, scoliosis, bowed tibiae, dislocated elbows, short fourth metacarpals, calcaneum valgus

AR

Me´garbane´: joint dislocationabnormal skin306

Delayed growth, severe retardation, ptosis, prominent and low-set ears, beaked nose, joint laxity with dislocations, delayed bone age, abnormal blood vessel walls in skin; consanguinity

AR or XLR

Me´garbane´-LeMerrerKallab307

Growth retardation, hypertelorism, downslanting palpebrae, ptosis, broad nasal tip, short and webbed neck, low posterior hairline, seizures, cerebral atrophy

AR

Megalocornea-mental retardation309

Short stature, hypotonia, moderate to severe mental retardation, occasional ataxia/ choreoathetosis, seizures, possible macrocephaly

AR (249310)

MEHMO310

Severe developmental delay, early onset seizures, prenatal microcephaly, obesity, short stature, narrow forehead, facial telangiectasias, simple ears with large lobules, downturned mouth, cryptorchidism, micropenis, edematous hands and feet, tapered fingers

XLR Xp21-Xp22

Mehta: heart-ptosishypodontia311

Sagittal synostosis, ptosis, blepharophimosis, prominent ears, prominent lower lip, small and abnormally shaped teeth, long fingers and toes, generalized joint laxity, total anomalous pulmonary venous drainage. Single case, similar to Mutchinick; see entry this table.

Unknown

Mental retardationosteosclerosis312

Profound retardation, progressive osteosclerosis, short and narrow frontal and occipital areas, prominent supraorbital ridges, cataract, gray teeth, prominent ears, saber chins

Unknown

Mesobrachyphalangytracheoesophageal fistulaRett–like508

Similar to Feingold-mesobrachyphalangy-tracheoesophageal fistula198 with regression, autistic signs, seizures, stereotypic hand movements

Unknown

Methylmercury, prenatal313

Severe neurologic disturbance with postnatal growth failure, spasticity, pyramidal and cerebellar signs, seizures, mental retardation, microcephaly in 60%

Prenatal exposure

Microcephaly-cardiacdigital315

Growth retardation, hypertelorism with broad nasal bridge, cleft or pseudocleft lip, distally placed thumbs, variable mild 2nd and 5th digit hypoplasia and mild skin syndactyly

AD (600987)

Microcephalycardiomyopathy316

Mental retardation, abnormal ear helix, 5th finger clinodactyly, sandal gap, non-progressive dilated cardiomyopathy, may have stippled pigment in retina

AR (251220)

Microcephaly-cleftingpreauricular tags317

Growth and developmental retardation, sparse eyebrows, short and upslanting palpebrae, epicanthus, short nose with anteverted nares, thin upper lip, micrognathia, preauricular pits/tags, long thin fingers, abnormal nipples

Unknown

Microcephaly-coarse faceskeletal318

Growth and developmental delay, prominent eyebrows, broad nose, large mouth with full lips, hirsute, delayed bone age, scoliosis, variable and mild skeletal anomalies

AR (601352)

Microcephaly-cortical blindness-polydactyly319

Growth and developmental delay, recurrent infections, prominent forehead, short nose, micrognathia, postaxial polydactyly, cortical blindness

AR (218010)

Microcephaly-cubitus valgus320

Mental retardation, midchildhood-onset obesity, strabismus, malar hypoplasia, short philtrum, multiple nevi, marked cubitus valgus, clinodactyly of great toes

XLR?

Microcephaly cutis verticis gyrata-edema321

Progressive microcephaly, cutis verticis gyrata, seizures, developmental delay, optic atrophy, cortical blindness, coloboma, onset hepatosplenomegaly and lymphedema in infancy, ventricular dilatation, abnormal granulation of white cells

AR

Microcephaly-deafness322

Short stature, severe mental retardation, deafness, seizures, spastic/ataxic movement, reduced/immature cells in cerebral layers III and IV; heterozygotes have dull mentality

XLR (309590)

Microcephaly-gray matter heterotopia324

Severe psychomotor delay and seizures, sloping forehead, tall stature, obesity; short wide hands and feet, mild quadriparesis, laminar heterotopias in centrum ovale

AR?

301

(continued)

487

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Microcephaly-lethal arthrogryposis326

Polyhydramnios and premature stillbirth, high forehead, upslanting palpebrae, absent glabellar angle, hypoplastic alae nasi, hypoplastic thenar eminence, severe joint restrictions

AR

Microcephalylymphedema327

Congenital lymphedema of hands and feet, prominent upper helix, epicanthus, flat nasal bridge; heterogeneity with some cases showing retinal changes

AD (152950)

Microcephalylymphedema328

Male with prenatal microcephaly and scalp rugae, female with microcephaly and scoliosis; both with mental retardation (distinct from benign AD form)

Unknown

Microcephaly-myopia (Achermann-Largo)329

Delayed development and bone age, short stature, bitemporal narrowness, epicanthus, periorbital fullness, full cheeks, pouting lower lip

AR or XLR

Microcephaly-nonpigmented retinopathy330

Timing of microcephaly unclear, developmental delay, early onset of visual impairment with pale optic discs, nystagmus, ERG with normal a-waves and attenuated b-waves

AR

Microcephaly-normal intelligence331

Short stature, receding forehead, upslanting palpebrae, epicanthus, long nose, high bridge, wide spaced teeth, high palate (no evident immunodeficiency but one death from leukemia and one from bronchopneumonia)

AR (251260)

Microcephaly-normal intelligence-digital332

Normal intelligence, short palpebrae, variable thumb hypoplasia, short 2nd and 5th middle phalanges, small feet, sandal gap, interdigital syndactyly, short first metacarpal with thin proximal end

AD (602585)

Microcephaly-normal intelligence-oligodontia333

Absent 3rd molars and mandibular permanent 2nd molars; single case

Unknown

Microcephaly-normal intelligence-retinal pigment334

Average to low average intelligence, small ears, cafe´-au-lait spots, normal visual acuity, numerous flat brown hyper- and tan-gray hypopigmented retinal patches

AR or XLR (145290)

Microcephaly-osteoplastic dysplasia335

Postnatal growth failure, normal intelligence, large fontanelle, beaked nose, brachydactyly, platyspondyly, odontoid hypoplasia, coned and ivory digital epiphyses, accessory metacarpal ossification centers

Unknown

Microcephaly-osteodysplastic primordial dwarfism336

Type I and II and Taybi-Lindes are equivalent. Marked IUGR, prominent nose, micrognathia, sloped forehead, alopecia, dry skin, contractures, early death, variety of skeletal changes

AR (210710)

Microcephaly-posterior rib gaps337

Severe microcephaly with sloping forehead, posteriorly rotated and low-set ears, prominent eyes, downslanting palpebrae, large nose, full lips, rib hypoplasia with posterior rib gaps, other bony hypoplasias, contractures

AR? (603394)

Microcephaly-short radius or tibia338

Severe developmental delay, short stature, hypotelorism, strabismus, epicanthus, short first metacarpals and/or tibia, long and dorsally flexed fingers and toes. One brother had anal atresia, one pulmonary artery atresia.

AR or XLR

Microcephaly-tapetoretinal degeneration339

Postnatal microcephaly, severe developmental delay, tapetoretinal degeneration, variable spasticity and muscle wasting; some patients with dystonic signs

AR (602685) 15q24

Microcephaly-tetralogy of Fallot-hydronephrosis323

Severe developmental delay, short stature, seizures, inappropriate laughter, telecanthus, hydronephrosis; long face, nose, and philtrum; prominent ears

AR or XLR

Microhydranencephaly340

Microhydranencephaly, resembles fetal disruption, severe growth and developmental delay, sloping forehead, exophthalmia, micrognathia, spastic quadriplegia, joint contractures, athetosis, respiratory and skin infection

AR (605013) 16p13.3-12.1

Micromelic short statureknee subluxation341

IUGR, FTT with vomiting, natal tooth, short neck, frontal bossing, thin sparse hair, hypertelorism, blue sclera, cleft palate, hypoplastic genitalia, small hands, camptoclinodactyly

Unknown

Microphthalmia-abnormal thumb/hallux342

IUGR, mild to moderate developmental delay, clinical anophthalmia, blepharophimosis, bitemporal narrowing, long face, cleft palate, adducted and hypoplastic thumbs with small nails, short in-turned halluces; single case

Unknown

Microphthalmia-absent abdominal muscles343

Growth and developmental delay, wide fontanels, telecanthus, narrow palpebrae, V-shaped eyebrows, flat nose with small nares, small ears, wide-spaced nipples, bifid sternum, deficient abdominal muscles

AR

Microphthalmia-colobomamicrocephaly344

Growth and developmental delay, mild facial dysmorphia with broad nasal bridge, long philtrum and high palate, colobomatous microphthalmia, congenital heart defects, radiographic anomalies

AR

Microphthalmia-corneal opacity345

Thick eyebrows, small nose, long philtrum, thin upper lip, small and low-set anomalous pinnae, seizures, hypertonicity, psychomotor delay, glycinuria

AR? (2515000) (continued)

488

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Microphthalmiaectrodactyly-prognathism346

Blindness, foot ectrodactyly, digitized thumbs, central cleft lip. Case with t(6;13)(q21;q12) that disrupted sorting nexin 3

AD? (601349) SNX3, 6q21

Microphthalmia-linear skin defects347

May have other CNS anomalies including septum pellucidum cyst, ACC, colpocephaly and hydrocephaly; microphthalmia, sclerocornea, linear dermal aplasia usually of the head and neck

del Xp22.3 (309801) XLD male lethal Xp22.3

Microphthalmia-retinal folds348

Variable syndrome with mental retardation, small cornea, falciform vitreoretinal folds, perinatal pedal edema

AD or XLD (180060)

Miles-Carpenter349

Asymmetric face, ptosis, strabismus, short palpebral fissures, joint hypermobility, camptodactyly of fingers and toes, rocker-bottom feet, excess of fingertip arches

XLD (309605) Xq21.31

Mitral valve prolapseasthenic habitus350

Mental retardation, mitral valve prolapse, flat nasal tip with small alae, high palate, pectus excavatum, short and slender hands. A single case with microcephaly resembled those without.

Unknown

Mixed sclerosing bone dysplasia351

Developmental delay, osteopoikilosis, melorheostosis, developmental delay, overfolded helices, beaked nose, short philtrum, thin upper lip, prominent chin, multiple pigmented nevi

Unknown

Mosaic variegated aneuploidy352

Severe microcephaly, frequent eye and renal malformations, variable but usually significant developmental delay, in vitro mosaic trisomy for different chromosomes, premature chromatid separation, endoduplication, high risk of malignancy

AR (257300) BUBIB, 15q15

Mubashir: situs inversusretardation353

Profound mental retardation, growth failure, situs inversus, long face with posteriorly rotated ears, hypertelorism, ptosis, anteverted nares, hypoplastic alae, long philtrum, tented upper lip, brachydactyly, mild interdigital webbing, short fourth and fifth metacarpals, cerebellar/brain stem migration disorder

Unknown

Multicore myopathyaganglionosis354

Developmental delay and microcephaly by  9 mos, short stature, ptosis, low anterior hairline, long nose with high bridge, small jaw, pharyngeal webbing, Hirschsprung, cerebellar dysfunction, multicore myopathy

Unknown

Mulvihill-Smith355

IUGR, short stature, retardation, broad forehead, lack of subcutaneous facial tissue, hypodontia, sensorineural deafness, small jaw, pigmented nevi, abnormal IgG, T-cell dysfunction

AD (176690)

Muscular build-rhizomeliacataracts356

IUGR, severe microcephaly with borderline intelligence, sparse hair and eyebrows, cataracts, hypotelorism, short and bowed legs, hypertrophic muscular build, micropenis, hypoplastic scrotum

AR?

Mutchinick-unusual face357

Developmental delay, brachycephaly, sloping forehead, hypertelorism, closed short palpebrae, photophobia, broad straight nose, wide mouth, hyperconvex thumbnails

AR

Myhre-unusual face358

Large simple ears and downturned mouth, maxillary hypoplasia, prognathism, lax joints, scoliosis, large ulnar styloid, short stature, retardation

AR

Nakata: cleft palate-lateral synechiae359

Mild to moderate mental retardation, short stature, triangular face, prominent ears with abnormal antihelix, large and upslanting palpebrae, cleft palate or uvula, lateral oral synechiae, everted lower lip

AR

Neonatal axonal dystrophy360

Neonatal onset; rapid deterioration; hearing loss; dystrophic axons; demyelination; cortical blindness with pyramidal, extrapyramidal, and bulbar signs

AR (256600)

Neonatal infantile spasms361

Refractory seizures with hypsarhythmia, progressive microcephaly, and lethal outcome

AR

Nephrotic syndromeinfantile spasms362

Developmental delay; early nephrotic signs due to focal glomerulosclerosis that may show IgM, IgG, and/or C3 deposits; areas of microgyria, cortical layer fusion; floppy ears, hiatal hernia, flexion contractures

AR (251300)

Nezelof: arthrogryposis-renal and hepatic disease363

Joint contractures, muscle atrophy, proximal thumbs, obstructive jaundice, variable liver histology, renal tubular degeneration and/or nephrocalcinosis; reported with microcephaly, corpus callosum anomalies

AR (301820)

Nicholaides-Baraitser: retardation-sparse hair364

Severe developmental delay, short stature, sparse hair, lack of subcutaneous tissue, triangular face, coarse features, thick lips, swollen interphalangeal joints, short 4th and 5th metacarpals with coned epiphyses

Unknown (601358)

Nijmegen breakage365

Growth and variable intellectual impairment, sloping forehead, prominent mid-face and long nose, large and abnormal pinnae, upslanting palpebrae, cafe´ au lait spots, immunodeficiency, chromosome breakage and rearrangements of chromosomes 7 and 14

AR (251260) NBS1, 8q21

Norrie366

Variable microcephaly and normal to severe mental retardation, progressive ocular pseudoglioma, opaque corneae, cataract, sensorineural deafness in one third, narrow nasal bridge, flat malar region, thin upper lip

XLR (310600) NPD, Xp11 (continued)

489

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Nowaczyk: IUGR-pigmentary retinopathy367

Severe IUGR, developmental and growth delay, large fontanel, prominent forehead, aged facial appearance, short palpebrae, choanal atresia, small mandible, large hands with long fingers, no subcutaneous fat, peripheral retinal pigmentary changes, radiographic anomalies

Unknown

Obesity-growth hormone deficiency368

Growth and developmental delay, truncal obesity, unusual fat distribution in mammary and submammary areas, mild hypotelorism, small nostrils, cleft lip/palate, aggressive; single case

Unknown

Obesity-short stature (X-linked)369

Delayed development, low implantation of thumbs

XLR

Oculocerebralhypopigmentation370

Severe developmental delay, spasticity, generalized hypopigmentation, gingival hyperplasia, opacified and vascularized cornea; some cases with cardiac, renal and CNS anomalies including Dandy-Walker cyst

AR (257800)

Oculocutaneous albinismgrowth hormone371

Short stature, isolated growth hormone deficiency, mild hypopigmentation, nystagmus, large teeth, high palate, micrognathia, long philtrum, 2-3 toe syndactyly. The female of two sibs was microcephalic.

AR?

Oculodentoosseous372

Microcephaly and retardation are occasional signs; microphthalmia, microcornea, short palpebrae, thin nose and hypoplastic alae, enamel hypoplasia, 4-5 finger and 3-4 toe syndactyly, fine and sparse hair

AD (164200) GJA1, 6q22-q24 (Connexin 43)

Oculo-palato-cerebraldysplasia373

IUGR, short stature, hypotonia, bulbous nose, cleft palate, large and pointed ears, small hands and feet, microphthalmia, persistent hyperplastic primary vitreous, hypermobile joints, soft skin

AR (257910)

Ohdo374

Retardation, blepharophimosis, mild microphthalmia, ptosis, hypoplastic teeth, variety of congenital heart defects, cryptorchidism; one report of agenesis of the corpus callosum

AR (249620)

Okamoto: microcephalyclefting-hydronephrosis375

Severe growth and mental retardation, malar hypoplasia, hypertrichosis, synophrys, flat nasal bridge, short and anteverted nose, cleft palate, open mouth, webbed neck, hydronephrosis, congenital heart

Unknown

Olivopontocerebellar hypoplasia-dysmorphia376

Like trisomy 18 with prominent occiput, overlapping fingers, rocker-bottom feet; neurologic signs of spasticity, extra-pyramidal dyskinesia, absent voluntary motor responses, marked pontocerebellar hypoplasia, progressive cerebral atrophy

AR (277470)

Opitz: C-trigonocephaly377

Progressive microcephaly, small nose with broad root and anteverted nares, long and simple philtrum, attached frenulum, anomalous pinnae, upslanting palpebrae, abnormal joints, contractures, nevi, hemangiomas, cardiac defects

AR (211750)

Oral-facial digital-retinal378

Variable retardation, short stature, chorioretinal atrophy, lateral pseudocleft, high arched palate, multiple oral frenula, bifid/lobulated/hamartomatous tongue, mild brachydactyly, zygodactyly, broad hallux, bifid terminal phalanges of toes 1-3

AR? (258865)

Orstavik: aplasia cutisretinal-brain379

Aplasia cutis on scalp and abdomen, broad bulbous nose, small chin, long philtrum, hypoplasia to absence of fingers with the nails attached to metacarpals, ventricular dilatation and cerebral atrophy, variable thalamic calcification. Male had agenesis of the corpus callosum.

AR

Osteogenesis imperfectacataracts380

Hypertelorism, low-set ears, blue sclera, bowed lower limbs, soft calvarium, fractures at birth, lethal, few large or absent gyri

AR (259410)

Osteoporosispseudoglioma381

Microphthalmia, anterior chamber and vitreoretinal anomalies, fractures and deformities, short stature, mental retardation, thin sparse hair, micrognathia

AR (259770) LRP5, 11q13.4

Oto-palatal-digital II382

Mandibular hypoplasia, cleft palate, malar hypoplasia, downslanting palpebrae, narrow ribs, bowed forearms and legs, absent fibulas and carpals, pelvic hypoplasia

XLR (311300) FLNA, xq28

Paes-Alves: pseudopapilledemaskeletal384

External auditory stenoses, mixed deafness, small pinnae, hypotelorism, downslanting palpebrae, pseuodopapilledema, blepharophimosis, abnormal tooth color, micrognathia, mild finger skin syndactyly, short metacarpals, palmar keratosis, abnormal feet

AR (264475)

Palant: toe anomaliesunusual face385

Severe retardation; cleft palate; almond shaped, deep-set eyes; upslanting and narrow palpebral fissures; bulbous nasal tip; broad distal phalanges of toes; 2-3 toe syndactyly; 4-5 toe camptodactyly; short stature

AR (260150)

Partington: microcephalydistinctive face386

Pre- and postnatal growth delay, mild developmental delay, friendly, thick eyebrows, short nose with hanging columella, full cheeks

AR

Parietal foraminabrachymicrocephaly387

Contiguous gene syndrome involving parietal foramina (ALX4), multiple exostosis (EXT2), with variable craniofacial dysostosis and developmental delay

del 11p11.2 (continued)

490

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Periodic alternating nystagmus-microcephaly388

Growth and developmental retardation, congenital periodic alternating nystagmus with decreased visual acuity, prominent ears, cerebellar hypoplasia

Unknown

Peters anomaly-colobomatacontractures389

Peters anomaly, chorioretinal colobomata, falciform retinal fold, and arthrogryposis multiplex; two unrelated males whose mothers had a flu-like illness in the 4th week of gestation

Unknown

3-phosphoglycerate dehydrogenase390

Growth and psychomotor retardation, hypertonia, seizures, polyneuropathy, hypogonadism, occasional cataracts, adducted thumbs

AR (601815) 1q12

Pierpont: plantar lipomatosis-unusual face391

Developmental delay, prominent forehead, malar hypoplasia, square nasal tip, anteverted nares, thin upper lip, wide spaced teeth, central palatal ridge, congenital fat pads on anteromedial heels, prominent fetal finger tip pads, deep palmar/ plantar grooves

Unknown

Pilodentoungular dysplasia392

Delayed development; thin, sparse scalp hair; dystrophic nails, severest on fingers; thin skin on hands; blue sclera; retrognathia, high palate, hypodontia

Unknown

Pilotto: clefting-vertebral defects393

Mental retardation, infections, cleft lip/palate, hypertelorism, abnormal pinnae, high nasal bridge, short neck, vertebral anomalies, hypoplastic external genitalia

Unknown

Pitt-Hopkins394

Severe developmental delay, voluntary overbreathing, variable microcephaly, prominent nose with wide bridge and flared nares, macrostomia, thick and fleshy lips, finger clubbing, seizures, cerebellar hypoplasia

Uncertain

Pitt-Rogers-Danks395

IUGR, delayed development, downslanting palpebral fissures, prominent eyes, short upper lip, hypoplastic labia, extra palmar and digital creases

(262350) del 4p16.3

Poland anomalymicrocephaly396

Possibly chance association of microcephaly, typical symbrachydactyly, and ipsilateral pectoral hypoplasia

Unknown

Polysyndactyly-ptosis397

Short stature, mental retardation, pre- and postaxial polysyndactyly, dacryostenosis, high palate, fusion of incisors, brachyphalangy; parents consanguineous

Uncertain

Porphyria-acute intermittent, homozygote398

Optic nerve changes, cataracts, ataxia, developmental delay, skin photosensitivity; microcephaly, porencephaly, vermis hypoplasia, anterior encephalocele

AD (176000) homozygote

Prader-Willi399

Almond-shaped eyes with or without upslanting palpebrae, early severe hypotonia, variable short stature and delay, early obesity, small hands and feet by midchildhood, hypogonadism

Pat del 15q11-q13 Mat UPD 15q (176270)

Preaxial polydactylyclefting400

Bifid thumb, cleft lip/palate, short stature, seizures, clinodactyly of 5th fingers, delayed development, consanguinity in the one case

Uncertain

Premature aging-short stature401

IUGR, progressive loss of subcutaneous tissue, small jaw, prominent ears, high ‘‘piping’’ voice, broad forehead, hypospadias, hypodontia, fine and sparse hair, sensorineural deafness

Unknown

Premaxillary agenesismidline cleft402

Mental retardation, cleft lip/palate, hypotelorism, downslanting palpebrae, chronic constipation, absent maxillary incisors

AD (157170)

Primordial dwarfismcataracts403

Growth and developmental retardation, enamel hypoplasia, delayed bone age, brachymesophalangy, large down-turned mouth

AR (251190)

Progeria-Giannotti type404

Progeroid face, frontal bossing, upslanting palpebrae, blepharophimosis, poor subcutaneous fat, large nose, thin lips. Son also had microcephaly and mild developmental delay

Uncertain (602249)

Proptosis-Pierre Robin405

Dolichocephaly; hirsute forehead; low posteriorly rotated ears; wide nasal bridge and alae; clenched hand with 2nd finger over 3rd; hypospadias; seven whorls

Unknown

Pseudo-Down406

Short stature and developmental delay with facial characteristics suggestive of Down syndrome but with normal dermatoglyphics and karyotype

AR (264450)

Pseudoprogeria/HallermanStreiff 407

Congenital absence of eyebrows and eyelashes; early-onset spasticity and delay; later glaucoma, optic atrophy; presenile appearance; ptosis, downslanting palpebrae; micrognathia

AR (200130) XLR

Pseudo-TORCH408

Severe retardation and seizures, extensive and variable deep and superficial supratentorial and basal ganglia calcification, hepatosplenomegaly, petechial rash; similar to, and may be allelic with, Aicardi-Goutieres and Cree encephalitis

AR (251290)

Pterygia-short stature409

Trigonocephaly, hypertelorism, epicanthus, small jaw, low and rotated ears, thin fingers with syndactyly, hypogonadism, growth failure and retardation, neck and elbow pterygia, crura knees

AD (177980)

Ptosis-subvalvular aortic stenosis410

Ptosis, downslanting palpebrae, hypertelorism, short nose with broad bridge, small mouth, high palate, bifid uvula, pectus, high-pitched voice

XLD or AD (continued)

491

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Radial microbrain

Brain weights of 16–50 g at term, variable acromicria and nephropathy, overall reduction by about 30% in neurons that have normal vertical distribution and appearance; deficit of the total number of vertical cell columns (radial-neuronal-glial units), perhaps from too few proliferative neuronal-glial units in the germative zone

AR

Radial ray-ulnar hypoplasiaretardation509

Developmental delay, short stature, absent thumbs, ulnar hypo/aplasia, cryptorchidism, micropenis. Single case

Unknown

Radioulnar synostosis-short stature412

Mild developmental delay, bilateral radioulnar synostosis, short stature, thoracic scoliosis; two sporadic cases with consanguinity in one

AR?

Raine dysplasia413

Short neck, craniofacial disproportion, wide fontanels, small nose with low root, dysplastic pinnae, small mouth, arthrogryposis, micrognathia, bone sclerosis, prenatal fractures

AR

Ramban-Hasharon: glycosylation defect IIc414

Severe developmental delay, short stature, minor face dysmorphia, variable craniostenosis, cortical atrophy, seizures, recurrent infections, neutrophil motility defect, absent red blood cell H antigen

AR (266265) FUCT1, 11p11.2

Reardon: microcephalyblepharophimosis415

Developmental delay, short palpebrae, ptosis, large ears; possible variant of Ohdo

AR?

Renal/Mu¨llerian duct hypoplasia-craniofacial510

Severe developmental delay, large anterior fontanel, tall and broad forehead, hypertelorism, small nose, short philtrum, renal malformations, absent uterus, dimples at the elbows and wrists, delayed bone age, hypoplastic distal phalanges

AR (266810)

Renpenning416

Moderate microcephaly, short stature, moderate to severe retardation, small to normal testicular size, normal ears

XLR (309500) PQBP1, Xp11.2

Respiratory chain deficiencycraniofacial malformations417

A variety of respiratory chain defects can cause pre- and postnatal growth retardation, and variable craniofacial dysmorphia including round face with high forehead, flat philtrum, short neck, hypoplastic middle and distal phalanges

AR and mitochondrial

Retinal detachment-acral anomalies418

IUGR, growth failure, profound retardation, rudimentary distal phalanges of fingers, absent distal creases, small toes 2-5, rudimentary nails

AR

Retinitis pigmentosa-mental retardation511

Mild to moderate mental retardation, retinitis pigmentosa, myopia, cataract; female carriers of normal intelligence, some had evidence of retinitis pigmentosa; possible contiguous gene syndrome

XLR Xp21-q21

Rett419

Typically presents in females after initial normal development and OFC; developmental arrest by about 18 mos, followed by regression and microcephaly; hand wringing; hyper/hypoventilation; occasional severe perinatal encephalopathy in males. Severe type with infantile spasms due to mutations in CDKL5.

XLD (312750) MECP2, Xq28

Rhizomelic chondrodysplasia punctata-type I420

Symmetric proximal shortness of humeri and femora, flat face, low nasal bridge, cataract, ichthyotic skin changes, coronal cleft vertebrae, punctate epiphyseal and extraepiphyseal calcification, peroxisomal defect

AR (215100) PEX7, 6q22-q24

Rhizomelic chondrodysplasia punctata-type II421

Equivalent phenotype to type I but lacks a peroxisomal defect biochemical profile

AR DHAPAT, Chr 1

Richeri-Costa: acro-frontofacio-nasal512

Microbrachycephaly, posteriorly rotated ears, hypertelorism, broad nose with midline groove and bilateral blind ending pit on nasal tip, hypospadias, 3-4 finger syndactyly, broad thumbs and halluces, consanguinity

AR (201181)

Richieri-Costa: microbrachycephalylumbosacral422

Mental retardation, short stature, long thin face with hypoplastic midface, cleft lip, obtuse mandibular angle, prominent chin, pelvic and lumbosacral modeling anomalies

AR

Roberts-SC phocomelia423

Growth failure, variable retardation, cleft palate, clouded cornea, hypoplastic nasal/ear cartilage, phocomelia, oligodactyly, silvery hair, penis/clitoris enlarged, centromere separation

AR (268300) ESCO2, 8p21

Robin sequence-aniridiagrowth delay513

Severe growth and developmental delay, triangular face, aniridia, micrognathia, cleft palate, delayed dental eruption, long and tapering fingers. Affected sib pair

Uncertain

Rothmund-Thompson424

Microcephaly and developmental delay are occasional findings; IUGR and postnatal growth failure, poikiloderma, hyperkeratosis, photosensitivity; sparse hair, premature graying; juvenile zonular cataract; micro/anodontia; nail dystrophy; probable heterogeneity

AR (268400) RECQL4, 8q24.3

Rubella, prenatal425

Defects depend on timing of infection from first to mid-second trimester; IUGR, growth and developmental retardation, deafness, cataracts, microphthalmia, chorioretinitis, patent ductus and peripheral vessel stenosis, signs of congenital infection

Prenatal infection with rubella virus

411

(continued)

492

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Rubinstein-Taybi

Mental retardation, short stature, downslanting palpebrae, hypoplastic maxilla, narrow palate, beaked nose, septum extending below alae, abnormal auricles, broad angulated thumbs and great toes

AD (268600) microdeletions (11%) CREB, 16p13.3

Ruvalcaba427

Mental retardation, short stature, downslanting palpebrae, small nose, narrow maxilla, thin vermillion, pectus carinatum, thin skin, short metacarpals, phalangeal tufting

AR (180870)

Salinas: atypical clefting428

Acrocephaly, craniosynostosis, lower lid colobomata, inner lid margin granulationlike tissue, no medial lashes, choanal atresia, redundant midfacial skin, cleft palate

Unknown

Saul: salt and pepper pigment429

Scattered hyper- and hypopigmentation, midface hypoplasia, prognathism, scoliosis, choreoathetosis, seizures, severe mental retardation, overtubulated bones

AR

Say: cleft palate-large ears430

Short stature, hypoplastic toenails and nipples, tapering fingers with hypoplastic tips, proximal thumbs, marked micrognathia, hypospadias

AD (181180)

Scalp defects-polythelia431

Developmental delay, cutis aplasia of the scalp, protruding ears, wide nasal bridge and alar base, thin upper lip, micrognathia, polythelia

AD

Schachter: hypotelorismsmall mouth-prognathism514

Short stature, developmental delay, small and low-set ears, hypotelorism, epicanthus, strabismus, cataracts, small and cupid-bow–shaped mouth, prognathism, 3-4 finger syndactyly, abnormal skin pigmentation

Unknown

Schimke: immuno-osseous dysplasia432

Usually normal intellect with childhood onset of disproportionately short trunk, mild craniofacial dysmorphia, defective cellular immunity with immune complex nephropathy; variant with microcephaly and retardation

AR (242900) SMARCAL1, 2q35

Schlichtemeier: multiple coagulation defects515

Mental retardation, congenital hypotonia, mild hypertelorism, arched eyebrows, prominent teeth, narrow hands with long fingers; variable blood vessel anomalies including hemorrhage, narrowness, tortuosity, aneurysm and thrombosis; abnormalities of multiple anticlotting factors

AR (216550)

Sclerocornea-short stature433

Postnatal growth failure, short limbs, small hands and feet, microphthalmia, sclerocornea, coloboma, delay beyond expectation for visual impairment; like Peters-plus

AR?

Seckel434

Severe IUGR, proportionate growth failure, severe mental retardation, receding forehead and chin, downslanting palpebrae, prominent curved nose, dislocated radial head

AR (210600) ATR, 3q22.1-q24, SCKL2, 18p11.31q11.2

Seckel-like, ataxiaendocrinopathy435

Proportionate primordial dwarfism, gonadal insufficiency (testicular atrophy, ovarian aplasia), insulin resistance, onset of goiter in teens, progressive ataxia, mental retardation

AR

Seckel-like, MajoorKrakauer436

IUGR, extreme micrognathia, dysplastic low and rotated ears, beak-like nose, prominent eyes, absent gyral pattern (subject to early prenatal diagnosis)

AR

Seckel-like, osteodysplastic types I and III437

Seckel face but disproportionate dwarfism with short limbs; type I, short bowed humerus and femur; type III, long clavicles, cervical arch clefts, lumbar platyspondyly; difference may be part of an age-dependent spectrum

Unknown

Seckel like-pancytopenia516

Sloping forehead, micrognathia, prominent midface, slightly hooked nose, onset of pancytopenia in infancy, increased chromosome breakage and mitomycin C sensitivity, seizures, cryptorchidism, hypoplastic scrotum, glandular hypospadias, hyper- and hypo-pigmentation, ‘‘spindle-shaped’’ fingers

Unknown (600546)

Seckel-like, premature senility438

Normal birth weight, developmental delay, sloping forehead and chin, prominent nose, ptosis, nystagmus, early graying and alopecia, low-set ears, atrophic epidermis

Unknown

Seckel-like, short limbs439

Severe IUGR, growth failure, small forehead, some nasal prominence, disproportionate limb shortness, brachymesophalangy and metacarpy, femoral metaepiphyseal changes

AR (210720)

Setlies: temporal forceps marks517

Temporal cutis aplasia, upslanting eyebrows, absent eyelashes of upper or lower lids, double eyelashes upper lid, narrow palpebrae, excess periorbital skin, floppy eyelids, ptosis, full nasal tip, scar-like vertical ridge on the chin; single report with microcephaly

AR/AD (227260)

Seidel: microcephaly440

IUGR, growth and developmental delay, hypotonia, receding hairline, broad lateral eyebrows, long eyelashes, flat nasal tip, microdontia, large ears with crus anomalies, pectus excavatum, cutis laxa, mild skeletal anomalies

AR or XLR

Sequeiros-Sack: linear skin atrophy441

Congenital crusted erosions and blisters of skin and tongue that heal to reticulated scars, scarring alopecia, variable anonychia; microcephaly and developmental delays in a subset of cases

Unknown

426

(continued)

493

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Severe microcephaly-absent pyramidal tracts442

Sloping forehead, hypertelorism, broad nasal tip, micrognathia, absent pyramidal tracts, dysplastic inferior olives, microphthalmia, joint contractures

AR

Severe microcephaly-choreacataracts518

Early onset of choreiform movement, cataracts, sensorineural deafness, profound mental retardation

Unknown

Short stature-cleft mandibleradial ray443

Short stature, microstomia, micrognathia, cleft lower alveolar ridge, laryngeal anomalies, variable radial ray defects; OFC not recorded in many of ten case reports but one documented case of microcephaly

AR (268305)

Short stature-deafnessclefting-digital444

IUGR, frontal bossing, short premaxilla, Pierre-Robin, prominent nose, sensorineural deafness, myopia, small hands and feet with digital angulation due to accessory triangular phalanges; single case

Unknown

Short stature-skin pigment anomalies445

Growth failure, hypertonia, distal finger camptodactyly, hypoplastic third toes and terminal 5th digit, chorioretinitis, optic atrophy, cafe´-au-lait and other pigment changes

Unknown

Skeletal dysplasia-CNS degeneration446

Postnatal growth failure, short limbs, variable postnatal microcephaly, short and anteverted nose, short neck, small thorax, platyspondyly with wafer-thin vertebrae, progressive encephalopathy, early death

AR (602613)

Skeletal dysplasia-Robin anomaly-polydactyly447

Postnatal microcephaly, developmental delay, abnormal pinnae with stenotic canals, prominent forehead, small mouth, micrognathia, cleft palate, broad and varus thumbs, valgus halluces, postaxial hexadactyly of the feet, skeletal anomalies

Unknown

Slender bone osteodysplasiapituitary-retinopathy519

Postnatal growth and developmental delay, dysmorphic appearance, pigmentary retinopathy, pituitary hypoplasia, growth hormone deficiency, micropenis; like type III osteodysplastic primordial dwarfism but no IUGR; single case

Unknown

Smith-Fineman-Myers448

Dolichocephaly, upslanting palpebrae, hyperopia, decreased frontonasal angle and nasolabial folds, patulous lower lip, flat philtrum, micrognathia, pale with freckles, short, delayed development, seizures (some may be X-linked alpha thalassemia without hemoglobin H bodies)

XLR (309580) XNP, Xq13 Heterogeneity

Smith-Lemli-Opitz449

Postnatal growth failure, mental retardation, narrow forehead, ptosis, epicanthus, broad anteverted nasal tip, broad alveolar ridges, micrognathia. Severe end of spectrum has more marked genital and internal anomalies, and postaxial polydactyly

AR (270400) DHCR7, 11q12-q13

Smith-Magenis450

Short stature, square and broad face, upslanting palpebrae, deep-set eyes, full cheeks, depressed and broad nasal root, marked malar hypoplasia, fleshy and tented upper lip, bulky philtral pillars, characteristic and possibly unique behaviors (nail yanking, body insertions)

(182290) del 17p11.2

Spastic paraplegia-optic atrophy-sex reversal451

Spastic paraplegia with normal cognition, optic atrophy, poor vision, XY-sex reversal

AR (603117)

Sparse hair-seizures452

Sparse hair on scalp and brows growing at normal rate, moderate retardation, generalized seizures

AD or AR?

Spondyloepiphyseal dysplasia-retinal dystrophy453

IUGR, postnatal growth and developmental delay, anteverted nares, long philtrum, thin upper lip, upslanting palpebrae, epithelial dysplasia, retinal dystrophy, variable immunodeficiency

AR (300258) XLR

Stimmler: enamel hypoplasiadiabetes454

Severe retardation, dwarfism, early-onset insulin-dependent diabetes, small teeth with enamel hypoplasia, ataxia, alaninuria

AR (202900)

Stoll: congenital heartneurofibromatosis520

Ear asymmetry, long nose, short philtrum, prominent lower lip, multiple cafe´-au-lait spots, complex congenital heart defect, phaeochromocytoma, consanguinity; concurrence of a syndrome with NF1?

AR?

Sutherland-Haan: microcephaly-spastic diplegia455

IUGR, short stature, brachycephaly, lean build, mild to moderate spasticity, small testes, delayed puberty, anal stenosis/atresia

XLR (309470) PQBP1, Xp11.2

Tall stature-infraauricular creases456

Postnatal microcephaly and developmental delay, hypotonia, flat midface and philtrum, mildly tented upper lip, advanced bone age, horizontal crease below ear lobes. Single case

Unknown

Tapetoretinal degeneration457

Growth and developmental delay, sensorineural deafness, severe joint laxity with dislocations and scoliosis, hypotonia, short stature

Unknown

TAR-like458

IUGR with borderline microcephaly at birth, small nose, anteverted nares, cataracts, glaucoma, malar hypoplasia, rhizomelia, radial aplasia, five digits both hands, low platelets; consanguinity

AR?

(continued)

494

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Temtamy: brachydactylyhyperphalangism521

Short stature, mild developmental delay, deafness, low-set ears, mid-face hypoplasia, arched eyebrows, synophrys, narrow nose, small mouth, micrognathia, dental anomalies, shawl scrotum, short hands, proximally placed and abducted thumbs, various clinical and radiographic hand and foot anomalies

Unknown

Tetra-amelia-ectodermal dysplasia459

Postnatal microcephaly, tetra-amelia, upslanting palpebrae, abnormal lacrimal ducts, prominent and bulbous nose, preauricular pits, hypotrichosis, absent medial clavicle

AR (273390)

Theile: unusual face460

Severe retardation, small nose with broad bridge, epicanthus, narrow palpebrae, high palate, low-set ears, cryptorchidism

Unknown

Thrombocytopenia-skeletalcardiac461

Stenotic ear canals, hypertelorism, pallor of optic disc, prominent nose, prognathism, high palate, ventricular and atrial septal defect, tapering phalanges, partial zygodactyly of fingers, carpal fusion

Unknown

Toluene embryopathy462

Abnormal hair pattern, narrow bifrontal diameter, deep-set eyes, short palpebral fissures, small midface, low-set ears, small nose, micrognathia, blunt finger tips, small nails, hypotonia, hyperreflexia

In utero exposure to toluene

Toriello: branchial arch463

Downslanting fissures, high palate, low protruding ears, hearing loss, slight neck web, cryptorchidism, subvalvular pulmonic stenosis

XLR (301950)

Torres-Aybar: microcephalycardiac defect464

Two sisters with developmental delay, large patent ductus, ear anomalies, deafness, broad nasal bridge, nail hypoplasia, delayed dentition; brother with dextrocardia

AR?

Toxoplasmosis465

Spectrum of disease includes IUGR, developmental delay, hydrocephalus, microcephaly, intracranial calcifications, chorioretinitis, hearing loss

Prenatal infection

Trichodental dysplasiamicrocephaly466

Fine, dry, and slow-growing hair; hypodontia and peg-shaped teeth; single case reported with microcephaly and mental retardation

AD? (601453)

Trichothiodystrophyichthyosis467

Low birth weight, short stature, mental retardation, aged look, nail dysplasia, cataracts, osteosclerosis, brittle hair showing alternating light and dark bands under polarization, cystine deficiency in hair. Mutations in the helicase subunits of TFIIH.

AR (601675) ERCC3, 2q21 ERCC2, 19q13.2q13.3

Trigonocephalyhypospadias468

Moderate retardation, high palate, hooked nose, posteriorly rotated ears, maxillary hypoplasia, ‘‘beaked’’ nails

AR (241760) XLR

Trigonocephalymicrognathia-zygodactyly522

Trigonomicrocephaly, large ears, severe and asymmetric micrognathia, atrioventricular septal defect, vertebral anomalies, cutaneous syndactyly of hands and feet, cafe´-au-lait-spots; single case

Unknown

Trigonocephaly-short stature-developmental delay469

IUGR, hypotelorism, posteriorly rotated ears, 5th finger clinodactyly

XLR (314320)

Trimethadione, prenatal470

Mental retardation, abnormal helices, cleft lip/palate, heart defects, renal anomalies, hypospadias, 2/40 were microcephalic

Prenatal exposure

Troyer-like523

Developmental delay, marfanoid appearance with normal stature, evidence of peripheral muscle atrophy with fasciculation in males and electrical evidence of neuropathy in females; EMG and nerve biopsy in the males suggested an axonal neuropathy

AR

Tsukahara-Sugio: micromelia-microcephaly471

Borderline developmental and growth delay, variable mild microcephaly and trigonocephaly, narrow bifrontal diameter, upslanting palpebrae, anteverted nares, micrognathia, small hands

AD (603572)

t(X;Y) female-linear skin defects-microphthalmia472

Linear, erythematous skin defects; variable microphthalmia, anterior chamber defects, sclerocornea; short stature; congenital heart defects; variable corpus callosum defect

del Xp22 (309801)

Type A1 brachydactylydwarfism473

Delayed growth and development, ptosis, epicanthus, bulbous nose, mesomelia, short digits, hypoplastic toenails, severe myopia, chronic otitis media

Unknown

Upper limb-cardiovascular474

Delayed growth and development, hypertelorism, high palate, small mandible, low-set ears, asymmetric limb hypoplasia, radioulnar synostosis, congenital heart Sparse hair, large fontanel, macroglossia, saddle nose, high palate, short stature, flat acetabulae, digitalized thumb, bifid terminal phalanx, pulmonic stenosis, developmental delay

Unknown

Moderate mental retardation, small and malformed pinnae, telecanthus, epicanthic folds, flat and broad nose, wide mouth, camptodactyly/clinodactyly of the fingers, mild skin syndactyly; similarities with blepharo-naso-facial syndrome

Unknown

Urbach: short humeri475

Van Maldergem: blepharonaso-facial-hand524

AR (268250)

(continued)

495

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Varicella

Variable IUGR, seizures, wide spectrum of development, cortical atrophy, chorioretinitis, limb and/or digit hypoplasia, cutaneous scarring; high mortality, infection between 8–20 weeks

In utero infection

Vasquez: hypogonadismgynaecomastia525

Moderate mental retardation, short stature, variable brachycephaly, micrognathia, obesity, hypogonadism, clinodactyly/camptodactyly of the hands369

XLR (309590)

Velo-cardio-facial477

Long narrow face, retrognathia, prominent nose with hypoplastic tlip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay, congenital heart; especially conotruncal defects

AD (192430) del 22q11 del 10p

Ventricular extrasystolehyperpigmentation478

Ventricular extrasystoles, short stature, small mandible, absent mandibular first molars, patchy areas of hyperpigmentation

AD (133750)

Verloes: male pseudohermaphroditismmu¨llerian526

Short stature, mental retardation, coarse face with deep-set eyes, microphthalmia, full lips; males with genital ambiguity, persistent mu¨llerian structures, obesity. One sib had anal atresia and a sacral spina bifida.

AR (600122)

Viljoen-van Vuuren: broad thumbs and toes479

Microbrachycephaly, growth and developmental retardation, downslanting palpebrae, large ears, prominent nose, malar hypoplasia, broad thumbs and toes, hyperextensible interphalangeal joints

AR

Vitamin A, prenatal480

Spontaneous abortion, microtia, microphthalmia, anophthalmia, congenital heart, limb reduction defects, thymic hypoplasia, jaw hypoplasia, hydrocephalus

In utero exposure

Vohwinkel: mutilating keratoma plus481

Diffuse hyperkeratosis of palms and soles, constriction of phalanges, starfish-shaped dorsal hyperkeratosis of hands and feet; may have hearing loss, alopecia, nail anomalies; single case with long face, clefting, and microcephaly

AD (124500)

Warfarin, prenatal482

Significant developmental delay, small and grooved nose with depressed bridge, stippled epiphyses, mild nasal hypoplasia, short fingers; other CNS defects reported

In utero exposure ARSE inhibition

Weaver-Hansma: microcephaly-cataracts483

Growth and developmental delay, cataracts, optic nerve hypoplasia, malar hypoplasia, epicanthus, short anteverted nose, fair skin, hypoplastic toenails

AR?

Weaver-Williams: unusual face-weight deficiency484

Mental retardation, decreased subcutaneous tissue and muscle, prominent ears, small downturned mouth, malformed teeth, cleft palate, downsloping ribs, bone hypoplasia

AR

Wiedemann: fibrolipomatoid hamartoma485

Mild mental retardation; short stature; long furrowed tongue; round to lobular tongue and alveolar surface; white to yellow brown, congenital tumour-like polypoid growths

AR?

Wiedemann: microcephalygrowth retardation527

Mental retardation, short stature, hypotonia, unusual cry, hypoplastic optic nerves, irregular fundal pigmentation, complete 3-4 skin syndactyly of the fingers, mild 1-2 syndactyly of the toes, congenital heart defect

Unknown

Wiedemann-retardation unusual face486

Narrow palpebral fissures and alae nasi; large mouth; low, prominent, simple ears; small mandible, broad wrists; syndactyly of fingers 2-5; brachytelephalangy

Unknown

Wiedemann: thumb anomaly-short stature487

Developmental delay, downslanting palpebrae, low-set ears, small chin, short stature, stubby and broad thumbs and toes, micropenis, scrotal hypoplasia

AD or XLD

Wiedemann: unusual faceanal atresia488

Low-set cupped ears with folded helix, downslanting palpebrae, ptosis, thin upper vermillion, short stature, developmental delay

Unknown

Williams489

Mild microcephaly and growth failure, short palpebrae, stellate irises, periorbital fullness, anteverted nares, full lips, supravalvular aortic stenosis, friendly personality; oligogyric microcephaly reported. Contiguous gene syndrome.

AD (194050) 7q11.2

Winter: distinctive face-broad thumbs and toes490

Frontal cowlick, midface hypoplasia, deep-set eyes, convex nasal profile, small ears, mandibular overbite, broad thumbs and toes, mild developmental delay

AD or XLD

Wolcott-Rallison491

Neonatal or early infancy onset diabetes mellitus, epiphyseal dysplasia, growth retardation; microcephaly an occasional finding

AR (226980) EIF2AK3, 2p12

Woods-Huson: microcephaly-syndactyly492

Severe developmental delay, growth failure, broad and hirsute forehead, broad nasal bridge with prominent columella and hypoplastic alae, long and narrow toes, dystonic movements, 3-4 finger syndactyly

AR (272440)

Worster-Drought: supraorbital paresis493

Variably severe suprabulbar paresis impairing orbicularis oris, tongue, soft palate, larynx, and pharyngeal muscles; a subset have developmental delay and microcephaly

AD (185480)

Wrinkly skin494

IUGR, developmental delay, hypotonia, winged scapulae, hip dysplasia, joint hyperextension, wrinkled skin on dorsum hands and feet, secondary plantar and palmar creases, hypoelasticity, prominent veins

AR (278250) 2q32

476

(continued)

496

Brain

497

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Cutaneous sun sensitivity and early carcinomas, corneal changes, 18% progressive neurologic change; DNA repair defect with heterogeneity shown by complementation studies

AR (278800) ERCC6, 10q11

X-linked complex spastic paraplegia-Claes496

Borderline microcephaly with severe mental retardation, hyperreflexia, hypertonia, and muscle hypoplasia of lower limbs, facial hypotonia, shuffling gate

XLR Xp21.1-Xq21.3 or Xq23-Xq27.1

XLMR-Christianson497

Mild microcephaly, profound mental retardation, no speech, ophthalmoplegia, truncal ataxia, lowered life expectancy, cerebellar and brain stem ‘‘atrophy’’; females may show delay

XLR (300243) Xq24-q27

XLMR (MRX14)-Gendrot498

Nonsyndromic moderate to severe mental retardation with mild microcephaly, seizures, prominent ears, macroorchidism

XLR Xp11.22-Xq11.2

XLMR-growth hormone deficiency499

Variable microcephaly, short stature, high palate, dental crowding, gynecomastia, clinodactyly, infantile behavior, isolated growth hormone deficiency

XLR SOX3, Xq24-q27.3

XLMR-Hyde-Forster500

Two severely retarded male maternal half-sibs whose maternal aunts had learning problems; coarse facial features, brachycephaly, plagiocephaly; one was microcephalic

XLR (300064)

XLMR-ophthalmoplegiadeafness501

Postnatal microcephaly, growth and mental retardation, childhood onset of choreoathetosis and spasticity, external ophthalmoplegia, variable neurosensory deafness

XLR (312840)

X-linked microcephalymicrophthalmia-genital hypoplasia502

Congenital cataracts, microcornea, microphthalmia, short and upslanting palpebrae, large ears, thin upper lip, downturned mouth, genital hypoplasia, growth failure

XLR

Young-Simpson503

Developmental and growth delay, hypothyroidism, small and low-set ears, blepharophimosis, bulbous nasal tip, tented upper lip, congenital heart defects

Unknown

Yunis-Varon: cleidocranial dysostosis504

Wide anterior fontanel; sparse scalp hair; short philtrum; narrow palate; micrognathia; thin lips; absent/hypoplastic thumbs, great toes, clavicles; distal toe/finger aphalangia

AR (216340)

Zerres: postnatal microcephaly-syndactyly505

Mental retardation, postnatal onset growth failure and microcephaly, 2-5 finger and 1-4 toe syndactyly, brachymesophalangy of fingers 2-5, sparse hair, short nose, poor philtrum, small penis

Unknown

Zlotogora-Dagan: thumb anomalies506

IUGR, growth and developmental delay, aplastic or malpositioned thumb, amenorrhea, azoospermia, some with skin hyperpigmentation; occasionally other anomalies, including case with holoprosencephaly

Uncertain

Xeroderma pigmentosum

495

at risk siblings was not given. In a study of a population selected for consanguinity and an OFC between 4 SD and 14 SD, 38 of 56 showed linkage to one of the five, then known, isolated genetic microcephaly (MCPH) loci.13 As these and related genes are cloned16 and testing can be applied, it will be interesting to see how often such genes account for this form of microcephaly in the general population of non-consanguineous, simplex families. To date, six loci for true (primary) microcephaly have been mapped (MCPH1– MCPH6) and the genes for MCPH1 (Microcephalin),566 MCPH5 (ASPM),567 MCPH3 (CDK5RAP2), and MCPH6 (CENPJ)568 have been found. It should be kept in mind that an intrinsic fetal metabolic disease can have a developmental impact and lead to prenatalonset microcephaly.17 Degenerative conditions show progressive neurologic signs and may be accompanied by increasingly severe microcephaly. Most are genetic and include the broad spectrum of early-onset metabolic and abiotrophic diseases. However, post-infection complications, such as subacute sclerosing panencephalitis or early postnatal exposure to toxins such as lead, may also cause the degeneration of a previously normal brain. Microcephaly may accompany gross disruptive abnormalities such as craniofacial amniotic bands, but more often it represents a subtler clinical situation. Major disruption of blood supply will likely give rise to clastic lesions, and perinatal hypoxia may also leave a characteristic footprint on neuroimaging. The pregnancy

and perinatal history may lend important clues, and invasive prenatal diagnostic procedures may occasionally give rise to vascular disruption.529,530 In a study of children with learning disability, respiratory distress syndrome and intraventricular hemorrhage were the perinatal factors most strongly associated with microcephaly.531 The type of microcephaly and the associated clinical signs will vary with the ascertainment, and there is an interesting contrast between prenatal and newborn cases. In a prenatally ascertained series of 30 cases with a mean gestation of 28 weeks, more than half the fetuses were small for dates.37 Five had isolated microcephaly, five had holoprosencephaly, seven had a chromosome anomaly, six had a known genetic syndrome, and seven had multiple anomalies. Thus in 83%, the microcephaly was part of a complex problem. Dalgren and Wilson came to a similar conclusion after a retrospective review of 21 infants with a prenatal diagnosis of microcephaly that had been confirmed postnatally.532 The common etiologies included infection, complications of monochorionic twinning, genetic syndromes, and chromosome anomalies. In contrast, in a case-control study of infants whose microcephaly was ascertained through the systematic measurement of 19,000 consecutive newborns, only 4 (6.2%) of those with an OFC of  2 SD were considered dysmorphic or had a major malformation.533 One malformation syndrome and one metabolic disease were recognised, and the infants with microcephaly did not have an excess of minor anomalies.

498

Neuromuscular Systems

Any attempt to study the prevalence of microcephaly is challenged by a discouraging array of methodologic problems, and some of these have been discussed by Leviton et al.534 The prevalence of microcephaly is highly dependant on the age at ascertainment. Second trimester studies will miss many conditions that become apparent toward term; newborn ascertainment will not include those whose microcephaly has a peri- or postnatal onset. The study of an adult population will miss severe cases that have died and is likely to be biased toward a selected population, such as those with a learning disability.531 The causal mix of microcephaly should show a temporal change as certain causes are largely eliminated (congenital rubella) and others are introduced (gestational cocaine use) or are modified through improved pediatric and obstetric care, or by interventions such as prenatal screening for major malformations and chromosome abnormalities. The study of Vargas et al.533 verified the cranial measurements of the 850 infants in the lowest quartile from their study of 19,000 neonates. They found 106 with a confirmed OFC  2 SD below the mean, giving a birth prevalence of microcephaly of 5.5/1000 (0.55%). The prevalence was well below the statistically expected 25 per 1000, which suggests either a significant skew from the normal distribution or that the OFC charts in use are not representative of the current population. There does not appear to be a good current estimate of the rate of isolated genetic microcephaly. A 1955 Japanese study estimated the prevalence to be 1/25,000 to 1/50,000 livebirths.535 A broad range of intrauterine exposures to medications, drugs, chemicals, and infections, including cytomegalovirus, toxoplasma, rubella, and other viruses, may lead to microcephaly (Table 15-1). It is not the intention to review here the evidence for and against the various putative environmental teratogens. Instead, comments are limited to a few factors that are of particular contemporary interest. That pregnant women should not be exposed to x-rays has been indoctrinated into all medical practitioners. The accepted maximal in utero exposure to radiation is 0.05 Gy (5 rads). In assessing risk, it is paramount to distinguish diagnostic from therapeutic radiation. All single diagnostic procedures involve less than 0.05 Gy,536and the true threshold for malformation is likely significantly higher. The critical period for exposure is between 8 and 15 weeks, although there is evidence that high-dose radiation later in gestation can be harmful to the brain. Data on high exposure derive mainly from survivors of Hiroshima and anecdotal clinical experience. Microcephaly is the single major malformation associated with atomic bomb survivors, and children exposed within 1500 m of the hypocenter had an average OFC of 1.1 cm less than unexposed controls at the age of 17 years.537 The exposure of five survivors with the most severe intellectual impairment ranged between 0.69 Gy and 1.76 Gy.539 Reports of effects at levels as low as 0.10 Gy have involved unusually high neutron levels. Neutrons carry 5 to 20 times the radiation weighting factor of standard gamma or x-rays.539 There has been no evidence of an increase of microcephaly following in utero exposure to fallout from Chernobyl.540 Therapeutic radiation can expose the fetus to teratogenic levels. Case reports of infants with microcephaly include ocular changes that have been associated with radiation following maternal radiation therapy.541 Careful abdominal shielding may reduce fetal exposure by up to 50% and increase the margin of safety when maternal treatment of certain tumors is required.537 Guidelines to the systematic documentation and assessment of in utero radiation exposure have been published and can be followed in individual cases.542

At present, there is no evidence that diagnostic obstetric ultrasound is harmful to the developing brain. There is a single report of a developmentally delayed, microcephalic child with sacral agenesis born to a mother who received therapeutic ultrasound, and McLeod and Fowlow caution against this type of embryonic exposure.543 Microcephaly may occur due to in utero exposure to a number of drugs (Table 15-1), but two substances merit further discussion. Vitamin A deficiency and excess have long been known to be potent teratogens in animals, and an embryopathic effect in humans was anticipated when these compounds were introduced for the treatment of cystic acne (isotretinoin) and psoriasis (etretinate). Despite package warnings, the education of physicians about the potential hazards, and efforts to control prescriptions, the inevitable in utero exposures occurred, with a resultant high rate of spontaneous abortion and fetal abnormality.544 Typical malformations of the central nervous system include microcephaly/ hydrocephaly, posterior fossa cysts, and cortical blindness, and these are found associated particularly with ear, thymic, and cardiovascular malformations. Isotretinoin has a short half-life, and the outcome is favorable if exposure is discontinued by 4 weeks before the last menstrual period. The half-life of etretinate is months and therefore raises concern even for preconceptional exposure. There have been a few case reports of infants exposed to topical tretinoin who have had malformations compatible with retinoid teratogenicity.545 Vitamin A is available across the counter, without a pregnancy warning label, and in some cases with doses as high as 25,000 to 100,000 IU, although the recommended daily allowance is in the range of 5000 IU. Vitamin A may also have a role in reducing the chance of vertical transmission of HIV. Human malformations have been associated with doses as low as 25,000 IU/day, and a study that was criticized on methodologic grounds raised concerns about doses as low as 10,000 IU/day.546 Mulder et al.546 were able to produce subtle evidence of neural crest disturbance in mice with a single dose of 10 mg (29,000 IU)/kg administered at critical day 9 (human weeks) postconception. The conservative approach would be to advise against doses greater than 10,000 IU/day in women who may become pregnant. The fact that a single center was able to report on 505 newborns exposed during intrauterine life to illicit drugs547speaks to the magnitude of the problem in society today. Cocaine has emerged as an agent that causes fetal damage and is associated with spontaneous abortion, abruptio placenta, prematurity, stillbirth, and IUGR. In extreme cases, vascular damage may lead to the fetal brain disruption sequence,203 and abnormalities of vasculature and neuronal migration have been observed at autopsy.548 Several studies have shown an increased rate of microcephaly in exposed infants, variably estimated to be eight-fold greater than in controls, or up to 20% of cases.547,549–552 Neonatal neurologic signs and symptoms are considered to be a drug effect, rather than withdrawl,547and long-term developmental consequences have been noted. Comparison with other illicit drugs,547and studies that have controlled for confounding variables, confirm that the pathology is due to cocaine and not sociodemographic factors.549 Abuse of alcohol,53 solvents such as toluene553 and gasoline,554 and poisons such as methylmercury313 and carbon monoxide555 can result in microcephaly, in some cases with severe neurologic signs and mental retardation. Prognosis, Treatment, and Prevention

Microcephaly is a reflection of a small brain, and the outlook for a patient, which can range from normal to profound mental retardation, will vary with the nature and severity of the underlying

Brain

pathology. Every effort should be expended to determine a specific etiology and to define any associated intra- and extracranial malformations. As greater numbers of syndromes with microcephaly are defined, and their long-term outcomes become known, it should be increasingly possible to provide an expected range of developmental potential and/or neurologic complications. The paucity of associated neurologic signs and relatively normal early developmental milestones of some forms of autosomal recessive microcephaly have been alluded to. Microcephaly is strongly correlated with developmental delay. Nelson and Deutschberger556 analyzed data from the U.S. Collaborative Perinatal Project and found that children with microcephaly (2 SD) at 1 year of age had a 50% chance of having an IQ of < 80 at age 4 years. However, one-half of the children had IQ scores above this level. In a follow-up at age 7 years of children ascertained from the same cohort, Dolk557 found that 51% of the children with OFC below 3 SD had an IQ of < 70, and 17% were between 71 and 80. In those children with OFC below 2 SD, rates were 11% and 28%, respectively. In the absence of a specific diagnosis, a cautious approach should be taken toward predicting developmental potential simply on the basis of microcephaly. By definition, when using a cut-off value of 2 SD below the age-, sex-, and gestation-appropriate means, 2.5% of the population is expected to fall below this level and presumably many will simply reflect the lower range of normal OFC. Comparison with first-degree relatives may suggest this possibility. The further that the OFC falls below the mean, the greater is the risk of mental retardation. Current dogma is that the child with microcephaly whose head continues to grow parallel to the normal centiles has a better prognosis than does the child whose OFC continues to fall from normal. Good practice requires the clinician to consider the relative proportions of body measurements such as height, weight, and OFC to each other. Therefore, it is relevant to consider the question of ‘‘relative microcephaly,’’ that is, a head size that falls within the normal range but is disproportionately small when compared with the patient’s length or weight centiles. OFC and weight are correlated during the first year of life, but Brennan et al.558 found that infants whose head circumferences were significantly disproportionate relative to their weights, but were between the 10th and 90th centiles, were not at increased risk for an adverse outcome. A similar study with respect to length would be of interest, as adult OFC has been shown to correlate with height.5 The prospect for primary treatment and reversal of symptomatic microcephaly remains problematic. By the time the abnormality has been recognized, the causative factor is usually no longer operative, the damage has been done, and one is left to provide appropriate family, paramedical, and developmental support. Glazier et al.559 have pointed to the possibility of undiagnosed functional bladder anomalies in patients with severe delay associated with microcephaly and have suggested that such patients undergo a urologic evaluation. An important proportion of symptomatic microcephaly is the result of teratogenic events such as exposure to toxins, infections, and anoxia. Development and promotion of vaccination, and specific diagnostic intervention when infection is suspected, can have a significant benefit. There has been some success in increasing general public awareness about the hazards of ingesting alcohol and related substances during pregnancy, although perhaps one must be less sanguine about the prospects of influencing those who practice substance abuse. Infants born to women with untreated maternal phenylketonuria have a 93% risk for mental retardation and a 72% risk

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for microcephaly but barriers remain to the prevention of this problem.560 Abdel-Salam and Czeizel561 reported a 40–50% reduction in the prevalence of isolated microcephaly among the offspring of women who took pharmacologic doses of folic acid (6 mg/day) and iron (50 mg/day). However, their definition of microcephaly was < 10%, no comparisons of the development of the children were provided, and clearly questions arise as to possible negative effects at this level of supplementation. Thorough investigation and, when appropriate, genetic counseling should be offered to all families. Notwithstanding sophisticated advances in clinical, molecular, and neuroimaging approaches to diagnosis, it is not always possible to distinguish reliably between a genetic and nongenetic etiology in patients who have a negative family history and isolated microcephaly. Earlier empiric recurrence risk estimates may well be too low, but a risk of about 20% appears appropriate, although some would routinely counsel unexplained, isolated microcephaly as autosomal recessive.11 Advances in prenatal ultrasound and, in some centers, MRI neuroimaging have greatly improved the ability to detect malformations associated with specific syndromes, accompanying brain abnormalities, and subtle biometric differences in the fetal brain that may predate the appearance of measurable microcephaly.31,32 Concerns remain about positive and negative predictive values, and caution should be exercised in offering ultrasound as a basis for the prenatal diagnosis of microcephaly. This is especially true in the case of syndromes or situations where there is no precedent of successful and timely diagnosis. Detectable cerebral architectural changes or growth failure of the head may not occur until after such time as termination of the pregnancy would normally be available. An approach to the ultrasound diagnosis of microcephaly has been outlined by Romero et al.562 and can be modified with some of the newer information. The case reported by Winter et al.563 is a reminder that not all apparent microcephaly bodes a poor prognosis, and this must be kept in mind when microcephaly is detected in utero and there is no other abnormality in the pregnancy and no significant family history. It was suggested that the fetus suffered microcephaly on the basis of in utero constraint from a bicornate uterus and showed subsequent normal postnatal development and catch up of the OFC. Amniocentesis should be offered when there is a risk of a recurrent chromosome abnormality or enzymopathy. There has been remarkable recent progress in the identification of genes responsible for several types of isolated microcephaly11–13,568 and for many syndromes with microcephaly (Table 15-1). Careful evaluation of patients and families should allow the selective use of current molecular techniques in some cases. However, further technological advances are needed before a molecular screening approach can be applied to individual cases of unexplained isolated microcephaly. Multiplex families with isolated microcephaly, and patients with concurrent balanced translocations and microcephaly, may continue to aid in the isolation of causative genes. Qazi and Reed22 reported a high rate of subnormal intelligence among the close relatives of patients with isolated genetic microcephaly, and if confirmed in families with proven mutations, this might prove useful in selecting families for mutational studies. References (Microcephaly) 1. Hecht F, Kelly JV: Little heads, inheritance and early detection. J Pediatr 95:731, 1979. 2. Goodman RM, Gorlin RJ: The Malformed Infant and Child. Oxford University Press, New York, 1983, p 7.

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3. Friede RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 271. 4. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989, p 80. 5. Bushby KM, Cole T, Matthews JN, et al.: Centiles for adult head circumference. Arch Dis Child 67:1286, 1992. 6. Gooskens RHJM, Gielen CCAM, Hanlo PW, et al.: Intracranial spaces in childhood macrocephaly: comparison of length measurements and volume calculations. Dev Med Child Neurol 30:509, 1988. 7. Lusted LB, Keats TE: Atlas of Roentgenographic Measurements, ed 3. Year Book Medical, Chicago, 1972, p 30. 8. Lindley AA, Benson JE, Grimes C, et al.: The relationship in neonates between clinically measured head circumference and brain volume estimated from head CT-scans. Early Hum Dev 56:17, 1999. 9. Barkovich AJ, Ferriero DM, Barr RM, et al.: Microlissencephaly: a heterogeneous malformation of cortical development. Neuropediatrics 29:113, 1998. 10. Hanefeld FA: Oligogyric microcephaly. Neuropediatrics 30:102, 1999. 11. Dobyns WB: Primary microcephaly: new approaches for an old disorder. Am J Med Genet 112:315, 2002. 12. Mochida GH, Walsh CA: Molecular genetics of human microcephaly. Curr Opinion Neurol 14:151, 2001. 13. Roberts E, Hampshire DJ, Pattison L, et al.: Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J Med Genet 39:718, 2002. 14. Peiffer A, Singh N, Leppert M, et al.: Microcephaly with simplified gyral pattern in six related children. Am J Med Genet 84:137, 1999. 15. Sztriha L, Al-Gazali LI, Varady E, et al.: Autosomal recessive microcephaly with simplified gyral pattern, abnormal myelination and arthrogryposis. Neuropediatrics 30:141, 1999. 16. Jackson AP, Eastwood H, Bell SM, et al.: Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71:136, 2002. 17. Kelley RI, Robinson D, Puffenberger EG, et al.: Amish lethal microcephaly: A new metabolic disorder with severe congenital microcephaly and 2ketoglutaric aciduria. Am J Med Genet 112:318, 2002. ¨ ztu¨rk MH, Aydingoz U ¨ , et al.: CT and MRI of micro18. Yelgec¸ S, O cephalia vera. Paediatr Neuroradiol 40:332, 1998. 19. Custer DA, Vezina LG, Vaught DR, et al.: Neurodevelopmental and neuroimaging correlates in nonsyndromal microcephalic children. J Dev Behav Pediatr 21:12, 2000. 20. Penrose LS: Microcephaly. Folia Hered Pathol 5:79, 1956. 21. Baraitser M: The Genetics of Neurologic Disorders. Oxford University Press, Oxford, 1985, p 22. 22. Qazi QH, Reed TE: A problem in diagnosis of primary versus secondary microcephaly. Clin Genet 4:46, 1973. 23. Sujatha M, Kumari CK, Murty JS: Segregation frequency in microcephaly. Hum Genet 81:388, 1989. 24. Brandon MWG, Kirman BH, William CE: Microcephaly. J Ment Sci 57:637, 1959. 25. Tolmie JL, McNay M, Stephenson JBP: Microcephaly: genetic counselling and antenatal diagnosis after the birth of an affected child. Am J Med Genet 27:583, 1987. 26. Haslam RHA, Smith DW: Autosomal dominant microcephaly. J Pediatr 95:701, 1979. 27. Newbury-Ecob RA, Young ID. Dominant inheritance of microcephaly, short stature and congenital dislocation of the hips. Clin Dysmorphol 2:34, 1993. 28. Rossi LN, Candini G, Scarlatti G, et al.: Autosomal dominant microcephaly without mental retardation. Am J Dis Child 141:655, 1957. 29. Ramirez ML, Rivas F, Cantu JM: Silent microcephaly: a distinct autosomal dominant trait. Clin Genet 23:281, 1983. 30. Chervenak FA, Rosenberg J, Brightman RC: A prospective study of the accuracy of ultrasound in predicting fetal microcephaly. Obstet Gynecol 69:908, 1987. 31. Pilu G, Falco P, Milano V, et al.: Prenatal diagnosis of microcephaly assisted by vaginal sonography and power Doppler. Ultrasound Obstet Gynecol 11:357, 1998.

32. Goldstein I, Reece EA, Pilu GL, et al.: Sonographic development of the normal developmental anatomy of the fetal cerebral ventricles. I. The frontal horns. Obstet Gynecol 72:588, 1988. 33. Viora E, Sciarrone A, Bastonero S, et al.: Prenatal diagnosis of fetal microcephaly: contribution of power Doppler. Ultrasound Obstet Gynecol 15:263, 2000. 34. De Laveaucoupet J, Audibert F, Guis F, et al.: Fetal magnetic resonance imaging (MRI) of ischemic brain injury. Prenat Diagn 21:729, 2001. 35. Bromley B, Benacerraf BR: Difficulties in the prenatal diagnosis of microcephaly. J Ultrasound Med 14:303, 1995. 36. Malinger G, Lerman-Sagie T, Watemberg N, et al.: A normal secondtrimester ultrasound does not exclude intracranial structural pathology. Ultrasound Obstet Gynecol 20:51, 2002. 37. Den Hollander NS, Wessels MW, Los FJ, et al.: Congenital microcephaly detected by prenatal ultrasound: genetic aspects and clinical significance. Ultrasound Obstet Gynecol 15:282, 2000. 38. Abidi F, Hall BD, Feldman GL, et al.: X-linked mental retardation with variable stature, head circumference, and testicular volume linked to Xq12-q21. Am J Med Genet 85:223, 1999. 39. Stevens CA, Sargent LA: Ablepharon-macrostomia syndrome. Am J Med Genet 107:30, 2002. 40. Truel MC, Hernandez-Sampelayo T, Fermosel J, et al.: Multiple malformations: unusual facies, absent abdominal musculature, microphthalmia, and joint laxity. Dysmorphol Clin Genet 1:126, 1987. 41. Kogut MD, Sensenbrenner J: HH-low birth weight syndrome in two brothers. Birth Defects Orig Artic Ser XI(2):450, 1975. 42. Tsao CY, Romshe CA, Lo WD, et al.: Familial adrenal insufficiency, achalasia, alacrima, peripheral neuropathy, microcephaly, normal plasma very long chain fatty acids, and normal muscle mitochondrial respiratory chain enzymes. J Child Neurol 9:135, 1994. 43. Khalifa MM: Familial achalasia, microcephaly, and mental retardation. Clin Pediatr 27:509, 1988. 44. Kaplan P, Plauchu H, Fitch N, et al.: A new acro-cranio-facial dysostosis. Am J Med Genet 29:95, 1988. 45. Wulfsberg EA, Campbell AB, Lurie IW, et al.: Confirmation of the Catania brachydactylous type of acrofacial dysostosis: report of a second family. Am J Med Genet 63:554, 1996. 46. Palomeque A, Pastor X, Bellesta F: Nager anomaly with severe facial involvement, microcephaly and mental retardation. Am J Med Genet 36:356, 1990. 47. Greally JM, Boone LY, Lenkey SG, et al.: Acrometageria: a spectrum of premature aging. Am J Med Genet 44:334, 1992. 48. Halal F, Homsy M, Perrault G, et al.: Acro-renal ocular syndrome: autosomal dominant thumb hypoplasia, renal ectopia, and eye defect. Am J Med Genet 17:753, 1984. 49. Kunze J, Park W, Hansen K-H, et al.: Adducted thumb syndrome. Eur J Pediatr 141:122, 1983. 50. Blethen SL, Wenick GB, Hawkins LA: Congenital adrenal hypoplasia in association with growth hormone deficiency, developmental delay, partial androgen resistance, unusual facies, and skeletal abnormalities. Dysmorphol Clin Genet 4:110, 1990. 51. Castro-Gago M: A familial syndrome of microcephaly with oculocutaneous albinism and digital anomalies. An Esp Pediatr (Madrid) 19: 128, 1983. 52. Kotzot D, Richter K, Gierth-Fiebig K: Oculocutaneous albinism, immunodeficiency, hematological disorders, and minor anomalies: a new autosomal recessive syndrome. Am J Med Genet 50:224, 1994. 53. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 4. WB Saunders, Philadelphia, 1988, p 491. 54. al-Gazali LI, Khalil M, Devadask K: A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguinous parents. J Med Genet 30:470, 1993. 55. Wessel HB, Barmada MA, Hashida Y: Congenital alopecia, seizures, and psychomotor retardation in three siblings. Pediatr Neurol 3:101, 1987. 56. Cantu J-M, Hernandez A, Larracilla J: A new X-linked recessive disorder with dwarfism, cerebral atrophy, and generalized keratosis follicularis. J Pediatr 84:564, 1974.

Brain 57. Wessel HB, Barmada MA, Hashida Y: Congenital alopecia, seizures, and psychomotor retardation in three siblings. Pediatr Neurol 3:101, 1987. 58. Feinstein A, Engelberg S, Goodman RM: Genetic disorders associated with severe alopecia in children: a report of two unusual cases and a review. J Craniofac Genet Dev Biol 7:301, 1987. 59. Dumic M, Cvitanovic M, Ille J, et al.: Syndrome of short stature, mental deficiency, microcephaly, ectodermal dysplasia, and multiple skeletal anomalies. Am J Med Genet 93:47, 2000. 60. Fraser FC, Anderson RA, Mulvihill JI: An aminopterin-like syndrome without aminopterin (ASSAS). Clin Genet 32:28, 1987. 61. Hurst JA, Baraitser M, Winter RM: A syndrome of mental retardation, short stature, hemolytic anemia, delayed puberty, and abnormal facial appearance: similarities to a report of aldolase deficiency. Am J Med Genet 28:965, 1987. 62. Willems PJ, Dijksha I, Brower OF, et al.: Recurrence risk in the Angelman (‘‘happy puppet’’) syndrome. Am J Med Genet 27:773, 1987. 63. Al Frayh AR, Haque F, Haque KN: Anophthalmia, microcephaly, hypotonia, hypogonadism, failure to thrive, and developmental delay. Dysmorphol Clin Genet 1:64, 1987. 64. Teebi AS, Kaurah P: Total anonychia congenita and microcephaly with normal intelligence: a new autosomal recessive syndrome? Am J Med Genet 66:2457, 1996. 65. Jung C, Wolff G, Back E, et al.: Two unrelated children with developmental delay, short stature and anterior chamber cleavage disorder, cerebellar hypoplasia, endocrine disturbances and tracheostenosis: a new entity? Clin Dysmorphol 4:44, 1995. 66. Stromme P, Anderson W: Developmental aspects in apple peel intestinal atresia-ocular anomalies-microcephaly syndrome. Clin Genet 52:133, 1997. 67. Armendares S, Antillon F, del Castillo V, et al.: A newly recognized inherited syndrome of dwarfism, craniostenosis, retinitis pigmentosa and multiple congenital malformations. Birth Defects Orig Artic Ser XI(2):49, 1975. 68. Hall JG, Truog WE, Plowman DL: A new arthrogryposis syndrome with facial and limb anomalies. Am J Dis Child 129:120, 1975. 69. Schmidt R, Pajewski M, Mundel G: Unusual features in familial asphyxiating thoracic dysplasia (Jeune’s disease). Clin Genet 3:90, 1972. 70. Silengo M, Bell G, Biagioli M, et al.: Asymmetric crying facies with microcephaly and mental retardation: an autosomal dominant syndrome with variable expressivity. Clin Genet 30:481, 1986. 71. Di Rocco M, Arslanian A, Romanengo M, et al.: Ataxia, ocular telangiectasia, chromosome instability, and Langerhans histiocytosis in a patient with an unknown breakage syndrome. J Med Genet 36:159, 1999. 72. Holinski-Feder E, Reyniers E, Uhrig S, et al.: Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3). Am J Hum Genet 66:16, 2000. 73. Picketts DJ, Higgs DR, Bachoo S, et al.: ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. Hum Mol Genet 5:1899, 1996. 74. Yamagata T, Momoi MY, Saitoh S, et al.: A DNA repair defect in a patient with ataxia, mental retardation, and short stature. Pediatr Neurol 18:358, 1998. 75. Me´garbane´ A, Melki I, Souraty N, et al.: Overlap between BallerGerold and Rothmund-Thompson syndrome. Clin Dysmorphol 9:303, 2000. 76. Papadia F, Zimbalatti F, LaRosa GL: The Bartsocas-Papas syndrome: autosomal recessive form of popliteal pterygium syndrome in a male infant. Am J Med Genet 17:841, 1984. 77. Battalglia A, Ferrari AR, Ossitto E, et al.: New autosomal recessive syndrome of mental retardation, coarse face, microcephaly, epilepsy and skeletal abnormalities. Clin Dysmorphol 5:41, 1996. 78. Bavinck JNB, Weaver DD, Ellis FD, et al.: A syndrome of microcephaly, eye anomalies, short stature, and mental deficiency. Am J Med Genet 26:825, 1987.

501 79. Laegreid L, Olegard R, Walstrom J, et al.: Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr 114:126, 1989. 80. Brindewald B, Ulmer H, Muller U: Fallot complex, severe mental and growth retardation: a new autosomal recessive syndrome? Am J Med Genet 50:173, 1994. 81. Ishikiriyama S, Goto M: Blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) and microcephaly. Am J Med Genet 52:245, 1994. 82. Day-Salvatore D, McLean D: Blepharophimosis, hypoplastic radius, hypoplastic left heart, telecanthus, hydronephrosis, fused metacarpals and ‘‘prehensile’’ halluses: a new syndrome. Am J Med Genet 80:309, 1998. 83. Jorgenson RJ, Lenz W, Giovannucci Uzielli ML: Mild short stature, microcephaly, ptosis-blepharophimosis, facial asymmetry, and radioulnar synostosis. J Clin Dysmorphol 1(4):14, 1983. 84. Lower KM, Turner G, Kerr BA, et al.: Mutations in PHF6 are associated with Bo¨rjeson-Forssman-Lehmann syndrome. Nat Genet 32: 661, 2002. 85. Hunter AGW, Woerner SJ, Montalvo-Hicks LOC, et al.: The BowenConradi syndrome-a highly lethal autosomal recessive syndrome of microcephaly, micrognathia, low birth weight, and joint deformities. Am J Med Genet 3:269, 1979. 86. Richieri-Costa A, Colletto GMDD, Otto PA: Unusual type of brachydactyly associated with short stature and facial anomalies. A new syndrome? Am J Med Genet 21:637, 1985. 87. Mingarelli R, Mokina V, Scanderberg AC, et al.: Brachycephalosyndactyly with ptosis, cataract, colobomas, and linear areas of skin depigmentation. Clin Dysmorphol 8:73, 1999. 88. Graham JM: New syndrome of type A2 brachydactyly, microcephaly and diabetes in siblings born to consanguineous parents. Am J Hum Genet 45:A76, 1989. 89. Tonoki H, Kishino T, Niikawa N: A new syndrome of dwarfism, brachydactyly, nail dysplasia, and mental retardation in sibs. Am J Med Genet 36:89, 1990. 90. Faravelli F, Di Rocco M, Stella G, et al.: Brachyphalangy, feet polydactyly, absent/hypoplastic tibia: a further case and review of main diagnostic findings. Clin Dysmorphol 10:101, 2001. 91. Braeger C, Bottani A, Halle´ F, et al.: Unknown syndrome: ischiadic hypoplasia, renal dysfunction, immunodeficiency, and a pattern of minor congenital anomalies. J Med Genet 28:56, 1991. 92. Me´garbane´ A, Hawat N, Chedid P, et al.: Brancho-oculo-facial syndrome associated with a white forelock. Clin Dysmorphol 7:221, 1998. 93. Reish O, Gorlin RJ, Hordinsky M, et al.: Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/ BRESHECK): new X-linked syndrome?. Am J Med Genet 68:386, 1997. 94. Ogur G, Baykan N, De Paepe A, et al.: Clinical, ultrastructural and biochemical studies on two sibs with Ehlers-Danlos syndrome type VB-like features. Clin Genet 46:417, 1994. 95. Buntix IM, Lormans JAG, Martin JJ, et al.: A new association of mental retardation, short stature, unusual face, radio-ulnar synostosis and retinal pigment abnormalities. Genet Counseling 2:237, 1991. 96. Hennekam RCM, van Rhijn A, Hennekam FAM: Dominantly inherited microcephaly, short stature and normal intelligence. Clin Genet 41:248, 1992. 97. Talwai D, Smith: CAMFAK syndrome: a demyelinating inherited disease similar to Cockayne syndrome. Am J Med Genet 34:194, 1989. 98. Figuera LE, Ramirez-Duenas ML, Garcia-Crus D, et al.: Guadalajara camptodactyly syndrome type 1. A corroborative family. Clin Genet 43:11, 1993. 99. Rogers RC, Stevenson RE: Mental retardation, premature greying, and ligamentous laxity in four siblings. Proc Greenwood Genet Center 3:11, 1984. 100. Hashimoto LN, Bass WT, Green GA, et al.: Radial microbrain form of microcephaly: possible association with carbamazepine. J Neuroimaging 9:244, 1999.

502

Neuromuscular Systems

101. Schimke RN, Collins DL, Hiebert JM: Congenital nonprogressive myopathy with Mo¨bius and Robin sequence—the Carey-FinemanZiter syndrome: a confirmatory report. Am J Med Genet 46:721, 1993. 102. Abidi F, Schwartz CE, Carpenter NJ, et al.: Carpenter-Waziri syndrome results from a mutation in XNP. Am J Med Genet 85:249, 1999. 103. Castriota-Scanderberg A, Zelante L, Masala S, et al.: Acrodysplasia, severe ossification abnormalities with short stature and fibular hypoplasia. Am J Med Genet 84:68, 1999. 104. Wellesley D, Carman P, French N, et al.: Cataracts, aberrant oral frenula, and growth retardation: a new autosomal dominant syndrome. Am J Med Genet 40:341, 1991. 105. Heckmann JM, Carr JA, Bell N: Hereditary sensory and autonomic neuropathy with cataracts, mental retardation, and skin lesions: five cases. Neurology 45:1405, 1995. 106. Crome L, Duckett S, Franklin AW: Congenital cataracts, renal tubular necrosis and encephalopathy in two sisters. Arch Dis Child 38:505, 1963. 107. Lynch SA, Lee SG, Murday VA: Caudal appendage, short terminal phalanges, deafness, cryptorchidism and mental retardation: a new syndrome? Clin Dysmorphol 3:340, 1994. 108. Me´garbane´ A, Delague V, Ruchoux MM, et al.: A new autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family. Am J Med Genet 101:135, 2001. 109. Charrow J, Poznanski AK, Unger FM, et al.: Autosomal recessive cerebellar hypoplasia and endosteal sclerosis: a newly recognized syndrome. Am J Med Genet 41:464, 1991. 110. Kahn E, Markowitz J, Duffy L: Berry aneurysms, cirrhosis, pulmonary emphysema, and bilateral symmetrical cerebral calcifications: a new syndrome. Am J Med Genet (Suppl 3):343, 1987. 111. Spranger JW, Schinzel A, Myers T, et al: Cerebroarthrodigital syndrome: a newly recognized formal genesis syndrome in three patients with apparent amyodysplasia and sacral agenesis, brain malformation and digital hypoplasia. Am J Med Genet 5:13, 1980. 112. Plo¨tz FB, van Essen AJ, Bosschaart AN, et al.: Cerebro-costomandibular syndrome. Am J Med Genet 62:286, 1996. 113. Pena SDJ, Evans J, Hunter AGW: COFS revisited. Birth Defects Orig Artic Ser XIV(6B):205, 1978. 114. Lerman-Sagie T, Levi Y, Kidron D: Brief clinical report: syndrome of osteopetrosis and muscular degeneration associated with cerebrooculo-facial skeletal changes. Am J Med Genet 28:137, 1987. 115. Siber M: X-linked recessive microcephaly, microphthalmia with corneal opacities, spastic quadriplegia, hypospadias and cryptorchidism. Clin Genet 26:453, 1984. 116. Silengo MC, Lerone M, Pelizza A, et al.: A new syndrome with cerebrooculo-skeletal-renal involvement. Pediatr Radiol 20:612, 1990. 117. Lurie IW, Laziuk GI, Korotkova A, et al.: The cerebro-reno-digital syndromes: a new community. Clin Genet 39:104, 1991. 118. Barohn RJ, Dowd DC, Kragan-Hallet KS: Congenital ceroid-lipofuscinosis. Pediatr Neurol 8:54, 1992. 119. Frydman M, Cohen HA, Ashkenazi A, et al.: Familial segregation of cervical ribs, Sprengel anomaly, preaxial polydactyly, anal atresia, and urethral obstruction: a new syndrome? Am J Med Genet 45:717, 1993. 120. Zackai EH, Sly WS, McAlister WH: Microcephaly, mild mental retardation, short stature, and skeletal anomalies in siblings. Am J Dis Child 124:111, 1972. 121. Dumic M, Cvitanovic M, Saric B, et al.: Choanal stenosis, hypothelia, deafness, recurrent dacrocystitis, neck fistulas, short stature, and microcephaly. Am J Med Genet 113:295, 2002. 122. Hurst JA, Berry AC, Tettenborn MA: Unknown syndrome: congenital heart disease, choanal stenosis, short stature, developmental delay, and dysmorphic facial features in a brother and sister. J Med Genet 26:407, 1989. 123. Gillessen-Kaesbach G, Meinecke P, Ausems MGEM, et al.: Desbusquois syndrome: three further cases and review of the literature. Clin Dysmorphol 4:136, 1995. 124. Nivelon A, Nivelon JL, Mabille JP, et al.: New autosomal recessive chondrodysplasia-pseudohermaphroditism syndrome. Clin Dysmorphol 1:221, 1992.

125. Curry CJR, Magenis RE, Brown M, et al.: Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. New Engl J Med 311:1010, 1984. 126. Abdel-Salam GMH, Czeizel AE, Vogt G, et al.: Microcephaly with chorioretinal dysplasia: characteristic facial features. Am J Med Genet 95: 513, 2000. 127. Sadler LS, Robinson LK: Chorioretinal dysplasia-microcephaly-mental retardation syndrome: report of an American family. Am J Med Genet 47:65, 1993. 128. Opitz JM, Holt MC: Microcephaly: general considerations and aids to nosology. J Craniofac Genet Dev Biol 10:175, 1990. 129. Maraschio P, Peretti D, Lambriase S, et al.: A new chromosome instability disorder. Clin Genet 30:353, 1986. 130. Wegner RD, Metzger M, Hanefeld F, et al.: A new chromosomal instability disorder confirmed by complementation studies. Clin Genet 33:20, 1988. 131. Chudley AE, Lowry RB, Hoar DI: Mental retardation, distinct facial changes, short stature, obesity, and hypogonadism: a new X-linked mental retardation syndrome. Am J Med Genet 31:741, 1988. 132. Ben-Amatai D, Rachmel A, Levy Y, et al.: Hypodipsic hyponatremia and hypertriglyceridemia associated with cleft lip and cleft palate: a new hypothalamic dysfunction syndrome? Am J Med Genet 36:275, 1990. 133. Neuhauser G, Kaveggia EG, Opitz JM: Studies of malformation syndromes of man XXXVIII: the BD syndrome. A ‘‘new’’ multiple congenital anomalies/mental retardation syndrome with athetoid cerebral palsy. Z Kinderheilkd 120:191, 1975. 134. Breslau L, Laan L: Facial cleft and congenital megacolon: a specific disorder? Am J Med Genet 34:613, 1989. 135. Levy P, Baraitser M: Coffin-Siris syndrome. J Med Genet 28:338, 1991. 136. Coffin GS: Developmental retardation with unusual facies, arthritis and hearing impairment. Dysmorphol Clin Genet 4:103, 1990. 137. Norio R, Raitta C: Are the Mirhosseini-Holmes-Walton syndrome and the Cohen syndrome identical? Am J Med Genet 25:397, 1986. 138. Natacci F, Perri M, Rossetti M, et al.: New case of the Richieri-Costa/ Guion-Almeida syndrome. Am J Med Genet 83:419, 1999. 139. Pavone P, Parano E, Polizzi A, et al.: Colobomatous microphthalmia, microcephaly with cerebellar hypoplasia: association or new syndrome. Am J Med Genet 92:278, 2000. 140. Holmes GE, Schimke RN: Continuation of a case report. J Med Genet 30:445, 1993. 141. Rommen I, Mueller RF, Sybert VP: Developmental delay, growth deficiency, congenital heart defect, and multiple craniofacial anomalies. J Clin Dysmorphol l:10, 1983. 142. Reed UC, Tsanaclis AMG, Vainzof M, et al.: Merosine positive muscular dystrophy in two siblings with cataract and slight mental retardation. Brain Dev 21:274, 1999. 143. Levy J, Chung W, Garzon M, et al.: Congenital myopathy, recurrent secretory diarrhea, bullous eruption of skin, microcephaly, and deafness. Am J Med Genet 116:20, 2003. 144. Petty EM, Laxova R, Wiedemann H-R: Previously unrecognized congenital progeroid disorder. Am J Med Genet 35:383, 1990. 145. Diglio MC, Marino B, Giannotti A, et al.: Conotruncal heart defect/ microphthalmia syndrome: delineation of an autosomal recessive syndrome. J Med Genet 34:927, 1997. 146. Sammartino A, De Grecchio G, Federico A, et al.: Superficial annular corneal dystrophy, ichthyosis nigrans, microcephaly and mild mental subnormality. Ophthalmologica 185:226, 1982. 147. Cortada X, Kousseff BG, Matsumoto GM: Constricted maxilla and mandible, scoliosis, bowed radii, ulnar hypoplasia, acromicria and microcephaly, with mental retardation-a new autosomal recessive syndrome? Birth Defects Orig Artic Ser XVIII(3B):197, 1982. 148. Tamai S, Tojo M, Kamimaki T, et al.: Intrafamilial phenotypic variations in cranioectodermal dysplasia: propositus with typical manifestations and her brother with perinatal death. Am J Med Genet 107:78, 2002. 149. Horovitz DDG, Neto JGB, Boy R, et al.: Autosomal dominant osteosclerosis type Stanescu: the third family. Am J Med Genet 57:605, 1995.

Brain 150. Lowry RB: Absent fibula and craniosynostosis: a 25 year follow up. J Med Genet 30:445, 1993. 151. Flanagan N, Boyadjiev SA, Harper J, et al.: Familial anomalies and porokeratosis: CAP syndrome. J Med Genet 35:763, 1998. 152. Pfeiffer RA, Tietze U, Welte W: An unusual, possibly ‘‘new’’ MA/ MR syndrome with sagittal craniosynostosis. Eur J Pediatr 146:74, 1987. 153. Samson G, Gardner JC: Craniosynostosis, microcephaly, hydrancephaly, humero-radial synostosis, and thumb aplasia: a new syndrome? Am J Med Genet 61:174, 1996. 154. Ladda RL, Stoltzfus E, Gordon SL, et al.: Craniosynostosis associated with limb reduction malformations and cleft lip/palate: a distinct syndrome. Pediatrics 61:12, 1978. 155. Al-Torki NA, Sabry MA, Al-Awardi SA, et al.: Lowry-MacLean syndrome with osteopenic bones and possible autosomal dominant inheritance in a Bedouin family. Am J Med Genet 73:491, 1997. 156. Mukamel M, Weitz R, Metzker A, et al.: Spastic paraparesis, mental retardation, and cutaneous pigmentation disorder. Am J Dis Child 139:1090, 1985. 157. Allanson J, Austin W, Hecht F: Congenital cutis laxa with retardation of growth and motor development: a recessive disorder of connective tissue with male lethality. Clin Genet 29:133, 1986. 158. Lacassie Y, Morava E, LaMotta I: Provisional new syndrome of MR/ MCA with evolving phenotype. Am J Med Genet 113:213, 2002. 159. Me´garbane´ A, Waked N, Chouery E, et al.: Microcephaly, cutis verticis gyrata of the scalp, retinitis pigmentosa, cataracts, sensorineural deafness, and mental retardation in two brothers. Am J Med Genet 98:244, 2001. 160. al-Ali HY, Yasseen SA, Raof TY: Follow-up of pregnant women with active cytomegalic virus infection. East Mediterr Health J 5:949, 1999. 161. Czeizel A, Lowry RB: Syndrome of cataract, mild microcephaly, mental retardation and Perthes-like changes in sibs. Acta Paediatr Hung 30:343, 1990. 162. Naritomi K, Tohma T, Goya Y, et al.: Delineation of the da Silva syndrome. Am J Med Genet 49:313, 1994. 163. Ieshima A, Koeda T, Inagaki M: Peculiar face, deafness, cleft palate, male pseudohermaphroditism, and growth and psychomotor retardation: a new autosomal recessive syndrome? Clin Genet 30:163, 1986. 164. Kunze J, Majewsky F, Montgomery PH, et al.: de Barsy syndrome-an autosomal recessive, progeroid syndrome. Eur J Pediatr 144:348, 1985. 165. Fryns JP, Dereymaeker AM, Hoefnagels M, et al.: The Brachmann-de Lange syndrome in two siblings of normal parents. Clin Genet 31:413, 1987. 166. Delozier-Blanchet CD, Haenggeli CA, Engel E: Two brothers with severe mental and growth retardation, microcephaly, hypertonicity, obesity and hypogenitalism: a new syndrome? J Ge´ne´t Hum 37:353, 1989. 167. Meinecke P, Blunck W: Frontonasal dysplasia, congenital heart defect, and short stature: a further observation. J Med Genet 26:408. 1989. 168. D’ercole AJ: Case report 45. IUGR, short stature, microcephaly, congenital heart disease, X-linked recessive. Synd Ident IV:5, 1976. 169. Anderson HC, Kratz L, Kelley R: Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay. Am J Med Genet 113:315, 2002. 170. Winter RM: Eronen syndrome identical with DOOR syndrome? Clin Genet 43:167, 1993. 171. Pallister PD, Opitz JM: Brief clinical report: disequilibrium syndrome in Montana Hutterites. Am J Med Genet 22:567, 1985. 172. Di Rocco M: Distal aphalangia, an extra metatarsal, short stature, and microcephaly: a second case. Clin Dysmorphol 11:295, 2002. 173. Chitayat D, Hodgkinson A, Blaidman S, et al.: Syndrome of mental retardation and distal arthrogryposis in sibs. Am J Med Genet 41:49, 1991. 174. Flannery DB: Dolichospondylic dysplasia: syndromic short stature with tall vertebral bodies. Proc Greenwood Genet Center 3:96, 1984. 175. Rajab A, Riaz A, Paul G, et al.: Further delineation of the DOOR syndrome. Clin Dysmorphol 9:247, 2000. 176. Stoll C, Alembik Y, Dott B: Association of Duane anomaly with mental retardation, cardiac and urinary tract abnormalities: a new autosomal recessive condition? Ann Ge´ne´t 37:307, 1994.

503 177. Winter RM: Dubowitz syndrome. J Med Genet 23:11, 1986. 178. Drayer NM, Kamps W A, tenKate LP, et al.: Microcephaly, ocular hypertelorism, low set ears, hand and feet anomalies, short stature and mental retardation. Synd Ident V(1):9, 1977. 179. Yolken R, Konecny P, Elfman EL: Short limbed dwarfism, bowed femurs, coronal cleft vertebrae, metaphyseal irregularity. Synd Ident IV(2):13, 1976. 180. Cantu JM, Sanchez-Corona J, Garcia-Cruz D, et al.: Severe mental deficiency, proportionate dwarfism, and delayed sexual maturation. A distinct inherited syndrome. Hum Genet 56:231, 1980. 181. Stimmler L, Jensen N, Toseland P: Alaninuria, associated with microcephaly, dwarfism, enamel hypoplasia, and diabetes mellitus in two sisters. Arch Dis Child 45:682, 1970. 182. Juberg RC, Van Ness MB: A new syndrome of hereditary short limbed dwarfism with microcephalus. Clin Genet 7:111, 1975. 183. Rochiccioli P, Malpuech G: Nanisme avec vertebres hautes et e´troites. Ann Pe´diat 30:709, 1983. 184. Pai GS, Morgan S, Whetsell C: Etiologic heterogeneity in dyskeratosis congenita. Am J Med Genet 32:63, 1989. 185. Cohen A, Mulas R, Seri M, et al.: Meier-Gorlin syndrome (ear-patellashort stature syndrome in an Italian patient: clinical evaluation and analysis of possible candidate genes. Am J Med Genet 107:48, 2002. 186. Wallis CE, Beighton P: Ectodermal dysplasia with blindness on the island of Rodrigues. J Med Genet 29:323, 1992. 187. Haberlandt E, Lo¨ffler J, Hirst-Stadlmann A, et al.: Split hand/split foot malformation associated with sensorineural deafness, inner and middle ear malformation, hypodontia, congenital vertical talus, and a deletion of eight microsatellite markers in 7q21.1–q21.3. J Med Genet 38:405, 2001. 188. Roelfsema NM, Cobben JM: The EEC syndrome: a literature study. Clin Dysmorphol 5:115, 1996. 189. Ellis IH, Yale C, Thomas R, et al.: Three sibs with microcephaly, congenital heart disease, lung segmentation defects and unilateral absent kidney: a new recessive multiple congenital anomaly (MCA) syndrome? Clin Dysmorphol 5:129, 1996. 190. Elmer C, Bartier M, Deconinck H, et al.: Structural defects of the anterior chamber of the eye—mental retardation—multiple lentigines—situs inversus and marfanoid habitus: a new syndrome? 1st Eur Meeting Dysmorphol (Zaragoza) 1990, p 24. 191. Lowry RB, Wood BJ, Cox TA, et al.: Epiphyseal dysplasia, microcephaly, nystagmus, and retinitis pigmentosa. Am J Med Genet 33:341, 1989. 192. Evans DGR. Dominantly inherited microcephaly, hypotelorism and normal intelligence. Clin Genet 39:178, 1991. 193. MacDermot KD, Winter RM: Two brothers with facial anomalies, microcephaly, hypoplastic genitalia, and a failure of psychomotor development. Am J Med Genet 32:60, 1989. 194. Teebi AS, Awadi SA: Kuwait type faciodigitalgenital syndrome. J Med Genet 28:805, 1991. 195. Bindewald B, Ulmer H, Muller U: Fallot complex, severe mental, and growth retardation: a new autosomal recessive syndrome? Am J Med Genet 50:173, 1994. 196. Gross-Tsur V, Joseph A, Blinder G: Familial microcephaly with severe neurological deficits: a description of five affected siblings. Clin Genet 47:33, 1995. 197. Auerbach AD, Sagi M, Adler B: Fanconi anemia: prenatal diagnosis in 30 fetuses at risk. Pediatrics 76:794, 1985. 198. Konig R, Seizer G, Stolp A, et al.: Microcephaly mesobrachyphalangy, and tracheoesophageal fistula: MMT syndrome. Dysmorphol Clin Genet 4:83, 1990. 199. Feingold M, Trainer J: Case report 100. J Clin Dysmorphol 1:22, 1983. 200. Straussberg R, Regenbogen L, Goodman RM, et al.: A newly recognized partial alopecia syndrome associated with distinct personality traits. J Craniofac Genet Dev Biol 11:3, 1991. 201. Fernhoff PM, Blackston RD, Oakley GP: Case report 63. Synd Ident 6:10, 1980. 202. Archibald SL, Fennema-Notestine C, Gamst A, et al.: Brain dysmorphology in individuals with severe prenatal alcohol exposure. Dev Med Child Neurol 43:148, 2001.

504

Neuromuscular Systems

203. Corona-Rivera JR, Corona-Rivera E, Romero-Velarde E et al.: Report and review of the fetal brain disruption sequence. Eur J Pediatr 160: 664, 2001. 204. Stoll C, Alembik Y, Repetto M: Congenital bilateral fibular deficiency with facial dysmorphia, brachydactyly and mental retardation in a girl. Genet Couns 9:147, 1998. 205. Franceschini P, Licata D, Guala A, et al.: Filippi syndrome: a specific MCA/MR complex within the spectrum of so called ‘‘craniodigital syndromes.’’ Report of an additional patient with a peculiar MPP and review of the literature. Genet Couns 13:343, 2002. 206. Houlston RS, Collins AL, Dennis NR, et al.: Further observations on the Floating-Harbor syndrome. Clin Dysmorphol 3:143, 1994. 207. Giam Y-C, Khoo BP: Focal dermal hypoplasia (Goltz syndrome). Pediatr Dermatol 15:399, 1998. 208. Frydman M, Cohen HA, Karmon G, et al.: Autosomal recessive blepbarophimosis, ptosis, V-esotropia, syndactyly and short stature. Clin Genet 41:57, 1992. 209. Fryns JP, Verresen H, Van der Berghe H: Prenatal growth retardation, microphthalmos/iris coloboma, cloudy cornea, urogenital anomalies and microcephaly. A possible new sublethal syndrome. Clin Genet 51:164, 1997. 210. Sheriff SMM, Hegab S: A syndrome of multiple fundal anomalies in siblings with microcephaly without mental retardation. Ophthalmol Surg 19:353, 1988. 211. Borochowitz Z, Dar H, Bar-El CH, et al.: Familial mental and growth retardation with peculiar ‘‘shark-like’’ facies: a new multiple malformation syndrome with an autosomal recessive inheritance. Proc Greenwood Genet Center 10:98, 1991. 212. Gillessen-Kaesbach G, Meinecke P, Garrett C, et al.: New autosomal recessive lethal disorder with polycystic kidneys type Potter I, characteristic face, microcephaly, brachymelia, and congenital heart defects. Am J Med Genet 45:511, 1993. 213. Giuffre L, Corsello G, Giuffre M, et al.: New syndrome: autosomal dominant microcephaly and radio-ulnar synostosis. Am J Med Genet 51:266, 1994. 214. Golabi M, Ito M, Hall BD: A new X-linked multiple congenital anomalies/mental retardation syndrome. Am J Med Genet 17:367, 1984. 215. Cormier-Daire V, Chauvet ML, Lyonnet S, et al.: Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation. J Med Genet 37:520, 2000. 216. Verloes A, Lesenfants S, Jamar M, et al.: GOMBO syndrome: another ‘‘pseudorecessive’’ disorder due to a cryptic translocation. Am J Med Genet 95:185, 2000. 217. Kupchik GS, Ludman MD, Raab El, et al.: GMS syndrome: a new dominant condition with goniodysgenesis, mental retardation, and short stature. Am J Med Genet 42:1, 1992. 218. Marion RW, Goldberg RB, Young RS, et al.: The GRANDDAD syndrome: a disorder combining growth delay, ‘‘aged facies,’’ normal development, and deficiency of subcutaneous fat. Am J Hum Genet 45:A53, 1989. 219. Green AJ, Sandford RN, Davison BCC: An autosomal dominant syndrome of renal and anogenital malformations with syndactyly. J Med Genet 33:594, 1996. 220. Grix A, Blankenship W, Peterson R, et al.: A new familial syndrome with craniofacial abnormalities, osseous defects and mental retardation. Birth Defects Orig Artic Ser XI(5): 107, 1975. 221. Cohen LHF, Vamos E, Heinrichs C, et al.: Growth failure, encephalopathy, and endocrine dysfunction in two siblings, one with 5-oxoprolinase deficiency. Eur J Pediatr 156:935, 1997. 222. Kauschansky A, Cohen HA, Varsano I, et al.: Familial isolated growthhormone deficiency with advanced sexual maturation. Am J Dis Child 147:170, 1993. 223. Ainsworth SB, Baraitser M, Mueller RF, et al.: Selective IgG2 subclass deficiency—a marker for the syndrome of pre/postnatal growth retardation, developmental delay, hypotrophy of distal extremities, dental anomalies and eczema. Clin Dysmorphol 6:139, 1997.

224. Gurrieri F, Sammito A, Bellusi A, et al.: New autosomal recessive syndrome of mental retardation, epilepsy, short stature, and skeletal dysplasia. Am J Med Genet 44:315, 1992. 225. Gustavson K-H, Anneren G, Malmgren H, et al.: New X-linked syndrome with severe mental retardation, severely impaired vision, severe hearing defect, epileptic seizures, spasticity, restricted joint mobility, and early death. Am J Med Genet 45:654, 1993. 226. Halal F: Dominantly inherited syndrome of microcephaly and cleft palate. Am J Med Genet 15:135, 1983. 227. Halal F, Silver K: Syndrome of microcephaly, Brachmann-de Langelike facial changes, severe metatarsus adductus, and developmental delay: mild Brachmann-de Lange syndrome? Am J Med Genet 42:381, 1992. 228. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 110. 229. Silengo M, Rigardetto R: Hall-Riggs syndrome: a possible second affected family. J Med Genet 37:886, 2000. 230. Hamel BCJ, Mariman ECM, van Beersum SEC, et al.: Mental retardation, congenital heart defect, cleft palate, short stature, and facial anomalies: a new X-linked multiple congenital anomalies/mental retardation syndrome: clinical description and molecular studies. Am J Med Genet 51:591, 1994. 231. Hennekam RCM, Renckens-Wennen EGCM: Acquired alopecia, mental retardation, short stature, microcephaly, and optic atrophy (Case report). J Med Genet 27:635, 1990. 232. Tay CH, Rajagopalan K, McEvoy-Bowe E, et al.: A recessive disorder with growth and mental retardation, peculiar facies, abnormal pigmentation, hepatic cirrhosis and aminoaciduria. Acta Paediatr Scand 63:777, 1974. 233. Baldwin S, Whitley RJ: Teratogen update: intrauterine herpes simplex virus infection. Teratology 39:1, 1989. 234. Herrick MK, Strefling AM, Urich H. Intrauterine multisystem atrophy in siblings: a new genetic syndrome? Acta Neuropathol 61:65, 1983. 235. Fryer AE: Goldberg-Shprintzen syndrome: report of a new family and review of the literature. Clin Dysmorphol 7:97, 1998. 236. Curry CJB, Hall BD: A new familial syndrome with Hirschprung’s disease, cleft palate, digital abnormalities, mental retardation and growth deficiency. Clin Research 27:118A, 1979. 237. Mowat DR, Croaker GDH, Cass DT, et al.: Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. J Med Genet 35:617, 1998. 238. Qazi QH, Sheikh TM, Fikrig S, et al.: Lack of evidence for craniofacial dysmorphism in perinatal human immunodeficiency virus infection. J Pediatr 112:7, 1988. 239. Amiel J, Faivre L, Marianowskl R, et al.: Hypertelorism-microtiaclefting syndrome (Bixler syndrome): report of two unrelated cases. Clin Dysmorphol 10:15, 2001. 240. Stevenson RE, Abidi F, Schwartz CE, et al.: Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome. Am J Med Genet 94:383, 2000. 241. Houlston RS, Iraggori S, Murday V, et al.: Microcephaly, focal segmental glomerulonephritis and marfanoid habitus in two sibs. Clin Dysmorphol 1:111, 1992. 242. Hoffman HM, Bastian JF, Bird LM: Humoral immunodeficiency with facial dysmorphology and limb anomalies: a new syndrome. Clin Dysmorphol 10:1, 2001. 243. Hunter AGW, Dupont B, McLaughlan M, et al.: The Hunter-McAlpine syndrome results from duplication 5q35-qter. Clin Genet 67:53, 2005. 244. Hurst J A, Winter RM, Baraitser M: Distinctive syndrome of short stature, craniostenosis, skeletal changes, and malformed ears. Am J Med Genet 29:107, 1988. 245. Huson SM, Crowley S, Hall CM, et al.: Case report. Previously unrecognized form of familial spondyloepiphyseal dysplasia tarda with characteristic facies. Clin Dysmorphol 2:20, 1993. 246. Hutteroth H, Spranger J: Case report 34. Synd Ident III(2):15, 1975. 247. Hyams SW, Jaffe M: Cerebral palsy and juvenile glaucoma in siblings. Dev Med Child Neurol 12:467, 1970.

Brain 248. Hanson JW: Teratogen update: fetal hydantoin effects. Teratology 33:349, 1986. 249. Chitayat D, Meager-Villemure K, Mames OA, et al.: Brain dysgenesis and congenital intracerebral calcification associated with 3-hydroxyisobutyric aciduria. J Pediatr 121:86, 1992. 250. Mikati MA, Naiiar SS, Sahli IF, et al.: Microcephaly, hypogonadism, short stature, and minor anomalies: a new syndrome? Am J Med Genet 22:599, 1985. 251. Vasques SB, Hurst DL, Sotos SB: X-linked hypogonadism, gynaecomastia, mental retardation, short stature, and obesity-a new syndrome. J Pediatr 94:56, 1989. 252. Kuster W, Ko¨nig A: Hypomelanosis of Ito: no entity, but a cutaneous sign of mosaicism. Am J Med Genet 85:346, 1999. 253. Teebi AS: Hypoparathyroidism, retarded growth and development, and dysmorphism or Sanjad-Sakati syndrome: an Arab disease reminiscent of Kenny-Caffey syndrome. J Med Genet 37:145, 2000. 254. Baetz-Greenwalt B, Ratliff NB, Moodie DS: Hypoplastic right heart complex: a cluster of cases with associated congenital birth defects. A new syndrome. J Pediatr 103:399, 1983. 255. Clayton-Smith J, Donnai D: A new autosomal recessive syndrome of unusual facies, digital abnormalities and ichthyosis. J Med Genet 26: 339, 1989. 256. Amano R, Ohtsuka Y, Ohtahara S: Monozygotic twin patients with congenital ichthyosis, microcephalus, spastic quadriplegia, myoclonus, and EEG abnormalities. Pediatr Neurol 12:255, 1995. 257. Imaizumi K, Kuroki Y: Radial ray defects, triangular face, telecanthus, sparse hair, dwarfism, and mental retardation. Am J Med Genet 41:162, 1991. 258. Jaspers NGJ, Taalman RDFM, Baan C: Patients with an inherited syndrome characterized by immunodeficiency, microcephaly and chromosome instability: genetic relationship to ataxia telangiectasia. Am J Hum Genet 42:66, 1988. 259. Say B, Barber N, Miller GC, et al.: Microcephaly, short stature and developmental delay associated with a chemotactic defect and transient hypogammaglobulinemia in two brothers. J Med Genet 23:355, 1986. 260. Seemanova E, Parsarge E, Beneskova D, et al.: Familial microcephaly with normal intelligence, immunodeficiency and risk for lymphoreticular malignancies: a new autosomal recessive disorder. Am J Med Genet 20:639, 1985. 261. Inbal A, Avissar N, Shaklai M, et al.: Myopathy, lactic acidosis, and sideroblastic anemia: a new syndrome. Am J Med Genet 55:372, 1995. 262. Pitt D, Hopkins I: A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust Paediatr J 14:182, 1978. 263. Stromme P, Dahl E, Flage T, et al.: Apple peel intestinal atresia in siblings with ocular anomalies and microcephaly. Clin Genet 44:208, 1993. 264. Ippel PF, Wittebol-Post D, van Nesslrooij BPM: Sutural cataract, retinitis pigmentosa, microcephaly, and psychomotor retardation. Ophthalmic Genet 15:121, 1994. 265. Yuksel A, Seven M, Deviren A, et al.: Two female siblings with a previously unreported MCA/MR syndrome: pre- and postnatal growth retardation, iris colobomata, spasticity, facial dysmorphism and dilated ventricles. Genet Couns 10:265, 1999. 266. Ives El, Houston CS: Autosomal recessive microcephaly and micromelia in Cree Indians. Am J Med Genet 7:351, 1980. 267. Leichtman LG, Brown D, Arnold H: Syndrome identification case report 139. Arachnodactyly, joint laxity and spondylolisthesis. Dysmorph Clin Genet 2:13, 1988. 268. Janssen HCJP, Schaap C, Vandevijver N, et al.: Two sibs with microcephaly, hygroma colli, renal dysplasia, and cutaneous syndactyly: a new lethal MCA syndrome? J Med Genet 36:481, 1999. 269. Moeschler JB, Polak MJ, Jenkins JJ, et al.: The Johanson-Blizzard syndrome: a second report of full autopsy findings. Am J Med Genet 26:133, 1987. 270. Jones KL, Smith DW: Case report 3. Synd Ident 1:13, 1973. 271. Jorgenson RJ, Lenz W, Uzielli MLG: Mild short stature, microcephaly, ptosis-blepharophimosis, facial asymmetry, and radioulnar synostosis. J Clin Dysmorphol 1:14, 1983.

505 272. Nevin NG, Henry P, Thomas PTS: A case of orocraniodigital (JubergHayward) syndrome. Am J Med Genet 18:478, 1981. 273. Ryan SG, Chance PE, Zon C-H, et al.: Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing. Nat Genet 17:92, 1997. 274. Flanagan N, Boyadjiev SA, Harper J, et al.: Familial craniosynostosis, anal anomalies, and porokeratosis: CAP syndrome. J Med Genet 35:763, 1998. 275. Wilson GN: Thirteen cases of Niikawa-Kuroki syndrome: report and review with emphasis on medical complications and preventative management. Am J Med Genet 79:112, 1998. 276. Zelante L, Candela MA, Savoia A, et al.: Confirmation of KapurToriello syndrome in an Italian patient. Clin Dysmorphol 8:151, 1999. 277. Figuera LE, Garcia-Cruz D, Ramirez-Duenas ML, et al.: Kaufman oculocerebrofacial syndrome: report of two new cases and further delineation. Clin Genet 44:98, 1993. 278. Kawashima H, Tsuji N: Syndrome of microcephaly, deafness/ malformed ears, mental retardation and peculiar facies in a mother and son. Clin Genet 31:303, 1987. 279. Zollino M, Battaglia A, D’Avanzo MG, et al.: Six additional cases of the KBG syndrome: clinical reports and outline of the diagnostic criteria. Am J Med Genet 52:302, 1994. 280. Kelly TE, Kirson L, Wyatt J. Microcephaly and digital anomalies: a newly recognized syndrome of recessively inherited mental retardation. Am J Med Genet 43:353, 1993. 281. Kondoh T, Yamamoto T, Kono Y, et al.: Condition of microcephaly, growth retardation, joint contractures, atopic dermatitis, and mental retardation in two Japanese sisters: a new autosomal recessive MCA/ MR syndrome. Am J Med Genet 102:63, 2001. 282. Kozlowski K, Turner G: Mental retardation, congenital hip dislocation, wrinkled skin of the hands and feet (a new mental retardation, multiple anomalies syndrome). Radiol Diagn 24:175, 1983. 283. Kraus-Rupert R: Zur Frage ererbter diencephaler stovingen (Infantaler eunuchoidismus sowie 3 microcephalie bei recessivem erbgang. Z Menschl Ver Konsti 34:643, 1958. 284. Labrune P, Assathiany R, Penro D, et al.: Progressive vitiligo, mental retardation, facial dysmorphism, and urethral duplication without chromosome breakage or immunodeficiency. J Med Genet 29:592, 1992. 285. Buhler EM, Buhler UK, Beutler C, et al.: A final word on the trichorhino-phalangeal syndromes. Clin Genet 31:273, 1987. 286. Forrester S, Kavach MJ, Reynolds NM, et al.: Manifestations in four males with an obligate carrier of the Lenz microphthalmia syndrome. Am J Med Genet 98:92, 2001. 287. Elsas U, Endo F, Strumlauf E, et al.: Leprechaunism: an inherited defect in a high-affinity insulin receptor. Am J Hum Genet 37:73, 1985. 288. Spearritt DJ, Tannenberg AEG, Payton DJ: Lethal multiple pterygium syndrome. Report of a case with neurological anomalies. Am J Med Genet 47:45, 1993. 289. Le Merrer M, Guillot M, Briard M-L, et al.: Lethal progeroid syndrome with osteolysis: case report. Ann Ge´ne´t 34:82, 1991. 290. Mayatepek E, Flock B: Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome. Lancet 352:1514, 1998. 291. O’Driscoll M, Cerosaletti KM, Girard P-M, et al.: DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8:1175, 2001. 292. Lindstrom JA: GG-oligophrenic, low birth-weight dwarfism in sibs. Birth Defects Orig Artic Ser XI(2):443, 1975. 293. Podruch PE, Yen F-S, Dinno ND, et al.: Yq- in a child with livedo reticularis, snub nose, microcephaly, and profound mental retardation. J Med Genet 19:377, 1982. 294. Christian JC, Johnson VP, Biegel AA, et al.: Sisters with low birth weight dwarfism, congenital anomalies and dysgammaglobulinemia. Am J Dis Child 122:529, 1971. 295. McAlister WH, Coe JD, Whyte MP: Macroepiphyseal dysplasia with symptomatic osteoporosis, wrinkled skin, and aged appearance: a presumed autosomal recessive condition. Skel Radiol 15:47, 1986.

506

Neuromuscular Systems

296. Lungarotti MS, Martello C, Barboni G, et al.: X-linked mental retardation, microcephaly, and growth delay associated with hereditary bullous dystrophy macular type: report of a second family. Am J Med Genet 51:598, 1994. 297. Madokoro H, Ohdo S, Sonoda T, et al.: Association of severe microcephaly, short palpebral fissures, micrognathia, growth retardation and early death: a new syndrome. Acta Paediatr Jpn 29:186, 1987. 298. Williams MS, Josephson KD, Wargowski DS.: Marden-Walker syndrome: a case report and a critical review of the literature. Clin Dysmorphol 2:211, 1993. 299. Marion RW, Mayers MM. Facial dysmorphism, growth and developmental retardation, absence of early vocalization and other anomalies in siblings. Dysmorphol Clin Genet 4:149, 1990. 300. Hennekam RCM, van de Meeberg AG, Van Doorne JM, et al.: Martsolf syndrome in a brother and sister: clinical features and pattern of inheritance. Eur J Pediatr 147:539, 1988. 301. Wolach B, Raas-Rothschild A, Metzer A, et al.: Skin mastocytosis with short stature, conductive hearing loss and microtia: a new syndrome. Clin Genet 37:64, 1990. 302. Warkany J: Teratogen update: hyperthermia. Teratology 33:365, 1986. 303. Lipson A, Beuhler B, Bartley J: Maternal hyperphenylalaninemia fetal effects. J Pediatr 104:216, 1984. 304. Matsoukas J, Liarikos S, Giannikas A, et al.: A newly recognized dominantly inherited syndrome: short stature, ocular and articular anomalies, mental retardation. Helv Paediatr Acta 28:383, 1973. 305. Me´garbane´ A, Kharrat K, Kreichati G.: Four sibs with dislocated elbows, bowed tibiae, scoliosis, deafness, cataract, microcephaly, and mental retardation: a new MCA/MR syndrome. J Med Genet 35:755, 1998. 306. Me´garbane´ A, Ruchoux MM, Loeys B, et al.: Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome. Am J Med Genet 104:221, 2001. 307. Me´garbane´ A, LeMerrer M, El Kallab K: Ptosis, down-slanting palpebral fissures, hypertelorism, seizures and mental retardation: a possible new MCA/MR syndrome. Clin Dysmorphol 6:239, 1997. 308. Abdel-Salam GM, Svekus A, Pelle Z, et al.: Microcephaly, microphthalmia, congenital cataract, with calcification of the basal ganglia: MCA/MR syndrome. Genet Couns 11:391, 2000. 309. Del Giudice E, Sartorio R, Romano A, et al.: Megalocornea and mental retardation syndrome: two new cases. Am J Med Genet 26:417, 1987. 310. Steinmuller R, Steinberger D, Muller U: MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to Xp21.2–p22.13. Eur J Hum Genet 6:201, 1998. 311. Mehta L, Lewis I, Patton MA: Unknown syndrome: congenital heart disease, ptosis, hypodontia, and craniosynostosis. J Med Genet 26:664, 1989. 312. Hunter AGW, Macpherson RI: Mental retardation and osteosclerosis. Am J Med Genet 2:267, 1978. 313. Harada M: Congenital Minamata disease: intrauterine methylmercury poisoning. Teratology 18:285, 1978. 314. Me´garbane´ A, Ghanem I, Romana S, et al.: Congenital contractures, short stature, abnormal face, microcephaly, scoliosis, hip dislocation, and severe psychomotor retardation in two unrelated girls. A new MCA/MR syndrome? Genet Couns 13:123, 2002. 315. Perc¸in EF, Duzcan F, Kafali G, et al.: A new syndrome with cardiac malformation, cleft lip-palate, microcephaly and digital anomalies? Clin Genet 48:264, 1995. 316. Kennedy SJ, Leek J, McCrindle BW, et al.: Microcephaly-cardiomyopathy syndrome: confirmation of the phenotype. J Med Genet 36:854, 1999. 317. Guion-Almeida ML, Zechi-Ceide RM, Richieri-Costa A: Multiple congenital anomalies syndrome: growth and mental retardation, microcephaly, preauricular skin tags, cleft palate, camptodactyly, and distal limb anomalies. Report on two unrelated Brazilian patients. Am J Med Genet 87:72, 1999. 318. Battaglia A, Ferrari AR, Orsitto E, et al.: New autosomal recessive syndrome of mental retardation, coarse face, microcephaly, epilepsy and skeletal anomalies. Clin Dysmorphol 5:41, 1996.

319. Herna´ndez A, Garcia-Esquivel L, Reynoso MC, et al.: Cortical blindness, growth and psychomotor retardation and postaxial polydactyly: a probably distinct autosomal recessive syndrome. Clin Genet 28:251, 1985. 320. Jones KL, Smith DW: Case report 21. Synd Ident 11(2):7, 1974. 321. Alexander IE, Tauro GP, Bankier A: Fetal brain disruption sequence in sisters. Eur J Pediatr 154:654, 1995. 322. Renier WO, Gabriels FJM, Jasper HHJ, et al.: An X-linked syndrome with microcephaly, severe mental retardation, spasticity, epilepsy and deafness. J Ment Defic Res 26:27, 1982. 323. Ryan A, Burn J, Court S, et al.: Two brothers with varying combinations of severe developmental delay, epilepsy, microcephaly, tetralogy of Fallot and hydronephrosis. Clin Dysmorphol 8:15, 1999. 324. Nardelli E, Rizzuto N: Familial microcephaly with bilateral heterotopias of gray matter in the centrum ovale. Acta Neurol (Napoli) 2:36, 1980. 325. Okajima K, Ito T, Wakita A: Male siblings with dyserythropoiesis, microcephaly and intrauterine growth retardation. Clin Dysmorphol. 11:107, 2002. 326. Mulliez N, Roux Ch, Loterman JP, et al.: Microce´phalie, arthrogrypose. Syndrome le´tal re´cessif autosomique. Arch Fr Pediatr 37:591, 1980. 327. Kozma C, Scribanu N, Gersh E: The microcephaly-lymphoedema syndrome: report of an additional family. Clin Dysmorphol 5:49, 1996. 328. Hersh JH, Holmes JW: The microcephaly lymphedema phenotype: a possible heterogeneous group of disorders with intellectual variability. Am J Hum Genet 45:A77, 1989. 329. Achermann S, Largo R, Kotzot D, et al.: Short stature, myopia, severe developmental delay, and peculiar facial appearance in two brothers: a new syndrome. Am J Med Genet 86:486, 1999. 330. Harbord MG, Lambert SR, Kriss A, et al.: Autosomal recessive microcephaly, mental retardation with non-pigmentary retinopathy and a distinctive electroretinogram. Neuropediatrics 20:139, 1989. 331. Teebi AS, AI-Awadi SA, White AG: Autosomal recessive nonsyndromal microcephaly with normal intelligence. Am J Med Genet 26:355, 1987. 332. Innis JW, Asher JH Jr, Poznonski AK, et al.: Autosomal dominant microcephaly with normal intelligence, short palpebral fissures, and digital anomalies. Am J Med Genet 71:150, 1997. 333. Melamed Y, Katznelson MB-M, Frydman M: Oligodontia, short stature and small head circumference with normal head circumference. Clin Genet 46:316, 1994. 334. Parke JL, Riccardi VM, Lewis RA, et al.: A syndrome of microcephaly and retinal pigmentary abnormalities without mental retardation in a family with coincidental autosomal dominant hyperreflexia. Am J Med Genet 17:585, 1984. 335. Hersh JH, Joyce MR, Spranger J: Microcephalic osteodysplastic dysplasia. Am J Med Genet 51:194, 1994. 336. Sigaudy S, Toulain A, Monda A, et al.: Microcephalic osteodysplastic primordial dwarfism Taybi-Linder type: report of four cases and review of the literature. Am J Med Genet 80:16, 1998. 337. Duval A, Boute O, Devisme L, et al.: New autosomal recessive syndrome of severe microcephaly and skeletal anomalies including posterior ribgap defects. Am J Med Genet 80:429, 1998. 338. Hadziselimovic F, Fliegel CH, Miny P: A novel syndrome involving primary skeletal growth and retardation in siblings. Clin Dysmorphol 10:33, 2001. 339. Mitchell SJ, McHale DP, Campbell DA, et al.: A syndrome of severe mental retardation, spasticity and tapetoretinal degeneration linked to chromosome 15q24. Am J Hum Genet 62:1070, 1998. 340. Schram A, Kroes HY, Sollie K, et al.: Hereditary fetal brain degeneration resembling fetal brain disruption sequence in two families. Am J Med Genet 127A:172, 2004. 341. Willems PJ, DeVries-Van der Weerd S, Los FJ, et al.: Short-limbed dwarfism, subluxation of the knees, hypogenitalism, and dysmorphic facies: a new syndrome. J Clin Dysmorphol 2:19, 1984. 342. Verloes A, Dresse M-F, Keutgen H, et al.: Microphthalmia, facial anomalies, microcephaly, thumb and hallux hypoplasia, and agammaglobulinemia. Am J Med Genet 101:209, 2001.

Brain 343. Teruel MC, Hernandez-Sampelayo T, Fermosel J, et al.: Multiple malformations: unusual facies, absent abdominal musculature, microphthalmia, and joint laxity. Dysmorphol Clin Genet 1:126, 1987. 344. Me´garbane´ A, Haddad-Zebouni S, Nabbout R, et al.: Microcephaly, colobomatous microphthalmia, short stature, and severe psychomotor retardation in two male first cousins. A new MCA/MR syndrome? Am J Med Genet 83:82, 1999. 345. Balci S, Say B, Firat T: Corneal opacity, microphthalmia, mental retardation, microcephaly and generalized muscular spasticity associated with hyperglycinemia. Clin Genet 5:36, 1974. 346. Vervoort VS, Viljoen D, Smart R, et al.: Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype. J Med Genet 39:893, 2002. 347. Kayserilli H, Cox TC, Cox LL, et al.: Molecular characterization of a new case of microphthalmia with linear skin defects (MLS). J Med Genet 38:411, 2001. 348. Young ID, Fielder AR, Simpson K: Microcephaly, microphthalmos and retinal folds: report of a family. J Med Genet 24:172, 1987. 349. Tackels D, Schwartz CE, Carpenter NJ, et al.: Refined gene localisation for the Miles-Carpenter syndrome (MCS). Am J Med Genet 85:221, 1999. 350. Fryer A: Mental retardation, mitral valve prolapse, and characteristic face: another report? Am J Med Genet 51:277, 1994. 351. Jurenka SB, Van Allen MI: Mixed sclerosing bone dysplasia, small stature, seizure disorder, and mental retardation: a syndrome?. Am J Med Genet 57:6, 1995. 352. Kajii T, Ikeuchi T, Yang ZQ, et al.: Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: report of five infants. Am J Med Genet 104:57, 2001. 353. Mubashir MA, Sabry MA, Farah S, et al.: New syndromic entity of situs inversus totalis. Clin Dysmorphol 8:2, 1999. 354. Kim JJ, Armstrong DD, Fishman MA: Multicore myopathy, microcephaly, aganglionosis, and short stature. J Child Neurol 9:275, 1994. 355. De Silava DC, Wheatley DN, Herriot R, et al.: Mulvihill-Smith progeria like syndrome: a further report with delineation of phenotype, immunologic deficits, and novel observations of fibroblast abnormalities. Am J Med Genet 69:56, 1997. 356. Verloes A, Lesenfants S, Misson J-P, et al.: Microcephaly, muscular build, rhizomelia, and cataracts: description of a possible recessive syndrome and some comments on the use of electronic databases in syndromology. Am J Med Genet 68:455, 1997. 357. Doerfler W, Wieczorek D, Gillessen-Kaesbach G, et al.: Three brothers with mental and physical retardation, hydrocephalus, microcephaly, internal malformations, speech disorder, and facial anomalies: Mutchinick syndrome. Am J Med Genet 73:210, 1997. 358. Myhre SA: Short stature, mental retardation, skeletal abnormalities and unusual facial appearance. Synd Ident IV(2):22, 1976. 359. Nakata NMK, Guion-Almeida ML, Richieri-Costa A: Cleft palatelateral synechiae syndrome: report on three patients with additional findings and evidence for variability and heterogeneity. Am J Med Genet 47:330, 1993. 360. Seven M, Ozkilic A, Yuksel A: Dysmorphic face in two siblings with infantile neuroaxonal dystrophy. Genet Couns 13:465, 2002. 361. Pescia C: Encephalopathie epileptogene precoce, a transmission re´cessive, dans deux families d’un isolat Valasian. J Genet Hum 21: 147,1973. 362. Garty BZ, Eisenstein B, Sandbank J, et al.: Microcephaly and congenital nephrotic syndrome owing to diffuse mesangial sclerosis: an autosomal recessive syndrome. J Med Genet 31:121, 1994. 363. Coleman RA, Van Hove JLK, Morris CR, et al.: Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: additional findings or a new syndrome (ARCC-NDI). Am J Med Genet 72:335, 1997. 364. Krajewska-Walasek M, Chrzanowska K, Czermiska-Kowalska A.: Another patient with an unusual syndrome of mental retardation and sparse hair? Clin Dysmorphol 5:183, 1996. 365. Kleir S, Herrmann M, Wittwer B, et al.: Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegan breakage syndrome. Clin Genet 57:384, 2000.

507 366. Rehm HL, Gutierrez-Espeleta GA, Garcia R, et al.: Norrie disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency. Hum Mutat 9:402, 1997. 367. Nowaczyk MJM, Hughes HE, Costa T, et al.: Severe prenatal growth retardation, dysmorphic features, pigmentary retinopathy, and generalised absence of subcutaneous tissues: a new entity? Clin Dysmorphol 7:263, 1998. 368. Gabrielli O, Carloni I, Cordiali R, et al.: Peculiar facies, obesity, cleft lip and palate, growth hormone deficiency and mental retardation: a new syndrome? Clin Dysmorphol 9:153, 2000. 369. Deshaies Y, Rott HD, Wissmuller HF, et al.: Microcephalie recessive lie´e a 1’X. J Ge´ne´t Hum 27:221, 1979. 370. Tezcan I, Demir E, Asan E, et al.: A new case of oculocerebral hypopigmentation syndrome (Cross syndrome) with additional findings. Clin Genet 51:118, 1997. 371. Bitoun P, Morel-Charron J: A hereditary syndrome association of oculocutaneous albinism, dysmorphic features and short stature. Ophthalmic Paediatr Genet 11:209, 1990. 372. Paznekas WA, Boyadjiev SA, Shapiro RE, et al.: Connexin 43 (CJA1) mutations cause the pleitrophic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408, 2003. 373. Pellegrino JE, Engel JM, Chavez D, et al.: Oculo-palatal-cerebral syndrome: a second case. Am J Med Genet 99:200, 2001. 374. Sonoda T, Ohdo S, Ohba K, et al.: Association of congenital heart disease, blepharoptosis, and short stature. Jpn J Hum Genet 34:291, 1989. 375. Okamoto N, Matsumoto F, Shimada K, et al.: New MCA/MR syndrome with generalized hypotonia, congenital hydronephrosis, and characteristic face. Am J Med Genet 68:347, 1997. 376. Young ID, McKeever PA, Squier MV, et al.: Lethal olivopontoneocerebellar hypoplasia with dysmorphic features in sibs. J Med Genet 29:733, 1992. 377. Zampino G, Di Rocco C, Butera G, et al.: Opitz C Trigonocephaly syndrome and midline brain anomalies. Am J Med Genet 73:484, 1997. 378. Nevin NC, Silvestri J, Kernohan DC, et al.: Oral-facial-digital syndrome with retinal abnormalities: OFDS type IX. A further case report. Am J Med Genet 51:228, 1994. 379. Orstavik KH, Stromme P, Spetalen S, et al.: Aplasia cutis congenita associated with limb, eye, and brain anomalies in sibs: a variant of the Adams-Oliver syndrome? Am J Med Genet 59:92, 1995. 380. Buyse M, Bull MJ: A syndrome of osteogenesis imperfecta, microcephaly, and cataracts. Birth Defects Orig Artic Ser XIV(6B):95, 1978. 381. Gong Y, Dallapiccola B, De Paepe A, et al.: Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12–13. Am J Hum Genet 59:146, 1996. 382. Robertson SP, Twigg SRF, Sutherland-Smith AJ, et al.: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 383. Krakowiak PA, Wassif CA, Kratz L, et al.: Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5desaturase deficiency. Hum Mol Genet 12:1631, 2003. 384. Bertola DR, Wolf LM, Toriello H, et al.: Acro-oto-ocular syndrome: further evidence for a new autosomal recessive disorder. Am J Med Genet 73:442, 1997. 385. Palant Dl, Feingold M, Berkman MD: Unusual facies, cleft palate, mental retardation, and limb abnormalities in siblings—a new syndrome. J Pediatr 78:686, 1971. 386. Partington M, Anderson D: Mild growth retardation and developmental delay, microcephaly, and a distinctive facial appearance. Am J Med Genet 49:247, 1994. 387. Hall CR, Wu Y, Shaffer LG, et al.: Familial case of Potocki-Shaffer syndrome associated with microdeletion of EXT2 and ALX4. Clin Genet 60:356, 2001. 388. Valmaggia C, Gottlab I: Periodic alternating nystagmus in two children with similar, unusual phenotype. Pediatr Neurol 23:432, 2000. 389. Sullivan TJ, Clarke MP, Heathcote JG, et al.: Multiple congenital contractures (arthrogryposis) in association with Peters’ anomaly and chorioretinal colobomata. J Pediatr Ophthalmol Strabismus 29:370, 1992.

508

Neuromuscular Systems

390. Klomp LWJ, de Koning TJ, Malingre HEM, et al.: Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency-a neurometabolic disorder associated with reduced L-serine biosynthesis. Am J Hum Genet 67:1389, 2000. 391. Pierpont MEM, Stewart FJ, Gorlin RJ: Plantar lipomatosis, unusual facial phenotype and developmental delay: a new MCA/MR syndrome. Am J Med Genet 75:16, 1998. 392. Tajara EH, Pinheiro M, Freire-Maia N: Pilodentoungular dysplasia with microcephaly: a new ectodermal dysplasia/malformation syndrome. Am J Med Genet 26:153, 1987. 393. Stromme P, Knudtzon J, Westvik J, et al.: Cleft lip and palate, scoliosis, skeletal and cardiac malformations and other dysmorphic features in a child. Case report. Scand J Plastic Rec Surg 27:71, 1993. 394. Orrico A, Galli L, Zappella M, et al.: Possible case of Pitt-Hopkins syndrome in sibs. Am J Med Genet 103:157, 2001. 395. Kant SG, Van Haeringen A, Bakker E, et al.: Pitt-Rogers-Danks syndrome and Wolf-Hirschhorn syndrome are caused by a deletion in the same region on chromosome 4p16.3. J Med Genet 34:569, 1997. 396. Fryns JP, De Smet L: On the association of Poland anomaly and primary microcephaly. Clin Dysmorphol 3:347, 1994. 397. Engelhard D, Yatziv S: Pre and post axial polysyndactyly, microcephaly and ptosis. Eur J Pediatr 130:47, 1979. 398. Beukeveld GJJ, Wolthers BG, Nordman, et al.: A retrospective study of a patient with homozygous form of acute intermittent porphyria. J Inherit Metab Dis 13:673, 1990. 399. Nicholls RD, Knoll JHM, Butler MG, et al.: Uniparental disomy for chromosome 15 in Prader-Willi syndrome. Am J Hum Genet 45:A209, 1989. 400. Howard FH, Young ID: Unknown syndrome: microcephaly, facial clefting, and preaxial polydactyly. J Med Genet 25:272, 1988. 401. Baraitser M, Insley J, Winter RM: A recognizable short stature syndrome with premature aging and pigmented nevi. J Med Genet 25:52, 1988. 402. Martin AO, Perrin JCS, Muir WA: An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly. Clin Genet 12:65, 1977. 403. Toriello HV, Horton WA, Oostendorp A, et al.: An apparently new syndrome of microcephalic primordial dwarfism and cataracts. Am J Med Genet 25:1, 1986. 404. Giannotti A, Diglio MC, Mingarelli R, et al.: Progeroid syndrome with characteristic facial appearance and hand anomalies in a father and a son. Am J Med Genet 73:227, 1997. 405. Sanderson DM, Fraser FC: Proptosis, Robin association, clenched hands, and multiple abnormalities. J Clin Dysmorphol 1(2):19, 1983. 406. Gale AN, Lacassie Y, Rogers JG, et al.: Two ‘new’ autosomal recessive mental retardation syndromes observed among the Amish. Birth Defects Orig Artic Ser XIII(3B):127, 1977. 407. Hall BD, Berg BD, Rudolph RS, et al.: Pseudoprogeria/HallermanStreiff (PHS) syndrome. Birth Defects Orig Artic Ser X(7):137, 1974. 408. Crow YJ, Black DN, Ali M, et al.: Cree encephalitis is allelic with Aicardi-Goutieres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism. J Med Genet 40:183, 2003. 409. Haspeslagh M, Fryns JP, De Muelenaere A, et al.: Mental retardation with pterygia, shortness and distinct facial appearance. Clin Genet 28:550, 1985. 410. Bazopoulou-Kyrkanidou E, Neou P, Bartsocas CS, et al.: Familial bilateral blepharoptosis and subvalvular aortic stenosis. Genet Couns 6:227, 1995. 411. Evard P, de Saint-Georges P, Kadhim HJ, et al.: Pathology of prenatal encephalopathies. In: Child Neurology and Developmental Disabilities. JH French, S Harel, P Casaer, eds. Paul H Brookes, Baltimore, 1989, p 153. 412. Udler Y, Halpern GJ, Sohat M, et al.: Tsukahara syndrome of radioulnar synostosis, short atature, microcephaly, scoliosis, and mental retardation. Am J Med Genet 80:526, 1998. 413. Acosta AX, Peres LC, Chimelli LC, et al.: Raine dysplasia: a Brazilian case with a mild radiological involvement. Clin Dysmorphol 9:99, 2000. 414. Lubke T, Marquardt T, Etzioni A, et al.: Complementation cloning identifies CDG-IIc, a new type of congenital disorder of glycosylation, as a new CDG-fucose transporter deficiency. Nat Genet 28:73, 2001.

415. Reardon W, Winter RM, Wilson J, et al.: Mental retardation, microcephaly and blepharochalasis in brothers. Clin Dysmorphol 3: 128, 1994. 416. Lenski C, Abidi F, Meindl A, et al.: Novel truncating mutations in the polyglutamine tract binding protein 1 gene (PQBP1) cause Renpenning syndrome and X-linked mental retardation in another family with microcephaly. Am J Hum Genet 74:777, 2004. 417. Cormier-Daire V, Rustin P, Rotig A, et al.: Craniofacial anomalies and malformations in respiratory chain deficiency. Am J Med Genet 66: 457, 1996. 418. Fryns JP, Van Den Berghe H: Pre and postnatal growth retardation with severe mental retardation, acral limb deficiencies and ocular anomalies. Acta Paediatr Belg 30:227, 1977. 419. Bourdon V, Philippe C, Labrune O, et al.: A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett patients. Hum Genet 108:43, 2001. 420. Wanders RJ, Saelman D, Heymans HSA, et al.: Genetic relation between the Zellweger syndrome, infantile Refsum’s disease, and rhizomelic chondrodysplasia punctata. N Engl J Med 314:787, 1986. 421. Moser AB, Rasmussen M, Naidu S, et al.: Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr 127:13, 1995. 422. Richieri-Costa A, Guion-Almeida ML, Ramos AL: Mental retardation, microbrachycephaly, hypotelorism, palpebral ptosis, thin/long face, cleft lip and lumbosacral/pelvic anomalies. Am J Med Genet 43:565, 1992. 423. Romke C, Froster-Iskenius U, Heyne K, et al.: Roberts syndrome and SC phocomelia: a single genetic entity. Clin Genet 31:170, 1987. 424. Wang LL, Levy ML, Lewis RA, et al.: Clinical manifestations in a cohort of 41 Rothmund-Thompson syndrome patients. Am J Med Genet 102:11, 2001. 425. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 574. 426. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 92. 427. Hunter AGW: Ruvalcaba syndrome. Am J Med Genet 21:785, 1985. 428. Salinas CF, Jorgenson RJ, Strickland A: Colobomas of lower lids, malar hypoplasia, antimongoloid slant and clefting: case report 38. Synd Ident IV(1):5, 1976. 429. Saul RA, Wilkes G, Stevenson RE: ‘‘Salt-and-pepper’’ pigmentary changes with severe mental retardation: a new neurocutaneous syndrome? Proc Greenwood Genet Center 2:6, 1983. 430. Pagnan NA-B, Ribeiro EM, Poerner F: Say syndrome: report of a familial case. Am J Med Genet 86:165, 1999. 431. Marble M, Pridjian G: Scalp defects, polythelia, microcephaly and developmental delay: a new syndrome with apparent autosomal dominant inheritance. Am J Med Genet 108:327, 2002. 432. Sigurdardottir S, Myers SM, Woodsworth JM, et al.: Mental retardation and seizure disorder in Schimke immunoosseous dysplasia. Am J Med Genet 90:294, 2000. 433. Thompson EM, Winter RM: A child with sclerocornea, short limbs, short stature, and distinct facial appearance. Am J Med Genet 30:719, 1988. 434. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497, 2003. 435. Bangstad JH, Beck-Nielsen H, Hother-Nielson O, et al.: Primordial birdheaded nanism associated with progressive ataxia, early onset insulin resistant diabetes, goiter and primary gonadal insufficiency. Acta Paediatr Scand 78:488, 1989. 436. Majoor-Krakauer DF, Wladimiroff IN, Stewart PA, et al.: Microcephaly, micrognathia, and bird-headed dwarfism: prenatal diagnosis of a Seckel-like syndrome. Am J Med Genet 27:183, 1987. 437. Winter RM, Wigglesworth J, Harding BN: Osteodysplastic primordial dwarfism: report of a further patient with manifestations similar to those seen in patients with types I and III. Am J Med Genet 21:569, 1985. 438. Fitch N, Pinsky L, Lachance RC: A form of bird-headed dwarfism with features of premature senility. Am J Dis Child 120:260, 1970.

Brain 439. Majewski F, Goecke TO: Microcephalic osteodysplastic primordial dwarfism type II: report of three cases and review. Am J Med Genet 80:25, 1998. 440. Seidel H, Stengel-Rutowski S, Schimanek P, et al.: Nonchromosomal dysmorphic syndromes (MCA/MR syndromes): 1 Similar abnormal phenotype in two mentally retarded brothers. Dysmorphol Clin Genet 1:101, 1987. 441. Gapta AK, Rasmussen JE, Headington JT: Extensive congenital erosions and vessicles healing with reticulate scarring. J Am Acad Dermatol 17:369, 1987. 442. Ten Donkelaar HJ, Wesseling P, Semmekrot BA, et al.: Severe, non Xlinked congenital microcephaly with absence of the pyramidal tracts in two siblings. Acta Neuropathol 98:203, 1999. 443. Walter-Nicolet E, Coe¨lier A, Joriot S, et al.: The Richieri-Costa and Pereira form of acrofacial dysostosis: first case in a non-Brazilian infant. Am J Med Genet 87:430, 1999. 444. Perszyk AA: Primordial dwarfing condition with cleft palate, neurosensory deafness and digital anomalies: case report and critical review. Am J Hum Genet 57:A99, 1995. 445. Sybert VP, Smith DW: Case report 62. Synd Ident VI(1):8, 1980. 446. Khosravi M, Weaver DD, Bull MJ, et al.: Lethal syndrome of skeletal dysplasia and progressive central nervous system degeneration. Am J Med Genet 77:63, 1998. 447. Martsolf JT, Reed MH, Hunter AGW: Skeletal dysplasia, Robin anomalad, and polydactyly. Synd Ident V(1):14, 1977. 448. Villard L, Fontes M, Ades LC, et al.: Identification of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers syndrome. Am J Med Genet 91:83, 2000. 449. Kelley RI.: RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. Am J Hum Genet. 63:322, 1998. 450. Smith ACM, Gropman A: Smith-Magenis syndrome. In: Management of Genetic Syndromes, ed 2, SB Cassidy, JE Allanson, eds. Wiley-Liss, New York, 2005, p 507. 451. Teebi AS, Miller S, Ostrer H, et al.: Spastic paraplegia, optic atrophy, microcephaly with normal intelligence, and XY sex reversal: a new autosomal recessive syndrome? J Med Genet 35:759, 1998. 452. Van Haeringen A, Hurst JA, Savidge R, et al.: A familial syndrome of microcephaly, sparse hair, mental retardation, and seizures. J Med Genet 27:127, 1990. 453. Robertson SP, Roelda C, Bankier A: Hypogonadotropic hypogonadism in Roifman syndrome. Clin Genet 57:435, 2000. 454. Stimmler L, Jensen N, Toseland P: Alaninuria, associated with microcephaly, dwarfism, enamel hypoplasia, and diabetes mellitus in two sisters. Arch Dis Child 45:682, 1970. 455. Lossi AM, Millan JM, Villard L, et al.: Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: demonstration that the mutation is involved in the inactivation bias. Am J Hum Genet 65:558, 1999. 456. Stratton RF: Tall stature, microcephaly, hypotonia, advanced bone age, and unusual infra-auricular creases. Am J Med Genet 75:261, 1998 457. Liberfarb RM, Kaktsumi O, Fleischnick E, et al.: Tapetoretinal degeneration associated with multisystem abnormalities. Ophthalmol Pediatr Genet 7:151, 1986. 458. Ceballos-Quintal JM, Pinto-Escalante D, Gongora-Biachi RA: TARlike syndrome in a consanguineous Mayan girl. Am J Med Genet 43: 805, 1992. 459. Ohdo S, Sonoda T, Ohba K: Natural history and postmortem anatomy of a patient with tetra-amelia, ectodermal dysplasia, peculiar face and developmental retardation (MIM 273390). J Med Genet 31:980, 1994. 460. Theile U: Case report 87. Synd Ident VIII(1):20, 1982. 461. Rupps R, Elliot AM, Azouz EM, et al.: Skeletal and cardiac malformations with thrombocytopenia. Am J Med Genet 64:497, 1996. 462. Arnold GL, Kirby RS, Langendoefer S, et al.: Toluene embryopathy: clinical delineation and developmental follow-up. Pediatrics 93:216, 1994. 463. Toriello HV, Higgins JV, Abrahamson J, et al.: X-linked syndrome of branchial arch and other defects. Am J Med Genet 21:137, 1985. 464. Torres-Aybar FG: A syndrome of multiple congenital anomalies. J Pediatr 92:507, 1978.

509 465. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 681. 466. Giannotti A, Diglio MC, Albertini G, et al.: Sporadic trichodental dysplasia with microcephaly and mental retardation. Clin Dysmorphol 4:334, 1995. 467. Toelle SP, Valsangiacomo E, Botthauser E: Trichothiodystrophy with severe cardiac and neurological involvement in two sisters. Eur J Pediatr 160:728, 2001. 468. Goldblatt J, Wallis C, Viljoen D: A new hypospadias-mental retardation syndrome in three brothers. Am J Dis Child 141:1168, 1987. 469. Say B, Meyer J: Familial trigonocephaly associated with short stature and developmental delay. Am J Dis Child 135:711, 1981. 470. Feldman GL, Weaver DD, Lourien EW: The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome. Am J Dis Child 131:1389, 1977. 471. Tsukahara M, Sugio Y: New dominant syndrome of microcephaly, facial abnormalities, micromelia, and mental retardation. J Hum Genet 43:224, 1998. 472. Paulger BR, Kraus EW, Pulitzer DR, et al.: Xp microdeletion syndrome characterized by pathognomonic linear skin defects on the head and neck. Pediatr Dermatol 14:26, 1997. 473. Tsukahara M, Azuno Y, Kajii T: Type A1 brachydactyly, dwarfism, ptosis, mixed partial hearing loss, microcephaly, and mental retardation. Am J Med Genet 33:7, 1989. 474. Tamari I, Goodman RM: Upper limb-cardiovascular syndromes: a description of two new disorders with a classification. Chest 65:632, 1974. 475. Urbach D, Hertz M, Shine M, et al.: A new skeletal dysplasia syndrome with rhizomelia of the humeri and other malformations. Clin Genet 29:83, 1986. 476. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 576. 477. Mitnick RJ, Bello JA, Shprintzen RJ: Brain anomalies in velo-cardiofacial syndrome. Am J Med Genet 54:100, 1994. 478. Char F, Douglas JE, Dungan WT: Familial multiforme ventricular extrasystoles with short stature, hyperpigmentation and microcephalya new syndrome. Birth Defects Orig Artic Ser XI(5):63, 1975. 479. Viljoen DL, Kallis J, Voges S, et al.: An apparently new mental retardation syndrome in three elderly sisters. Clin Genet 40:6, 1991. 480. De Wals P: Surveillance of retinoic acid embryopathy. Teratology 40:274, 1989. 481. Sensi A, Bettoli V, Zampino E, et al.: Vohwinkel syndrome (mutilating keratoderma) associated with craniofacial anomalies. Am J Med Genet 50:201, 1994. 482. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 4. WB Saunders, Philadelphia, 1988, p 568. 483. Weaver DD, Hansma DI: An apparent new autosomal recessive syndrome with microcephaly, unusual facial appearance, eye anomalies, hypotonia and developmental delay. Proc Greenwood Genet Center 7:162, 1988. 484. Weaver OD, Williams CPS: A syndrome of microcephaly, mental retardation, unusual facies, cleft palate and weight deficiency. Birth Defects Orig Artic Ser XIII(3B):69, 1977. 485. Wiedemann HR, Grosse K-R, Dibbern H: An Atlas of Characteristic Syndromes: a Visual Aid to Diagnosis. Wolfe Medical Publications Ltd, London, 1985, p 48. 486. Wiedemann HR, Grosse K-R, Dibbern H: An Atlas of Characteristic Syndromes: a Visual Aid to Diagnosis. Wolfe Medical Publications Ltd, London, 1985, p 322. 487. Nevin NC, Stewart FJ, Corkey CW, et al.: Microcephaly with large anterior fontanelle, generalized convulsions, micropenis, and distinct anomalies of the hands and feet. Another example of Wiedemann syndrome? Clin Genet 46:205, 1994. 488. Zampino G, Balducci F, Mariotti, et al.: Growth and developmental retardation, ocular ptosis, cardiac defect, and anal atresia: confirmation of the ROCA-Wiedemann syndrome. Am J Med Genet 90:358, 2000. 489. Faravelli F, D’Arrigo S, Bagnasco I, et al.: Oligophrenic microcephaly in a child with Williams syndrome. Am J Med Genet A 117:169, 2003.

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490. Winter RM: Distinctive autosomal or X-linked dominant syndrome of microcephaly, mild developmental delay, short stature, and distinctive face. Am J Med Genet 47:917, 1993. 491. Biason-Lauber A, Lang-Muritano M, Vaccoro T, et al.: Loss of kinase activity in a patient with Wilcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes 51:2301, 2002. 492. Woods CG, Crouchman M, Huson SM: Three sibs with phalangeal anomalies, microcephaly, severe mental retardation, and neurological abnormalities. J Med Genet 29:500, 1992. 493. Palton MA, Baraitser M, Brett EM: A family with congenital suprabulbar paresis (Worster-Drought syndrome). Clin Genet 29: 147, 1986. 494. Kreuz FR, Wittwer BH: Del(2q)—cause of the wrinkly skin syndrome? Clin Genet 43:132, 1993. 495. Kraemer KH, Lee MM, Scotto J: Xeroderma pigmentosum: cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 123:241, 1987. 496. Claes S, Deviendt K, Van Goethem G, et al.: Novel syndromic form of X-linked complicated spastic paraplegia. Am J Med Genet 94:1, 2000. 497. Christianson AL, Stevenson RE, van der Meyden CH, et al.: X-linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia and cerebellar atrophy in a large South African kindred is localized to Xq24-q27. J Med Genet 36:759, 1999. 498. Gendrot C, Ronce N, Toutain A, et al.: X-linked mental retardation exhibiting linkage to DXS255 and PGKP1: a new MRX family (MRX14) with localization in the pericentromeric region. Clin Genet 45:145, 1994. 499. Raynaud M, Ronce N, Ayrault A-D, et al.: X-linked mental retardation with isolated growth hormone deficiency is mapped to Xq22-Xq27.2 in one family. Am J Med Genet 76:255, 1998. 500. Hyde-Forster I, McCarthy G, Berry AC: A new X linked syndrome with mental retardation and craniofacial dysmorphism? J Med Genet 29:736, 1992. 501. Schimke RN, Horton WA, Collins DL, et al.: A new X-linked syndrome comprising progressive basal ganglion dysfunction, mental and growth retardation, external ophthalmoplegia, postnatal microcephaly and deafness. Am J Med Genet 17:323, 1984. 502. Seemanova´ E, Lesny I: X-linked microcephaly, microphthalmia, microcornea, congenital cataract, hypogenitalism, mental deficiency, growth retardation, spasticity: possible new syndrome. Am J Med Genet 66:179, 1996. 503. Masuno M, Imaizumik I, Okada T, et al.: Young-Simpson syndrome: further delineation of a distinct syndrome with congenital hypothyroidism, congenital heart defects, facial dysmorphism, and mental retardation. Am J Med Genet 84:8, 1999. 504. Hughes HE, Partington MW: The syndrome of Yunis and Varon— report of a further case. Am J Med Genet 14:539, 1983. 505. Zerres K, Rietschel M, Rietschel E, et al.: Postnatal short stature, microcephaly, severe syndactyly of hands and feet, dysmorphic face, and mental retardation: a new syndrome? J Med Genet 29:271, 1992. 506. Zlotogora J, Dagan J, Ganen A, et al.: A syndrome including thumb malformations, microcephaly, short stature, and hypogonadism. J Med Genet 34:813, 1997. 507. Delb W, Lipfert S, Henn W: Mandibulofacial dysostosis, microcephaly and thorax deformities in two brothers: a new recessive syndrome? Clin Dysmorphol 10:105, 2001. 508. Shetty AK, Chatters R, Tilton AH, et al.: Syndrome of microcephaly, mental retardation, and tracheoesophageal fistula associated with features of Rett syndrome. J Child Neurol 15:61, 2000. 509. Wieczorek D, Koster B, Gillessen-Kaesbach G: Absence of thumbs, a/ hypoplasia of radius, hypoplasia of ulnae, retarded bone age, short stature, microcephaly, hypoplastic genitalia, and mental retardation. Am J Med Genet 108:209, 2002. 510. Davee MA, Moore CA, Bull MJ, et al.: New syndrome? Familial occurrence of renal and Mullerian duct hypoplasia, craniofacial anomalies, severe growth and developmental delay. Am J Med Genet 44:293, 1992. 511. Aldred MA, Dry KL, Knight-Jones EB, et al.: Genetic analysis of a kindred with X-linked mental handicap and retinitis pigmentosa. Am J Hum Genet 55:916, 1994.

512. Teebi AS: Naguib-Richieri-Costa syndrome: hypertelorism, hypospadias, and polysyndactyly syndrome. Am J Med Genet 44:115, 1992. 513. Poole AE, Saal HM: RAG syndrome. In: Birth Defects Encyclopedia. Buyse ML, ed. Blackwell Scientific Pub, Cambridge, 1990, p 1457. 514. Hall BD: Schachter syndrome (hypotelorism, small cupid bow mouth, prognathism, abnormal ears, mental retardation): report of a second case. Am J Hum Genet 49(Suppl):139, 1991. 515. Schlichtmeier TL, Tomlinson GE, Kamen BA, et al.: Multiple coagulation defects and the Cohen syndrome. Clin Genet 45:212, 1994. 516. Woods CG, Leversha M, Rogers JG: Severe intrauterine growth retardation with increased mitomycin C sensitivity: a further chromosome breakage syndrome. J Med Genet 32:301, 1995. 517. Frederick DR, Robb RM: Ophthalmic manifestations of Setleis forceps marks syndrome: a case report. J Pediatr Ophthalmol Strabismus 29: 127, 1992. 518. Plomp AS, Baraitser M, Slaney SF, et al.: Severe microcephaly, choreiform movements, cataracts and sensorineural deafness in two patients: a new syndrome? Clin Dysmorphol 9:11, 2000. 519. Maclean K, Ambler G, Flaherty M, et al.: A variant microcephalic osteodysplastic slender-bone disorder with growth hormone deficiency and a pigmentary retinopathy. Clin Dysmorphol 11:255, 2002. 520. Stoll C, Alembik Y, Dott B: Complex congenital heart disease, microcephaly, pheochromocytoma and neurofibromatosis type I in a girl born from consanguineous parents. Genet Couns 6:217, 1995. 521. Temtamy SA, Meguid NA, Ismail SI, et al.: A new multiple congenital anomaly, mental retardation syndrome with preaxial brachydactyly, hyperphalangism, deafness and orodental anomalies. Clin Dysmorphol 7:249, 1998. 522. Al-Sannaa N, Forrest CR, Teebi AS: Trigonomicrocephaly, severe micrognathia, large ears, atrioventricular septal defect, symmetrical cutaneous syndactyly of hands and feet, and multiple cafe-au-lait spots: new acrocraniofacial dysostosis syndrome? Am J Med Genet 101:279, 2001. 523. Farah S, Sabry MA, Al-Shubaili AFK, et al.: A possible new Troyer-like syndrome. Am J Hum Genet 59:A92, 1996. 524. Van Maldergem L, Wetzburger C, Verloes A, et al.: Mental retardation with blepharo-naso-facial abnormalities and hand malformations: a new syndrome? Clin Genet 41:22, 1992. 525. Vasquez SB, Hurst DL, Sotos JF: X-linked hypogonadism, gynaecomastia, mental retardation, short stature, and obesity—a new syndrome. J Pediatr 94:56, 1979. 526. de Die-Smulders C, Van Schrojenstein L, de Valk H, et al.: Confirmation of a new MR/male pseudohermaphroditism syndrome, Verloes type. Genet Couns 5:73, 1994. 527. Wiedemann HR. A further microcephaly-growth deficiency-retardation syndrome. In: An Atlas of Clinical Syndromes: A Visual Aid to Diagnosis, ed 2. Wiedemann HR, Kunze J, Grosse F-R, et al., eds. Wolfe Publishing Ltd, London, 1992, p 172. 528. Voudris KA, Skardoutsou A, Vagiakou EA: Congenital microcephaly in two infants with the factor V Leiden mutation. J Child Neurol 17:905, 2002. 529. Villo N, Beceiro J, Cebrero M, et al.: Fetal brain disruption sequence in a newborn with a history of cordocentesis at 21 weeks gestation. Arch Dis Child Fetal Neonatal Ed 84:63, 2001. 530. Sherer DM, Salifia CM: Midtrimester amniocentesis of a twin gestation complicated by immediate severe bradycardia with subsequent associated fetal anomalies. Am J Perinatol 13:347, 1996. 531. Watemberg N, Silver S, Harel S, et al.: Significance of microcephaly among children with developmental disabilities. J Child Neurol 17:117, 2002. 532. Dalgren L, Wilson RD: Prenatally diagnosed microcephaly: a review of etiologies. Fetal Diagn Ther 16:323, 2001. 533. Vargas JE, Allred EN, Leviton A, et al.: Congenital microcephaly: phenotypic features in a consecutive sample of newborn infants. J Pediatr 139:210, 2001. 534. Leviton A, Holmes LB, Allred EN, et al.: Methodologic issues in epidemiologic studies of congenital microcephaly. Early Hum Dev 69:91, 2002. 535. Konai T, Kishimoto K, Ozaki Y: Genetic study of microcephaly based on Japanese material. Am J Hum Genet 7:51, 1955.

Brain 536. Toppenberg KS, Hill DA, Miller DP: Safety of radiographic imaging during pregnancy. Am Fam Physician 59:1813, 1999. 537. Greskovich JF Jr, Macklis RM: Radiation therapy in pregnancy: risk calculation and risk minimization. Semin Oncol 27:633, 2000. 538. Miller RW: Discussion: severe mental retardation and cancer among atomic bomb survivors exposed in utero. Teratology 59:234, 1999. 539. Radiation—quantities and units of ionizing radiation. Canadian Centre for Occupational Health and Safety. http://www.ccohs.ca/ oshanswers/phys_agents/ionizing.html 540. Gustavson KH, Jagell S, Blomquist HK, et al.: Microcephaly, mental retardation and chromosomal aberrations in a girls following radiation therapy during late fetal life. Acta Radiol Oncol 20:209, 1981. 541. Preliminary evaluation of the impact of the Chernobyl radiological contamination on the frequency of central nervous system malformations in 18 regions of Europe. The EUROCAT Working Group. Paediatr Perinatol Epidemiol 2:253, 1988. 542. Mossman KL, Hili LT: Radiation risks in pregnancy. Obstet Gynecol 60:237, 1982. 543. McLeod DR, Fowlow SB: Multiple malformations and exposure to therapeutic ultrasound during organogenesis. Am J Med Genet 34:317, 1989. 544. Rosa FW, Wilk AL, Kelsey FO: Teratogen update: vitamin A cogeners. Teratology 33:355, 1986. 545. Selcen D, Seideman S, Nigro MA: Otocerebral anomalies associated with topical tretinoin use. Brain Dev 22:218, 2000. 546. Mulder GB, Manley N, Grant J, et al.: Effects of Vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study. Teratology 62:214, 2000. 547. Rahbar F, Fomufod A, White D, et al.: Impact of exposure to phencyclidine (PCP) and cocaine on neonates. J Natl Med Assoc 85:349, 1993. 548. Kesrouani A, Fallet C, Vuillard E, et al.: Pathologic and laboratory correlation in microcephaly associated with prenatal cocaine exposure. Early Hum Dev 63:79, 2001. 549. Singer LT, Salvator A, Arendt R, et al.: Effects of cocaine/polydrug exposure and maternal psychological distress on infant birth outcomes. Neurotoxicol Teratol 24:127, 2002. 550. Leobstein R, Koren G: Pregnancy outcome and neurodevelopment of children exposed in utero to psychoactive drugs: the Motherisk experience. J Psychiatry Neurosci 22:192, 1997. 551. HadeedAJ, Siegel SR: Maternal cocaine use during pregnancy: effect on the newborn infant. Pediatrics 84:205, 1989. 552. Fulroth R, Phillips B, Durand DJ: Perinatal outcome of infants exposed to cocaine and/or heroin in utero. Am J Dis Child 43:905, 1989. 553. Hersh J, Podruch P, Rogers G: Toluene embryopathy. Proc Greenwood Genet Center 4:98, 1985. 554. Hunter AGW, Thompson D, Evans JA: Is there a fetal gasoline syndrome? Teratology 20:75, 1979. 555. Schardein JL: Chemically Induced Birth Defects. Marcel Dekker, New York, 1985, p 754. 556. Nelson KB, Deutschberger J: Head size at one year as a predictor of four year IQ. Dev Med Child Neurol 12:487, 1970. 557. Dolk H: The predictive value of microcephaly during the first year of life for mental retardation at seven years. Dev Med Child Neurol 33:974, 1991. 558. Brennan TL, Funk SG, Frothingham TE: Disproportionate intra-uterine head growth and developmental outcome. Dev Med Child Neurol 27:746, 1985. 559. Glazier DB, Cummings KB, Barone JG: Urodynamic evaluation of profound microcephaly in children. Br J Urology 80:825, 1997. 560. MMWR Report: Barriers to dietary control among pregnant women with phenylketonuria-United States, 1998-2000. Morb Mort Wkly Rep 51:117, 2002. 561. Abdel-Salem G, Czeizel AE: A Case-control study of microcephaly. Epidemiology 11:571, 2000. 562. Romero R, Pilu G, Jeanty P, et al.: Prenatal Diagnosis of Congenital Anomalies. Appleton & Lang, Norwalk, CT, 1987, p 54. 563. Winter RM, Dearlove J, Jolly H, et al.: Apparent microcephaly caused by bicornuate uterus. Br Med J 286:1640, 1983. 564. Keegan CE, Vilain E, Mohammed M, et al.: Microcephaly, jejunal atresia, aberrant right bronchus, ocular anomalies, and sex reversal. Am J Med Genet 125A:293, 2003.

511 565. Kajantie E, Otonkoski T, Kivirikko S, et al.: A syndrome with multiple malformations, mental retardation, and ACTH deficiency. Am J Med Genet 126A:313, 2003. 566. Trimborn M, Bell SM, Felix C, et al.: Mutations in Microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet 75:261, 2004. 567. Kumar A, Blanton SH, Babu M, et al.: Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations. Clin Genet 66:341, 2004. 568. Bond J, Roberts E, Springell K, et al.: A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37: 353, 2005.

15.2 Megalencephaly Definition

Megalencephaly is a brain weight/volume ratio greater than the age-appropriate 98th centile (or >2 SD above the mean), because of a true hyperplasia or overproduction of parenchyma.1 Generally megalencephaly is accompanied by macrocephaly (an occipitofrontal circumference—OFC—greater than the 98th centile). Adult head circumference has been found to correlate with height,2,3 and it is important that appropriate centile graphs are used.3 However, most cases of macrocephaly do not reflect underlying megalencephaly, so it is important to exclude hydrocephalus, cerebral edema, neoplasia, fluid collection, and a thickened calvarium.4 Megalencephaly is further divided into an anatomic type (developmental) and a metabolic type. The latter includes various storage and degenerative encephalopathies. With the exception of a small number of metabolic encephalopathies in which megalencephaly can be an important early sign, this summary is restricted to the anatomic form. Diagnosis

In most cases a patient with megalencephaly will be ascertained because of macrocephaly. In the past, confirmation was based on the weight of the brain drained of cerebrospinal fluid (CSF). The advent of neuroradiographic methods has made possible in vivo diagnosis. In most cases, anatomic megalencephaly is apparent at birth, and the head continues to be enlarged but grows at a rate parallel to the upper percentiles. A pattern of head growth that crosses centiles is more suggestive of a disturbance of CSF dynamics or a storage disorder, but it may also be seen in anatomic megalencephaly.5 In most cases of megalencephaly, a careful history and examination will suggest the likely diagnostic category, and neurologic evaluation, including CT and MRI, can be used to define the specific anatomy. Linear neuroimaging measurements have been used most often to estimate the ventricular and subarachnoid spaces and thus to determine the presence or absence of megalencephaly. More complex methods have been developed to better estimate the true parenchymal volume more precisely. Gooskens et al.6 applied one such method and were able to confirm megalencephaly in only three of eight patients in whom that diagnosis had been made using the traditional linear measurements. In contrast, the methods did agree well for the diagnosis of communicating hydrocephalus. Gooskens et al.7 also obtained a relatively poor correlation (r ¼ 0.59) between the OFC and their estimate of brain volume. The correlation was poorest the greater the head shape deviated from a circle (e.g., dolichocephaly, brachycephaly). A better correlation (r ¼ 0.72) with brain volume was obtained for the product of OFC squared

512

Neuromuscular Systems

and head height. The latter was measured with sliding callipers as the distance from the vertex to the line connecting the auditory canals. Tramo et al.8 found that OFC did correlate with forebrain volume, area of the corpus callosum, and cortical surface area. For most purposes, macrocephaly in the absence of a thickened cranial vault, hydrocephalus, tumor, or acute pathology is accepted as due to a megalencephaly. However, it has become clear that a significant proportion of children with the relatively common condition of benign macrocephaly (vide infra) have increased subarachnoid9 and/or Virchow-Robin10 spaces rather than true megalencephaly. Few patients with syndromic macrocephaly have been subject to rigorous estimates of brain size, and the presence of megalencephaly remains problematic for the majority of syndromes associated with a large head. With this caveat, Table 15-2 lists syndromes in which macrocephaly is present and neuroimaging has yet to demonstrate another consistent cause for the increased OFC. Mild hydrocephalus and megalencephaly can coexist,7 and some syndromes in which a mild degree of hydrocephaly does not appear to account for the macrocephaly are included. The POSSUM1 and London1 databases were used extensively, but not exclusively, to ascertain syndromes; but many syndromes so identified are not included. Excluded are conditions in which undefined macrocephaly appeared to be a chance or occasional finding of no diagnostic importance, accompanied a specific brain malformation that is considered elsewhere in this chapter, was a reflection of intracerebral storage, or was likely due to abnormal thickness of the cranial vault. Many syndromes (e.g., most of the lethal chondrodysplasias) are described as having relative macrocephaly, that is, an OFC of normal size for age but out of proportion to a small stature; but, for most, there is as yet no evidence of true brain abnormality. These syndromes, as well as case reports of conditions reported to have a ‘‘large head’’ but where no, or normal, OFC measurements are provided, are not included. The most common type of megalencephaly is benign, familial, and most often free from associated anomalies (benign familial megalencephaly—BFM). Thus, among the most important investigations of a patient is measurement of the OFCs of other family members. These measurements, together with an appropriate history and physical examinations, may be all that is required to point to BFM. However, newer clinical and neuroimaging studies have added complexity to the understanding of BFM. The traditional view that BFM is an autosomal dominant condition with male predominance1 has been challenged by Arbour et al.155 They showed that although parents and siblings of patients had an increased mean OFC, the distribution of measurements was unimodal, not bimodal as would be expected from a simple autosomal dominant trait. Those authors found further support for their argument in their analysis156 of the results of Miles et al.,157 and point out that the imposition of an arbitrary cut-off of >2 SD above the mean onto a continuous variable (OFC) can lead to apparent autosomal dominant inheritance in some families. Petersson et al.158 have provided support for the multifactorial inheritance of megalencephaly. In some families, the macrocephaly may be accompanied by ventriculomegaly, but the increased OFC persists in the presence of shunting procedures.5,157 In a study of 20 children with benign macrocephaly, Alper et al.9 found that 13 had enlarged arachnoid spaces and 7 had true megalencephaly. Although the former group tended to be younger, the groups did not differ with respect to parental history of macrocephaly. It is not clear whether such families represent simple anatomic variation or different conditions. Similarly, Cole and Hughes47 identified six patients from a study of

Sotos syndrome, who had macrocephaly, some characteristic facial and physical features (see Table 15-1), and resembled a number of their first- and second-degree relatives. Again, it is not universally agreed that this condition differs from BFM. DeRosa et al.160 reported the prenatal diagnosis of BFM and emphasized the need to carefully assess the family in such cases; it appears that the onset of megalencephaly was between 21 and 32 weeks gestation. It is important to consider the possibility of a subdural fluid accumulation in a child presenting with macrocephaly and pericerebral fluid collection visible on CT. Vanderschueren et al.161 demonstrated that CT may fail to detect a second fluid layer characteristic of a concurrent subdural collection. They found that macrocephaly associated with a subdural collection correlated with age under 5 months, acute clinical signs, and absence of a family history of macrocephaly. The observation of an excess of macrocephaly among children with autism162 has stirred a great deal of interest and further study. Macrocephaly has been shown to be an independent risk factor for autism, and macrocephaly is significantly more common among the parents of both macrocephalic and non-macrocephalic autistic propositi.157,162 Among autistic children, macrocephaly is not associated with developmental level, severity of autistic signs, gender, seizure prevalence, dysmorphia, or recurrence risk,157,163 although children with macrocephaly appear less likely to have a family history of attention deficit hyperactivity disorder157 and tend to be older.164 The diagnosis of the individual syndromic forms of megalencephaly will depend largely on the associated manifestations, and in some cases an increased OFC may be a presenting sign. It is important to emphasize that many of the syndromes in Table 15-2 may only occasionally present with a large head and/or that their associated intracranial findings have not been well documented. There is a need for much more information on specific syndromes; it is not uncommon to find a statement that the patient had a large, or relatively large, head but that the OFC is not recorded. Often in syndromic megalencephaly, a variety of gyral and structural anomalies, neuronal heterotopias, and abnormal and/or overproduction of specific cell types will be seen.6 Friede1 believes that cases of diffuse glial overgrowth published prior to 1940 represented well-differentiated infiltrating tumors. Unilateral megalencephaly, or hemimegalencephaly, is an uncommon condition characterized by a diffuse enlargement of one-half of the brain, which shows shallow sulci, wide gyri, loss of separation of the cell layers, subcortical neuronal heterotopias, and scattered giant neurons (neuronal hypertrophy) (Fig. 15-5).165 The condition may represent the extreme of the spectrum of cortical dysplasias (see Section 15.5). MRI is well suited to demonstrating the sulcal and gyral anomalies, in addition to the increased thickness of the cortical ribbon.165 Kato et al.166 studied the brain from four patients and found hypertrophy of the white matter with an increase in glial cells and reduction in the cortex. They demonstrated an excess epidermal growth factor like immunoreactivity in astrocytes and posited that it had a role in the overgrowth of the affected side, although the staining did not differ between the two sides of the brain. O’Kusky et al.167 showed that the total number and type of synapsis per unit of brain volume was normal in hemimegalencephaly, but that given the overall increased brain thickness that the total number of synapses in a radial column of cortex would be increased. Affected children may have a large and sometimes asymmetric head and usually have a poor prognosis, often with a grossly abnormal electroencephalogram (EEG), intractable seizures, hemiparesis, and mental retardation.

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly Syndrome

Prominent Features

Causation Gene/Locus

3-methylglutaconic aciduria type 111

Macrocephaly, delayed development of speech, motor delay, and symptomatic hypoglycemia variable; elevated 3-methylglutaconic acid in the urine; defect of 3-methylglutaconylCoA hydratase

AR (250950) AUH, Chr. 9

Achondroplasia12

Rhizomelic short stature, low nasal bridge, prominent forehead, trident hand, short cranial base, small foramen magnum, narrowed lumbar interpeduncular distance, short tubular bones; megalencephaly may relate to mild undetected hydrocephalus

AD (100800) FGFR3, 4p16.3

Adams-Oliver variantpolymicrogyria13

Cutis aplasia of scalp and transverse limb reduction in one sib who also had postnatal macrocephaly; both sibs had polymicrogyria; consanguinity

AR?

Alexander disease14

Megalencephalic leukodystrophy with psychomotor delay, spasticity, seizures, demyelination, degeneration of astrocytes, Rosenthal fibers, typical MRI findings

AR (203450) NDUFB1, 11q13 GFAP, 17q21

Al-Gazali: webbed neck-face dysmorphia15

Growth and developmental delay, short webbed neck, low-set ears, downslanting palpebrae, arched eyebrows, hypoplastic supraorbital ridges, large nose, pectus carinatum/excavatum, cardiac septal defects, 5th finger clinodactyly; one of four had hydrocephaly

AR

Alpha thalassemia-mental retardation-deletion16

Mild to moderate mental retardation, macrocephaly or microcephaly, tall/broad forehead, hypertelorism, horizontal to downslanting palpebrae, initially depressed nasal bridge, crowded/irregularly spaced teeth, talipes equinovarus, cryptorchidism

Microdeletion

Aminopterin sine aminopterin–like17

Severe mental retardation, prominent forehead, hypertelorism, downslanting palpebrae, simple philtrum, thin nose with thick septum, short neck, low posterior hairline, mild cutaneous syndactyly, progressive camptodactyly, postaxial polydactyly of hands

AR

Anophthalmiahypopituitarism-renal18

Micro/anophthalmia, cleft lip/palate, absent pituitary, nephronopthisis, delayed development, reduced cerebral white matter, multiple small porencephalic cysts; father had large head

Unknown

Anophthalmia-nasal proboscis19

Macrocephaly, hydrocephalus, craniosynostosis, anophthalmia and proboscis-like nose. 1 of 2 unrelated girls had frontal encephalocele

Unknown (605627)

Apert20

Severe craniofacial synostosis, marked syndactyly; developmental delay is common; CNS anomalies include corpus callosum, limbic system, gyri, heterotopia, and others

AD (101200) FGFR2, 10q25.3-q26

Ataxia-telangiectasia21

Immunodeficiency, visceral and cutaneous vascular anomalies and telangiectasia, cerebellar ataxia, hypoplasia of cerebellar granular and ganglion cells (megalencephaly uncommon?)

AR (208900) ATM, 11q22.3

Atelosteogenesis-boomerang dysplasia22

Spectrum of lethal chondrodysplasia, variable macrocephaly, flat and low nasal bridge, micrognathia, short neck, micromelia, bowed limbs, broad array of radiologic changes, multinucleated giant cells in cartilage

AD (108720, 112310) FLNB, 3p14.3

Atkin: Coffin-Lowry–like face23

Square forehead, prominent supraorbital ridges, hypertelorism, downslanting palpebrae, thick lips, dental anomalies, macroorchidism, short stature, mental retardation

XLD (300431)

Bagatelle-Cassidy: macrocephaly-shortdeafness24

Prominent forehead, delayed closure anterior fontanelle, hypertelorism, sparse frontal hair, downslanting palpebrae, relatively short limbs, normal radiographs

Unknown

Bannayan-Riley-Ruvalcaba25

Frontal bossing, downslanting palpebrae, delay in early motor and speech development; diffuse mesodermal hamartomas (lipomas and hemangiomas), which may be aggressive (see Cowden)

AD (153480) PTEN, 10q22-23

Bardet-Biedl26

Short stature, obesity, developmental delay, retinal dystrophy, eye anomalies, brachydactyly, postaxial polydactyly, renal anomalies, small genitalia in males, macrocephaly an occasional finding; overlap with McKusick-Kaufman on 20p12 (MKKS)

AR (209900) BBS1, 2q31 BBS2, 3p13-p12 BBS3, ARL6, 4q27 BBS4, 11q13 BBS5, 15q22.3-q23 MKKS, 16q21 BBS7, 20p12

Basal cell nevus27

Prominent supraorbital ridges, heavy eyebrows, broad nasal root, hypertelorism, long mandible, pouting lower lip, basal cell carcinomas, jaw cysts, rib anomalies, palmoplantar pits, calcified falx

AD (109400) PTCH, 1p32 PTCH2, 9q22.3

Basal cell carcinomahypotrichosis-milia28

Coarse and sparse scalp hair, thinned eyebrows and eyelashes, milia in childhood, excess sweating; similar to nevoid basal cell carcinoma syndrome with basal cell carcinomas in early adulthood

AD (109390)

Beveridge: macrocephalyabnormal pigment29

Protuberant abdomen, enlarged liver, large hands and feet, hoarse voice, sparse hair, brittle nails, palmar creases described as ‘‘dirty orange,’’ not carotenemic, nodules on dorsum of hands; dyskeratosis congenita, increased pigmentation in the basal epidermal layers

Unknown

(continued)

513

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Bo¨rjesson-ForssmanLehmann-like30

Moderate developmental delay, short stature, obesity, partial alopecia, large ears, round face, deep-set eyes, narrow palpebrae, prominent upper and lower lips, small jaw

AD

Brachytelephalangyanosmia31

Square forehead, small nose, telecanthus, thin upper lip, short stature, anosmia, normal CT, hypogonadotrophic hypogonadism.

AD or XLD (113480)

Campomelic dysplasia32

Mean OFC at birth 37 cm, micrognathia, flat nasal bridge, cleft palate, bowed femur and tibia, narrow chest, respiratory distress, laryngomalacia, cardiac and renal defects common, ambiguous genitalia in most males; characteristic radiographic changes

AD (114290) SOX9, 17q24q-25

Cantu: hypertrichosisosteochondrodysplasia33

Congenital hypertrichosis and coarse face, macrosomia, broad nasal bridge, long philtrum, full mouth, narrow shoulders and chest, broad ribs, platyspondyly, flared metaphyses, pelvic anomalies

AR (239850)

Cardio-facial-cutaneous34

Facial appearance resembles Noonan syndrome; sparse, friable, curly hair; bitemporal narrowness; dry and hyperkeratotic skin; frequent ptosis, strabismus, and nystagmus; pulmonary stenosis most common congenital heart defect

AD (115150)

Carey-Fineman-Ziter35

Developmental and growth delay, feeding difficulty, facial weakness, ptosis, downslanting palpebrae, ophthalmoplegia, cleft palate, brachydactyly, initial macrocephaly becoming microcephalic

AR (254940)

Char: patent ductus arteriosus36

Variable developmental delay; facial signs including low-set ears, ptosis, short philtrum, patulous lips; patent ductus arteriosus; digital anomalies

AD(169100) TFAP2B, 6p12

Chromosome (1)(q42-qter) trisomy37

Prominent forehead, large fontanel, flat nasal bridge, micrognathia, low-set ears, facial capillary hemangioma, cardiac malformation

Partial trisomy

Chromosome del(2)(q37qter)38

Developmental delay, frontal bossing, low nasal bridge, cardiac defect, repetitive behavior

Partial deletion

Chromosome del(4)(q33qter); dup (7)(q34-qter)39

Moderate developmental delay, behavioral problems, face dysmorphia, iris colobomas, supernumerary nipples

Partial deletion/ trisomy

Chromosome dup(4)(p16.3)40

Mild to moderate developmental delay, overgrowth, abundant hair, coarse face, bushy eyebrows, synophrys, prominent supraorbital ridges, small and anteverted nose, square jaw

Partial trisomy

Chromosome del (5)(q35.3)41

Excess pre- and postnatal nuchal thickness, telecanthus, flat and low nasal bridge, short fingers, atrial septal defect, narrow chest, slow motor milestones

Partial deletion

Chromosome dup (7)(q11.23)42

Postnatal macrocephaly, developmental delay, hypertonic legs with hyperreflexia, prominent forehead, downslanting palpebrae, long philtrum, high palate, low-set ears, normal ventricles, white matter hypodensities

Partial trisomy

Chromosome inv dup(8)(p12p23)43

Mild developmental delay, mild facial signs, frontal bossing, malformed pinnae, thin upper lip, everted lower lip, high palate, coloboma, cardiac defects, scoliosis, absent corpus callosum, cerebral atrophy; 3/21 macrocephalic

Partial trisomy

Chromosome 14 maternal disomy44

Short to above-normal stature, developmental delay to normal intelligence, premature puberty in both sexes, hydrocephalus, cleft uvula, hyperextensible joints

Disomy

Chromosome del (19)(q13.2)-DiamondBlackfan45

Diamond-Blackfan red cell aplasia, hypotonia, tall and wide forehead, hypertelorism, epicanthus, macrocephaly, developmental delay

Partial deletion

Cleidocranial dysplasia46

Macrobrachycephaly, wide fontanel with delayed closure, short stature, hypo/aplasia clavicles, midface hypoplasia, persistent primary dentition, delayed dental eruption, other dental anomalies

AD (119600) RUNX2, 6p21

Cole-Hughes: macrocephaly47

Macrocephaly, variable developmental delay, square face, frontal bossing, narrow parietal region, malar underdevelopment, long philtrum

AD (153470)

Complex I deficiency48

Variety of clinical presentations include Leigh syndrome, lactic acidosis, cardiomyopathy, and macrocephaly with progressive leukodystrophy

AR (252010) NDUFU1, NDUFS1,2,4,7,8 5q11.1, heterogeneity, also mitochondrial

Cortez-Lacassie: ectodermal dysplasia49

Agenesis of distal phalanges with hypoplastic nails, abnormal thumbs, absent toenails, absent palmar creases, small lower teeth, curly hair

Unknown

Costello50

Short stature, mental retardation, loose redundant skin on hands and feet, hyperextensible fingers, nasal and perioral papillomata, thick facial features, epicanthus, ptosis; elevated risk of neoplasia; may have true postnatal macrocephaly

AD (218040) 22q13.1

Cowden hamartomas51

Macrocephaly early marker with second-decade onset, facial papules, oral papillomas, acral and palmoplantar keratosis, cutaneous fibromas, gastrointestinal polyps, thyroid anomalies, fibrocystic breast disease, significant risk for malignancies

AD (158350) PTEN, 10q22-23 (continued)

514

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Cranioectodermal dysplasiaSensenbrenner52

Dolichocephaly, frontal bossing, sparse and fine hair, dental anomalies, marked brachydactyly, short narrow thorax, pectus excavatum. One case microcephalic and one macrocephalic of 14

AR (218330)

Craniofacial-conodysplasia53

Frontal bossing, flat nasal bridge, telecanthus, midface hypoplasia, prognathism, ventricular dilatation, stenosis of foramen magnum, cone-shaped epiphyses of thumb and index fingers, short proximal phalanges of thumb and middle phalanges of the 2nd and 5th fingers; resembles acrodysostosis

AD

Cronkite-Canada: infantile polyposis54

Juvenile intestinal polyps from stomach to rectum, hypotonia, hepatosplenomegaly, proteinlosing enteropathy, alopecia, nail dystrophy, clubbing

Unknown (175500) 10q22.3-q24.1 or 18q21.1?

Cutis marmoratamacrocephaly55

Congenital reticular vascular pattern seen in association with hemihypertrophy, hemiatrophy, aplasia cutis congenita, cavernous haemangiomas of the skin, and developmental delay; macrocephaly, seizures, and other associations are uncommon and include digital and congenital heart defects

Unknown (602501)

Cutis marmoratalymphangiectasia56

Prenatal overgrowth, flat nasal bridge, high palate, four-limb postaxial polydactyly, faint cutis marmorata, thick subcutaneous tissues, lymphedema of feet, vascular ectasia of gut, linear skin pigmentation

Unknown

Der Kaloustian: radioulnar synostosis-hypotonia57

Macrodolichocephaly, developmental delay, radio-ulnar synostosis, long and narrow face, prominent nasal bridge, high palate, structural renal anomalies

AR (266255)

Desmosterolosis58

Rhizomelia, short and malformed ribs, osteosclerosis, hypoplastic nasal bridge, cleft palate, gingival nodules, ambiguous genitalia; cardiac, gut, and renal anomalies; immature gyral pattern, hypoplastic corpus callosum; elevated desmosterol

AR (602398) DHCR24, 1p33-p31.1

Dinno: pseudomarfanoid59

Dislocated lenses, hypertelorism, downslanting palpebrae, arachnodactyly, increasingly abnormal bone density, ‘‘bone-within-bone’’ appearance to metacarpals; variable signs include communicating hydrocephalus, high palate, a pectus carinatum, joint laxity, abnormal capital femoral epiphyses

AD

Encephalocraniocutaneous lipomatosis60

Developmental delay common; lipodermoids of the conjunctiva, sclera, and eyelids; lipomas of cranium or face; intracranial pathology includes cerebral atrophy, porencephalic cysts, intracranial calcification

Unknown (176920)

Facio-oculo-acoustic-renal61

Developmental delay, large fontanel, hypertelorism, severe myopia, sensorineural deafness, proteinuria, diaphragmatic hernia; part of spectrum? (see OMIM 222448)

AR (227290)

Fragile X62

Long face with prominent jaw; thick nasal bridge; ears appear large; macroorchidism; mild connective tissue dysplasia includes lax skin and joints, kyphoscoliosis, and mitral prolapse; mental retardation and hyperactivity in males with >200 repeats, and generally milder symptoms in females

XLD (309550) FMR1, Xq28

Fryer: overgrowth63

Asymmetric postnatal overgrowth, increased bone age, large and prominent ears with pointed helices, long fingers with prominent joints, severe scoliosis; single case

Unknown

Fryns: macrocephaly-unusual face-spastic paraplegia64

Broad and high forehead, deep-set eyes, short philtrum, large mouth, spastic paraplegia

AR (600302)

Fryns: mental retardationcraniofacial dysmorphism65

Moderate to severe mental retardation, coarse face, hypertelorism, high palate, dental anomalies, one case short stature (similar to Atkin syndrome)

AR? (Authors state AD)

Glutaric aciduria type 166

Acute or subacute onset of encephalopathy from 3 months to 3 years, persistent dystonicdyskinesis and later psychomotor dysfunction with cerebral atrophy; macrocephaly may predate signs; increased urine glutaric, 3-OH glutaric and glutaconic acid

AR (231670) GCDH, 19p13.2

Glutaric aciduria type 267

Macrocephaly early sign, cryptorchidism, hypospadias; most show initial normal health and development; signs can include respiratory distress, hypoketotic hypoglycaemia, sweaty-foot odor, seizures, dystonic cerebral palsy; aliphatic mono- and dicarboxylic acids, sarcosine, glycine conjugates in blood and urine; abnormal electron transfer flavoprotein (ETF) or ETFubiquinone oxidoreductase (ETF-dehydrogenase)

AR (331680) ETF-dehydrogenase 15q23-25, 19q13

Goldblat-Singer: gingival fibromatosis-distinctive face68

Normal intelligence, synophrys, full eyebrows, hypertelorism, downslanting palpebrae, small and anteverted nares, gingival hypertrophy, cupid’s bow mouth

AR (228560)

Greig cephalopolysyndactyly69

Variable postaxial hand and preaxial toe polysyndactyly, telecanthus, hypertelorism, low and wide nasal root

AD (175700) GLI3, 7p13

Halal: progressive macrocephaly-hamartomas70

Normal birth OFC, developmental delay, muscle wasting, hyperteloriam, subcutaneous angiolipomas, congenital heart defect, cutis marmorata, telangiectasias, broad thumbs and halluces. Single case; consanguinity

Unknown PTEN spectrum? (continued)

515

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Heide: osteoporosisblindness71

Osteoporosis, wormian bones, frontal bossing, brachytelephalangy, hyperextensible joints, congenital blindness, mental retardation

AR

Hemihypertrophyhemimegalencephalypolydactyly72

Hemimegalencephaly, cutis marmorata, hemihypertrophy of face and limbs, 3-4 syndactyly and post-axial polydactyly of hands, polydactyly of left foot with 2-3 toe syndactyly, widesandal gap; single case

Unknown

Hidrotic ectodermal dysplasia-natal teeth73

Thin and sparse, slow-growing hair; variable natal teeth, premature loss of secondary dentition; flexural crease acanthosis nigricans; some heat intolerance; mild nail dystrophy

AD (601345)

Hirschsprunghemimegalencephaly74

Right-sided hemimegalencephaly, Hirschsprung disease; later onset seizures, status epilepticus, left hemiparesis; single case

Unknown

Hockey: XLMR-precocious puberty75

General overgrowth, advanced bone age, muscular, early development normal but two naternal uncles later considered retarded, premature puberty, mother of the proband obese with acanthosis nigricans, and a 46,XX,del(15)(q11-13) karyotype

XLR

Hypertelorism-short limbsdeafness76

Postnatal macrocephaly with mild ventriculomegaly, persistent anterior fontanel, prominent forehead, hypertelorism, downslanting palpebrae, sparse frontal hair, relatively short limbs

Unknown

Hypochondroplasia77

Rhizomelic short stature, slightly prominent forehead, decreased elbow extension and forearm supination, radiology similar but milder than achondroplasia; heterogeneity; macrocephaly associated with FGFR3 mutations

AD (146000) FGFR3, 4p16.3

Hypomelanosis of Ito78

Extremely variable syndrome of linear and swirled hypopigmentation, occasional asymmetry, microphthalmia and eye anomalies common, CNS anomalies include migrational abnormalities or isolated macrocephaly

Some AD (146150) Some have chromosome mosaicism

Immunodeficiencycentromere instability79

Mental retardation, variable macrocephaly, hypertelorism, flat nasal bridge, epicanthus, protruding tongue, small jaw; centromeric instability chromosomes 1, 9, and 16; variable immunodeficiency including combined, hypogammaglobulinaemia and low T-lymphocytes

AR (242860) 20q11-13

Ischiospinal dysostosis-rib gaps-nephroblastomatosis80

Nephromegaly due to nephroblastomatosis, rib gaps, vertebral ossification defects, hypoplastic ischia

Uncertain

Kaler: sparse hairosteopenia81

Developmental delay, OFC at 97%, prominent forehead, blue sclerae, hypertelorism, lax joints, sparse hair, frequent fractures, osteopenia of the long bones (this is likely geroderma osteodysplastica)

AR (259690)

Keiport82

Prominent forehead, hypertelorism, large and high-bridged nose, wide terminal phalanges, deafness

Uncertain

Klinefelter83

Patient with Klinefelter syndrome, tetralogy of Fallot, megalencephaly characterized by polymicrogyria and large pyramidal neurons

47,XXY karyotype

Klippel-Trenaunay-Weber84

Various hemangiomatous lesions, may involve limbs, skin, and internal organs; random hypertrophy of body parts

Unknown (149000)

L-2 hydroxyglutaric aciduria85

Variable clinical signs from normal with later regression to early-onset infantile spasms, hypsarrhythmia, seizures, action myoclonus, choreoathetosis, mental retardation, and macrocephaly; white matter changes on MRI; L-2 hydroxyglutaric aciduria

AR (236792)

Laryngeal stenosis-shortarthropathy86

Short limbs, deep-set eyes, malar flatness, trismus, campto/brachydactyly, progressive arthropathy; one of three said to be macrocephalic but no measurements

Unknown

Laxova-basal ganglia87

Cogwheel rigidity, parkinsonian tremors, postural changes, slurred speech, shuffling gait, OFC may be large at birth, variable mental retardation, L-DOPA no benefit

XLR (311510) Xq28

LeMarec: mesomelia88

Single case with brachymesomelia, club feet, frontal bossing, flat nasal bridge, symmetric ulnar and radial hypoplasia

Unknown

Linear nevus sebaceous89

Linear nevus sebaceous, variable hemihypertrophy with or without intracranial anomalies, pachygyria (megalencephaly and hemimegalencephaly useful marker for neurologic involvement)

Unknown (163200)

Lujan: marfanoid90

Tall stature, asthenia, long and narrow face, high palate, small jaw, double row of teeth, variable mental retardation, hyperextensible joints, pectus, atrial septal defect, absent corpus callosum

XLR (309520)

Macrocephaly-bowed limbs-vertebral91

Dolichomacrocephaly, ‘‘beaten copper’’ skull, congenital bowed long bones, hypertelorism; bowing improved with age

AR (211355)

Macrocephaly-cavum septum pellucidum92

Macrobrachycephaly, developmental delay, cavum septum pellucidum and cavum vergae

Uncertain (continued)

516

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Macrocephaly-cerebral atrophy-seizures93

Progressive cerebral atrophy, abnormal white matter on MRI, hypoplastic corpus callosum, increased third and lateral ventricles

AR/XLR?

Macrocephalydisproportionate tall stature94

Mild to moderate developmental delay, tall with long thorax and straight back but relatively short limbs, moderate hypotonia, high and narrow forehead, upswept frontal hair, wide and short ears, hypotelorism, blepharochalasis

AD

Macrocephaly-facio-skeletal95

Dolichomacrocephaly, hyperextensible joints, eccentric pupils, mild to moderate developmental delay, pectus carinatum, kyphoscoliosis, blue sclera, Dandy-Walker cyst

Uncertain

Macrocephaly-spastic paraplegia96

Developmental delay, progressive spasticity, short neck, broad chest, truncal obesity, broad and high forehead, deep-set eyes, short philtrum, prominent upper central incisors, alveolar ridges, megacisterna magna

AR (600302)

Macrocephaly-tremor97

Macrocephaly, slow tremor of head, trunk, and/or limbs developing before age 5 years; other neurologic and endocrine signs common; distortion of third ventricle by space occupying lesion or aqueduct stenosis

Sporadic

Mangano: macrosomiamental retardation98

Variable developmental delay, overgrowth, large hands and feet, coarse face, thick eyebrows

AD

Mascaro: follicular hamartomas-alopecia-joint laxity99

Old facial appearance, delayed closure of fontanels, dental malocclusion, joint hypermobility, alopecia, hypohidrosis, hyperelastic skin, follicular hamartomas, hepatomegaly, growth hormone deficiency, severe left pulmonary artery hypoplasia; consanguinity

AR

Megalencephalic leukodystrophy-subcortical cysts100

Diffuse swelling of cerebral white matter, spongiform leukodystrophy, large subcortical cysts in frontal and temporal lobes; onset in infancy, slowly progressive motor deterioration, cerebellar ataxia, seizures

AR(604004) MLC1, 22qter

Megalencephaly-benign familial101

No associated anomalies, most common type of megalencephaly

AD (155530)

Megalencephaly-hamartomas

See Bannayan-Riley-Ruvalcaba

AD PTEN

Megalencephaly-mega corpus callosum102

Mental retardation, no motor development, prominent forehead, low nasal bridge, large eyes; MRI evidence of megalencephaly, a broad corpus callosum, ‘‘enlarged’’ white matter, focal increased thickness of thick gray matter, pachygyric appearance, wide Sylvian fissures

Unknown

Megalencephaly-spasticataxia103

Progressive megalencephaly and dysmyelination, spasticity, ataxia, seizures; normal intellect, senses, and cranial nerves; consanguinity

AR? (212905)

Megalocornea-macrocephalymental retardation104

Macrocephaly, mental retardation, megalocornea, large and fleshy ears, long and tapering fingers, variable obesity and scoliosis

Unknown (249310)

MOMES105

Developmental delay, maxillary hypoplasia, prognathism, blepharophimosis, ptosis, abducens palsy, dental crowding, lateral deviation of halluces, coned epiphyses of toes

AR (606772)

MOMO106

Mental retardation, prominent forehead, hypertelorism, downslanting palpebrae, broad nasal root, truncal obesity, retinal coloboma, glaucoma

Unknown (157980)

Moreno: gigantism107

Large at birth, advanced bone age, loose skin, prominent supraciliary ridges, deep-set eyes, limited joint movement (same as Weaver syndrome?)

Unknown

Muller: cerebral malformationhypertrichosis108

Hypertelorism, telecanthus, microphthalmia, small and low-set ears, hypertrichosis, camptodactyly, overlapping fingers, absent swallowing and suck; variable CNS findings in sibs including macrocephaly, absent corpus callosum, septum pellucidum cyst, cerebellar hypoplasia

AR (213820)

Multiple epiphyseal dysplasia-edemamacrocephaly109

Normal stature, mild developmental delay, frontal bossing, short neck, hypertelorism, flat malar regions, flat epiphyses of long bones, mild metaphyseal flaring, mild frontal atrophy, variable lymphedema of the hands and legs

AR (607131) 15q26

Multiple pterygium-XY gonadal dysgenesis110

Cranial asymmetry, frontal bossing, small and low-set ears, micrognathia, partial finger zygodactyly, webbed neck, contractures and webbing at major joints. Single case

Unknown

Nephritis-macrocephalydeafness111

Hereditary nephritis and sensorineural hearing loss similar to Alport syndrome but with macrocephaly and mental retardation

XLR (301050) COL4A5, Xq22.3

Neuro-facio-digito-renal112

Mental retardation, high forehead, cowlick, hypertelorism, short and angulated ears, abnormal thumb, broad halluces, unilateral renal agenesis (similar to FG syndrome but without constipation and anal and joint abnormalities)(see also OMIM 222448 and 227290)

Uncertain (256690)

Neurofibromatosis113

Cafe´-au-lait spots, neurofibromata, Lisch nodules, occasional plexiforum neuromas, pseudarthrosis, and diverse complications of tumors. Two cases with hemimegalencephaly without hamartomas and heterotopias did well

AD (162200) neurofibromin, 17q11.2 (continued)

517

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Nokelainen: cerebral atrophyabnormal white matter114

Severe developmental delay, high forehead, small and concave nose with low bridge, tented mouth, gingival hyperplasia, downslanting palpebrae, seizures; patchy T-2–weighted periventricular increased signal intensity

XLR/AR?

Noonan115

Variable mental retardation and short stature, ptosis, downslanting palpebrae, low/abnormal ears, short/webbed neck, sternal malformation, pulmonary valve stenosis/dysplasia

AD (163950) PTPN11, 12q22

Noonanneurofibromatosis116

Noonan-like facial appearance, short/webbed neck, short stature, hypotonia and variable developmental delay in association with manifestations of neurofibromatosis; some cases shown to have neurofibromatosis mutations

AD (193520)

Optic disc druzenmegalencephaly117

Macrocephaly, pseudopapilledema due to optic disc drusen; one of four isolated cases had cleft lip and palate

Unknown

Orstavik: macrocephalyepilepsy-autism118

Developmental delay, high forehead, full eyebrows, short philtrum, epilepsy, autism; megalencephaly demonstrated at autopsy

Uncertain

Osteopathia striata-cranial sclerosis119

Macrocephaly may be presenting sign although CT may be consistent with cerebral atrophy; macrocephaly likely due to cranial sclerosis

AD/XLD? (166500)

Osteosclerotic-osteochondrodysplasia120

Lethal micromelic osteosclerotic osteochondrodysplasia with IUGR, marked platyspondyly, poor modelling and metaphyseal flaring, frontal bossing, low nasal bridge, pulmonary hypoplasia; absence of gray/white matter demarcation; hypercellular cortical and trabecular bone marrow fibrosis, dilated rough endoplasmic reticulum

AR (603393)

Overgrowth-vertebral fusion131

Normal intelligence, round face, hypertelorism, downslanting palpebrae, broad nasal bridge, maxillary hypoplasia, short philtrum, large mouth, thin lips, irregular vertebral end plates and disc spaces were most marked anteriorly, progressive vertebral fusion

Unknown

Parietal foramina-clavicular hypoplasia132

High prominent forehead, sloping parietal area and abrupt angle at occiput, mild mid-face hypoplasia, hypertelorism, lacrimal duct occlusion, short nasal septum, external ear anomalies, sloping shoulders (isolated parietal foramina with mutations of ALX4 and MSX2)

AD (168550)

Pena-Shokier without IUGR123

Hydramnios, small and immobile mouth, choanal atresia, low and angulated ears, pterygia, camptodactyly; normal CNS microscopy in one case

XLR or AR

Periventricular nodular heterotopia, bilateral124

Bilateral periventricular nodular heterotopias, usually mild phenotype with onset of frequent seizures age 4–25 years; pair of MZ twin sisters reported with BPNH, macrocephaly, and no neurologic signs

XLD (300049) filamin A FLNA, Xq28

Perlman: hamartomas125

Renal hamartomas, nephroblastomatosis, fetal gigantism, deep-set eyes, broad nasal bridge, low-set ears, everted lower lip, bifid sternum, neonatal death

AR (267000)

Pfeiffer-Hirschfelder-Rott: acromesomelia126

Ptosis, telecanthus, ureteral stenosis, acromesomelia, aplasia of distal ulna, bowed radii, dislocation of radial heads, short proximal phalanges and 2nd–5th metacarpals, modelling and fusion defects of metacarpals/metatarsals, wrists, and ankles

Unknown

Posterior fossa anomaliesleukodystrophy127

Macrosomia, developmental delay, prominent forehead, hypertelorism, flat nasal bridge, narrow palate, 4-5 clinodactyly of fingers, 2-4 toe syndactyly, central hypotonia, absent reflexes lower limbs with distal hypertonia. One sib had vermis aplasia and Dandy-Walker variant, the other a mega cisterna magna.

AR

Programmed cell death anomaly128

Normal intelligence and MRI, cutaneous syndactyly of hands and feet, stenotic auditory canals, hypoplastic lacrimal ducts, short palpebrae, small teeth, prominent jaw, mixed hearing loss

Unknown

Proteus129

Marked and asymmetric overgrowth that can lead to a range of complications; skin changes include linear verrucous epidermal nevi, intradermal nevi, shagreen patches, hemangiomas, lipomas, patchy dermal hypoplasia, characteristic hyperplastic and pebbly plantar overgrowth; frequent ocular problems. Some PTEN mutations claimed, but cases questioned.183

Uncertain (176920) 1q11-q25

PTEN-associated VATERlike-macrocephaly130

Bilateral thumb hypoplasia, 13 pairs of ribs, tracheoesophageal fistula, static ventriculomegaly; no other signs of PTEN spectrum

AD PTEN, 10q22-q23

Pyruvate carboxylase deficiency131

Typically a Leigh-like picture with onset by 6 months, vomiting and growth failure, lactic acidosis; cases with macrocephaly may represent a subset of patients

AR (266150) 11q13.4-q13.5

Richieri-Costa132

IUGR, broad nasal root, downslanting palpebrae, hypertelorism, joint restriction, hypoplastic digits, fused and missing ribs

Uncertain

Riley-Smith

See Bannayan-Riley-Ruvalcaba

AD PTEN

Robinow: fetal face133

Prominent forehead, wide mouth, small nose, hypertelorism, micropenis, variable mesomelic shortness, vertebral defects, oral clefts

AD (180700), AR (268310) ROR2, 9q22 (continued)

518

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Ruvalcaba-Myhre-Smith

See Bannayan-Riley-Ruvalcaba

AD PTEN

Schorderet: Robinow-like134

Macrocephaly, short forearms, hypertelorism, hepatosplenomegaly; one patient with hemiand fused vertebrae and scoliosis, the other a bifid rib; male with ambiguous genitalia, had a mosaic 45,X/46,X,dic(Y)/47,X,dic(Y),dic(Y) karyotype

AR (268310)

Short and broad hallucesmacrocephaly135

Short and broad great toes, proximally placed thumbs, mild developmental delay; single case

Unknown

Simpson-Golabi-Behmel136

Macrocephaly in 1/3, postnatal overgrowth, thick lips, large mouth, dental malalignment, prominent jaw, short neck, hoarse voice, hepatosplenomegaly, cardiac anomalies, cryptorchidism, broad hands and feet, some cases of delayed development

XLR (312870) Glypican 3, Xq26

Simpson-Golabi-Behmeltype 2137

A severe form; neonates are hydropic; low-set and posteriorly rotated ears; hypertelorism; short broad nose; short neck; redundant skin; limb and skeletal anomalies; marked neurologic impairment; lethal

XLR (300209) Xp22

Sotos: Cerebral gigantism138

Early overgrowth with large hands and feet, prominent and high forehead, downslanting palpebrae, long and prominent chin, high palate, somatomedian initially high and falls during first year, variable developmental delay

AD (117550) NSD1, 5q35

Sotos-Goldstein variant139

Looks like Sotos; authors consider marked hypotonia, nystagmus, and improving development distinctive

AD

Sotos-Blackett variant140

Some Sotos-like features, variable retardation, accelerated growth, precocious puberty, may show ventricular enlargement

AD

Teebi: overgrowth141

Developmental delay, prenatal overgrowth, advanced bone age, loose skin, joint laxity, thin and hypopigmented hair, downslanting palpebrae, dental anomalies, prominent fingertip pads; consanguinity

AR (277590)

Thanatophoric dysplasia142

Micromelic; short-limbed lethal dwarfism with a few survivors beyond 1 year; achondroplasia-like face; excess skin folds; ‘‘H’’ or ‘‘U’’ appearance of vertebrae on AP view; bowing and metaphyseal flare of long bones; very short, broad, small tubular bones, brain abnormalities, megalencephaly, prominent dysmorphic temporal lobes, abnormal dentate gyrus, stenosis of foramen magnum and spinal canal, narrow spectrum of mutations

AD (187600) FGFR3, 4p16

Tollner: polydactyly-visceral anomalies143

Hypertelorism, bilateral cleft lip/palate, macroglossia, hepatosplenomegaly, accessory lobe of right lung, horseshoe kidney, complex congenital heart defect, heptadactyly of hands, preaxial polysyndactyly of feet, micropenis, hydrocephalus, ependymal cysts, polygyria, leptomeningeal fibrosis. Single case

Unknown

Toriello: macrocephalyHirshsprung144

Single case with facial asymmetry, high palate, 13 pairs of ribs, broad and short hands, short distal phalanges

Unknown

Toriello: oculo-ectodermal145

Cutis aplasia of scalp, epibulbar dermoids, patchy skin hyperpigmentation; additional findings may include keloid, preauricular tag, epicanthus, strabismus; similar to linear nevus sebaceous

Unknown

Turner: XLMRmacrocephaly146

Moderate X-linked mental retardation, macrocephaly in males and some carrier females; holoprosencephaly a possible expression of the gene in males

XLD Xp21-q21

Turnpenny-Thwaites: rhizomelic short stature147

Pre- and postnatal growth failure, rhizomelia, high forehead, frontal bossing, malar flatness, small nose, macrostomia, gingival hypertrophy, thin lips, clitoral hypoplasia; single case

Unknown

Van Benthem148

Severe retardation, dolichocephaly, high palate, chest and spinal anomalies, arachnodactyly, hypospadias, testicular agenesis in one case, respiratory infection

XLR probable

Weaver149

High broad forehead, broad nasal root, telecanthus, micrognathia, large ears, accelerated growth and bone age, hypotonia, camptodactyly prominent finger pads

AR/AD (277590) Heterogeneity, 5q35 Some with NSD1 mutations

Wiedemann: dwarfismblepharophimosis150

Primordial dwarfism, macrodolichocephaly, low-set ears, downslanting palpebrae, blepharophimosis, cryptorchidism, delayed bone age; single case

Unknown

Wiedemann: megalencephaly-mental retardation151

Two male sibs with delayed closure of fontanel, deep-set eyes, small and pointed chin, mental retardation, large penis and testes; another sib had heart defects and megalencephaly

XLD or AD

Wiedemann: tibial ray defect152

Trigonocephaly, small and downslanting palpebrae, micromelia, asymmetric lower limb anomalies, tibial hypoplasia, high-level preaxial polydactyly of the foot

Uncertain

XLMR-macrocephalymacroorchidism153

Macrocephaly variable, seizures, triangular face, blue eyes, prominent jaw, macroorchidism, monotonous speech; females may show developmental delay

XLD Xq12-q21

Zimmerman-Laband154

Variable developmental delay, coarse features, hepatosplenomegaly, hirsutism; later onset gingival fibromatosis, joint hyperlaxity, nail hypoplasia; cases with cardiomyopathy

AD (135500) 3p21.2 or 8q24.3?

519

520

Neuromuscular Systems

Fig. 15-5. Gross pathological appearance of hemimegalencephaly in a child with a large flank lymphangioma but no vascular changes in the brain. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

A patient with high-output cardiac failure due to isolated hemimegalencephaly was reported by Walters et al.168 Although usually an isolated finding, hemimegalencephaly has also been reported in association with hemihypertropy, which, when it includes the head, has a poor prognosis. The hemihypertrophy may be limited to the craniofacies.169 There is no specific information as to whether the brain pathology in patients with hemifacial hypertrophy is similar to that of isolated hemimegalencephaly. Etiology and Distribution

The true prevalence of megalencephaly is not known. Marked variations in rates reported from autopsy studies, from 1/1146 to 1/50,000, may in part be explained by the standards of normal used for comparison, as well as by the handling of the brain prior to weighing. By statistical definition, 2.5% of the population are macrocephalic. In a follow-up study of an initial cohort of 150,229 boys, Pedersson et al.158 calculated gestational week and birth weight corrected centile curves for OFC. Because OFC was reported as whole centimeters in the study, the 98th centile was defined within a 1cm zone. Of 144,273 neonates with no malformations, 732 (1/197; 0.5%) were above the 98th centile and 3,555 (1/40.6; 2.46%) were within the 98 centile zone. However, the proportion of macrocephalic individuals who have anatomic megalencephaly will vary with the population studied and with the investigations carried out. Lorber and Priestly5 studied 557 children with macro-

cephaly and considered 126 (23%) of them to be megalencephalic. Seventeen of the latter had a specific associated syndrome; the majority of the remainder appeared to have benign familial megalencephaly. Gooskens et al.6 proposed a category of megalencephaly that they called ‘‘dynamic’’ to reflect a possible etiologic basis in a transient disturbance of CSF hemodynamics. In some cases of BFM and also in a variety of syndromes there is some evidence of mild ventricular dilation or subarachnoid fluid collection.159 Indeed, at least one study suggests that increased subarachnoid spaces may be the predominant MRI finding in BFM.9 Hartel et al.184 reported male and female siblings with progressive macrocephaly and dilated Virchow-Robin spaces. Gooskens et al.7 demonstrated the concurrence of true megalencephaly with communicating hydrocephalus. The etiology of BFM, at least in cases in which there is true megalencephaly, may simply represent brains at the upper limit of the distribution curve. Current arguments in favor of mutifactorial inheritance would support this interpretation, which is not contradicted by the idea that ‘‘bigger may not be better.’’ There is no known pathologic change in the brain, and it is not clear whether the increased size reflects overproduction of cells or glial fibers, or perhaps a diminution in programmed cell death. Knowledge about the cause of the megalencephaly, and indeed of its very presence, is fragmentary for most of the syndromes listed in Table 15-2. The majority of the conditions are rare; many represent single case reports. Frequently (notably those with cerebral dysfunction), disturbed neuroanatomy, including heterotopias, polymicrogyria, and abnormal cortical lamination, may be seen. The macrocephaly in neurofibromatosis 1 appears to be due to an increase in total, including frontal, white matter.170 Generalized cortical dysplasia of the type more often seen in hemimegalencephaly was reported in two girls with megalencephaly who presented with seizures at age 3 and 4 years,171 respectively, and it has also been reported in the cutis marmorata-macrocephaly association (Table 15-2). Prendiville et al.172 showed MRI evidence of subclinical, and apparently transient, brain involvement in nine of ten infants with neonatal lupus. One child had findings, including increased subarachnoid spaces, compatible with BFM. This may have been coincidence but does raise the question as to whether some cases of benign macrocephaly might have an inflammatory cause. In a study of C57BL/6 mice with maternal exposure to human influenza virus at day 9 of pregnancy, Fatemi et al.173 showed a significant increase in brain size and decrease in ventricular size in the exposed cohort. This appeared due primarily to an increase in pyramidal and non-pyramidal cell density. As adults the offspring also exhibited abnormal behaviour, suggesting the possibility of prenatal infection as a cause for megalencephaly. Prognosis, Treatment, and Prevention

Clearly the prognosis for the child with megalencephaly is highly dependent on the underlying pathogenesis and on any associated neurodevelopmental anomalies. When history, physical examination, and selective investigations lead to a specific syndrome diagnosis, prognosis can best be estimated on the basis of previous experience with that condition. As discussed, most individuals with anatomic megalencephaly do not have an associated syndrome. De Meyer4 introduced the concept of an optimum human brain size, with the relationship of intelligence to brain size represented by an inverted ‘‘U’’, with microcephaly at one extreme and megalencephaly at the other. He referred to data from the National Institutes of Health

Brain

Collaborative Perinatal study that, although indicating a shift toward increasing intelligence with increasing OFC, showed a decline beyond a specific point. Both the nature of the groups studied and the detail of their assessment will affect population-based estimates of the prognosis of children with megalencephaly. Lorber and Priestley7 studied patients referred for assessment of macrocephaly, and 109 of 126 megalencephalic children had no syndrome diagnosis. The concept of BFM was recognized late in the study (i.e., many parents were not examined), but 49 patients had parents with confirmed macrocephaly, and six others were affected by their histories. Ninety-six of the children were considered normal, six normal but below average, and seven clearly retarded. The retarded children were characterized by having additional positive family or personal history and/or clinical findings. No mention was made of fragile X studies. These data suggest a good prognosis for BFM. However, data from studies of non-referred children with macrocephaly suggest there is an increased risk for difficulties, some of which may be subtle. In their cohort study, Petersson et al.158 found that the odds ratio for low intelligence scores was 1.32 (CI 1.1-1-38) for the 732 children with an OFC >98th centile compared with those with an OFC in the normal range. The odds ratio for mental retardation was 1.31 but did not reach significance. A multivariate analysis comparing 20 children with macrocephaly with 19 normencephalic siblings and 16 age-matched controls showed a main effect of macrocephaly on psychometric measures.174 Univariate analysis confirmed poorer performance of the macrocephalic children on a number of measures including visuomotor control and integration, motor speed, bilateral coordination, and naming fluency. Arbour et al.155 noted that the macrocephalic propositi with psychomotor impairment had larger heads and a more frequent history of birth difficulty, thus raising the concern that some of the problems may be acquired and preventable. A cohort study of boys born with macrocephaly found an odds ratio of 5.44 (CI 1.11-52.15) for the development of autism,163 an association that has already been discussed. Gherpelli et al.175 followed 17 boys and one girl with congenital macrocephaly associated with increased subarachnoid spaces to the mean age of 56 months. They found that two (11%) had significant neurodevelopmental problems, but also that the macrocephaly had resolved in 45% of cases. This association can also usefully be examined from the starting point of children selected because of a syndrome and/or developmental problem. The association of macrocephaly with autism has been discussed,157,162–164and most studies have not shown an association with the specific pattern or severity of the autism. However, Deutsch and Joseph176 noted that autistic children with macrocephaly were more likely to show a discrepancy between their non-verbal and verbal abilities. Smith177 measured the OFC in children referred as ‘‘learning disabled’’ ( < 10th centile of achievement relative to expectation) and compared them with age- and sex-matched controls. An excess of macrocephaly was found in the learning disabled group. A more detailed study of a non-referred group in the regular school resource program found a similar excess of macrocephaly, but not of minor anomalies, among the children in the resource program compared with their controls.178 Resource children with macrocephaly showed lower achievement than normocephalic resource children, and a pattern of macrocephaly and similar learning problems was noted in several of their families. During evaluation of children with developmental delay, Neri et al.179 identified a group of 42 nondysmorphic children (39 male), selected for length and/or OFC

521

above the 75%, who presented with sporadic occurrence, a high prevalence of muscular hypotonia, advanced bone age, obesity, and seizures. Nineteen had an OFC
97 centile, and neuroimaging showed no major anomalies although some had a degree of ventriculomegaly. With the exception of two affected sisters, the families were negative for mental retardation, and the parents did not show overgrowth. Although parental OFCs were not discussed, the authors suggest this may be a heterogeneous overgrowth/ macrocephaly condition associated with mild developmental delay. With respect to specific syndromes, Bale et al.,2 by comparing height corrected OFC in propositi and their affected siblings with neurofibromatosis (NF1), concluded that it was a true macrocephaly syndrome. In contrast, they surmised that macrocephaly in nevoid basal cell carcinoma syndrome was related to proband status. Moore et al.180 carried out quantitative neuroanatomical measurements on 52 propositi with NF1 and demonstrated significantly greater total brain volume, most notably of the gray matter, in NF1. Gray matter volume and size of the corpus callosum was negatively correlated with performance on academic measures. Patients with Duchenne muscular dystrophy (DMD) are at significant risk for intellectual impairment. Appleton et al.181 found relative macrocephaly among a group of 64 patients with DMD, and although 12 had absolute macrocephaly, there was no correlation between OFC or true macrocephaly and intellectual abilities. Hemimegalencephaly has been reported in association with several syndromes including NF1, tuberous sclerosis, linear sebaceous nevus, and Klippel-Trenauny-Weber and has an almost uniformly poor prognosis. However, two patients with NF1 and hemimegalencephaly, and who lacked heterotopias or hamartomas, did well.182 Treatment of children with megalencephaly is directed toward palliation of the associated complications or malformations of specific syndromes, and provision of developmental services and support as required. All megalencephalic/macrocephalic children merit a careful history, including that of the family, and physical examination. For otherwise normal children, especially with a proven family history of benign megalencephaly, neuroradiologic studies are unnecessary. However, in light of the several studies showing that these children are at increased risk for neurodevelopmental problems, attention should be paid to the potential for learning disabilities. Some children with hemimegalencephaly may benefit from multilobar cortical resections and/or hemispherectomy for the control of intractable seizures. Prevention is largely directed toward syndromic anatomic megalencephaly and known metabolic causes. Genetic counselling, selective reproductive options, and targeted ultrasound directed at the detection of specific malformations or growth patterns are available. References (Megalencephaly) 1. Friede RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 273. 2. Bale SJ, Amos CI, Parry DM, et al.: Relationship between head circumference and height in normal adults and in the nevoid basal cell carcinoma syndrome and neurofibromatosis type I. Am J Med Genet 40:206, 1991. 3. Bushby KMD, Cole T, Matthews JNS, et al.: Centiles for adult head circumference. Arch Dis Child 67:1286, 1992. 4. De Meyer W: Megalencephaly: types, clinical syndromes, and management. Pediatr Neurol 2:321, 1987. 5. Lorber J, Priestley BL: Children with large heads: a practical approach to diagnosis in 557 children, with special reference to 109 children with megalencephaly. Dev Med Child Neurol 23:494, 1981.

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Neuromuscular Systems

6. Gooskens RHJM, Willemse J, Bijlsma JB, et al.: Megalencephaly: definition and classification. Brain Dev 10:1, 1988. 7. Gooskens RHJM, Gielen CCAM, Hanlo PW, et al.: Intracranial spaces in childhood macrocephaly: comparison of length measurements and volume calculations. Dev Med Child Neurol 30:509, 1988. 8. Tramo MJ, Loftus WC, Stukel TA, et al.: Brain size, head size, and intelligence quotient in monozygotic twins. Neurology 50:1246, 1998. 9. Alper G, Ekinci G, Yimaz Y, et al.: Magnetic resonance imaging characteristics of benign macrocephaly in children. J Child Neurol 15:630, 2000. 10. Artigas J, Poo P, Rovira A, et al.: Macrocephaly and dilated VirchowRobin spaces in childhood. Pediatr Radiol 29:188, 1999. 11. Gibson KM, Elpeleg ON, Jakobs C, et al.: Multiple syndromes of 3methylglutaconic aciduria. Pediatr Neurol 9:120, 1993. 12. Hall JG, Horton W, Kelly T, et al.: Head growth in achondroplasia: use of ultrasound studies [letter to the editor]. Am J Med Genet 13:105, 1982. 13. Amor D, Leventer RJ, Hayllar et al.: Polymicrogyria associated with scalp and limb defects: variant of Adams-Oliver syndrome. Am J Med Genet 93:328, 2000. 14. Meins M, Brockman K, Yadav S, et al.: Infantile Alexander disease: A GFAP mutation in monozygous twins and novel mutations in two other patients. Neuropediatrics 33:194, 2002. 15. Al-Gazali LI, Aziz SAA, Salem F: A syndrome of short stature, mental retardation, facial dysmorphism, short webbed neck, skin changes and congenital heart disease. Clin Dysmorphol 5:321, 1996. 16. Wilkie AOM, Buckle VJ, Harris PC, et al.: Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. I. Cases due to deletions involving chromosome band 16p13.3. Am J Hum Genet 46:1112, 1990. 17. Krajewska-Walasek M: Aminopterin Syndrome Sine Aminopterin (ASSA) syndrome in two siblings: further delineation of the syndrome and review of the literature. Genet Couns 5:345, 1994. 18. Rauchman M, Hoffman WH, Hanna J, et al.: Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure. Am J Med Genet 104:31, 2001. 19. Richeri-Costa A, Guin-Almeida ML: Mental retardation, structural anomalies of the central nervous system, anophthalmia and abnormal nares: A new MCA/MR syndrome of unknown cause. Am J Med Genet 47:702, 1993. 20. Cohen MM Jr, Kreiborg S: The central nervous system in Apert syndrome. Am J Med Genet 35:36, 1990. 21. Scott RE: Ataxia-telangiectasia. Arch Pathol 88:78, 1969. 22. Sillence DO, Worthington S, Dixon J, et al.: Atelosteogenesis syndromes: a review with comments on their pathogenesis. Pediatr Radiol 27:388, 1997. 23. Atkin JF, Flaitz K, Patil S, et al.: A new X-linked mental retardation syndrome. Am J Med Genet 21:697, 1985. 24. Bagatelle R, Cassidy SB: New syndrome of macrocephaly, hypertelorism, short limbs, hearing loss, and developmental delay. Am J Med Genet 55:367, 1995. 25. Marsh DJ, Kum JB, Lunetta KL, et al.: PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvaclcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 8:1461, 1999. 26. Katsanis N, Lupski R, Beals PL: Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 10:2293, 2001. 27. Gorlin RJ: Nevoid basal-cell carcinoma syndrome. Medicine 66:98, 1987. 28. Oley CA, Sharpe H, Chenevix-Trench G: New syndrome? Basal cell carcinomas, coarse sparse hair, and milia. Am J Med Genet 43:799, 1992. 29. Beveridge J: Case report 6. Synd Ident 1:4, 1973. 30. Petridou M, Kimiskidis V, Deligiannis K, et al.: Bo¨rjeson-ForssmanLehmann syndrome: two severely handicapped females in a family. Clin Neurol Neurosurg 99:148, 1997. 31. Hunter AGW, Feldman W, Miller J: Characteristic craniofacial appearance and brachytelephalangy in mother and son, with Kallman syndrome in the son. Am J Med Genet 24:527, 1986. 32. Cameron FJ, Hageman RM, Cooke-Yarborough CM, et al.: A novel germ line mutation in the SOX9 causes familial Campomelic dysplasia and sex reversal. Hum Mol Genet 5:1625, 1996.

33. Lazalde B, Sa´nchez-Urbina R, Nun˜o-Arana I, et al.: Autosomal dominant inheritance in Cantu´ syndrome (congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly): Am J Med Genet 94:421, 2000. 34. Sabatino G, Verrotti A, Domizio S, et al.: The Cardio-facio-cutaneous syndrome: a long term follow up of two patients, with special reference to the neurological features. Child Nerv Syst 13:238, 1997. 35. Ryan A, Marshall T, FitzPatrick DR: Carey-Fineman-Ziter (CFZ) syndrome: Report on affected sibs. Am J Med Genet 82:110, 1999. 36. Sweeney E, Fryer A, Walters M: Char syndrome: a new family and review of the literature emphasising the presence of symphalangism and the variable phenotype. Clin Dysmorphol. 9:177, 2000. 37. Chia NL, Bousfield LR, Poon CCS, et al.: Trisomy (1q) (q42-qter): Confirmation of a syndrome. Clin Genet 34:224, 1988. 38. Conrad B, Dewald G, Christensen E, et al.: Clinical phenotype associated with terminal 2q37 deletion. Clin Genet 48:134, 1995. 39. Moog U, Enlelen JJ, van Schrojenstein Lantman-de Valk HM, et al.: Familial cryptic translocation with deletion 4q33->4qter and duplication 7q34->7qter in brothers with mental retardation, macrocephaly and iris coloboma. Clin Dysmorphol 12:35, 2003. 40. Partington MW, Fagan K, Soubjaki V, et al.: Translocations involving 4p16.3 in three families: deletion causing the Pitt-Rogers-Danks syndrome and duplication resulting in a new overgrowth syndrome. J Med Genet. 34:719, 1997. 41. Stratton RF, Tedrowe NA, Tolworthy JA, et al.: Deletion 5q35.3. Am J Med Genet 51:150, 1994. 42. Drogo P, Carra S, Laverda AM, et al.: Macrocephaly and chromosome disorders: a case report. Brain Dev 18:312, 1996. 43. Tonk VS, Wilson GN, Velagaleti GV: Duplication 8 [inv dup(8)(p12p23)] with macrocephaly. Ann Ge´ne´t 44:195, 2001. 44. Penman Splitt M, Goodship J: Another case of maternal uniparental disomy chromosome 14 syndrome. Am J Med Genet 72:239, 1997. 45. Cario H, Bode H, Gustavsson P, et al.: A microdeletion syndrome due to a 3-Mb deletion on 19q13.2- Diamond-Blackfan anemia associated with macrocephaly, hypotonia, and psychomotor retardation. Clin Genet 55:487, 1999. 46. Cooper SC, Flaitz CM, Johnston DA, et al: A natural history of cleidocranial dysplasia. Am J Med Genet 104:1, 2001. 47. Cole TRP, Hughes HE: Autosomal dominant macrocephaly: Benign familial macrocephaly or a new syndrome? Am J Med Genet 41:115, 1991. 48. Loeffen JL, Smeitink JA, Trijbels JM, et al.: Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat 15:123, 2000. 49. Cortes F, Lacassie Y: An unusual case of ectodermal dysplasia. Am J Med Genet. 25:289, 1986. 50. van Eeghen AM, van Gelderen I, Hennekam RC: Costello syndrome: report and review. Am J Med Genet 82:187, 1999. 51. Eng C, Ji HL: Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddy waters. Am J Hum Genet 62:1020, 1998. 52. Tamai S, Tojo M, Kamimaki T, et al.: Intrafamilial phenotypic variations in cranioectodermal dysplasia: propositus with typical manifestations and her brother with perinatal death. Am J Med Genet 107:78, 2002. 53. Beals RK, Piatt JH, Zonana J: Craniofacial conodysplasia. J Pediatr Orthop 15:633, 1995. 54. Kucukaydin M, Patiroglu TE, Okur H, et al.: Infantile CronkiteCanada syndrome? Case report. Eur J Pediatr Surg 2:295, 1992. 55. Giuliano F, David A, Edery P, et al.: Macrocephaly-cutis marmorata telangiectasia congenita: seven cases including two with unusual cerebral manifestations. Am J Med Genet 126A:99, 2003. 56. Me´gabane´ A, Haddad J, Lyonnet S, et al.: Child with overgrowth, pigmentary streaks, polydactyly, and intestinal lymphangiectasia: macrocephaly-cutis marmorata telangiectasia congenita syndrome or new disorder. Am J Med Genet 116A:184, 2003. 57. Der Kaloustian VM, McIntosh N, Silver K, et al.: Unilateral radioulnar synostosis, generalized hypotonia, developmental retardation,

Brain

58. 59. 60.

61.

62. 63. 64.

65.

66. 67.

68. 69.

70. 71.

72. 73.

74.

75. 76.

77. 78.

79.

80. 81.

and a characteristic facial appearance in sibs: a new syndrome. Am J Med Genet 43:942, 1992. FitzPatrick DR, Keeling JW, Evans MJ, et al.: Clinical phenotype of Desmosterolosis. Am J Med Genet 75:145, 1998. Dinno ND, Shearer L, Weisskopf B: Familial pseudomarfanism, a new syndrome? Birth Defects Orig Artic Ser XV(5B):179, 1979. Kodsi SR, Bloom KE, Egbert JE, et al.: Ocular and systemic manifestations of encephalocraniocutaneous lipomatosis. Am J Ophthalmol 118:77, 1994. Devriendt K, Standaert L, Van Hole C, et al.: Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity. J Med Genet 35:70, 1998. Arvio M, Peippo M, Simola KOJ: Applicability of a checklist for clinical screening of the fragile X syndrome. Clin Genet 52:211, 1997. Fryer AE: A patient with a previously undescribed overgrowth syndrome. Clin Dysmorphol 4:255, 1995. Fryns JP, Hellemans M, Van den Berghe H: Macrocephaly, distinct craniofacial appearance and spastic paraplegia: an autosomal recessive subtype of complicated spastic paraplegia. Clin Genet 45:228, 1994. Fryns JP, Dereymaeker AM, Haegeman J, et al.: Mental retardation, macrocephaly, short stature and craniofacial dysmorphism in three sisters. Clin Genet 33:293, 1988. Hoffmann GF, Trefz FK, Barth PG, et al.: Macrocephaly: an important indication for organic acid analysis. J Inherit Metab Dis 14:329, 1991. Colombo I, Finocchiaro G, Garavaglia B, et al.: Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaric acidemia type II. Hum Mol Genet 3:429, 1994. Goldblatt J, Singer SL: Autosomal recessive gingival fibromatosis with distinctive facies. Clin Genet 42:306, 1992. Ausems MGEM, Ippel PF, Renardel de Lavalette PAWA: Greig cephalopolysyndactyly syndrome in a large family: a comparison of the clinical signs with those described in the literature. Clin Dysmorphol 3:21, 1994. Halal F, Silver K: Slowly progressive macrocephaly with hamartomas: a new syndrome? Am J Med Genet 33:182, 1989. Heide T: Ein syndrom bestehend aus Osteogenesis imperfecta, Makrozephalus mit Schaltknochen und prominenten Stimhockem, Brachytelephalangie, Gelenkuberstreckbarkeit, kongenitaler Amaurose und Oligophrenie bei drei Geschwistem. Klin Padiatr 193:334, 1981. Reardon W, Harding B, Winter RM, et al.: Hemihypertrophy, hemimegalencephaly, and polydactyly. Am J Med Genet 66:144, 1996. Turnpenny PD, De Silva DC, Gregory DW, et al.: A four generation hidrotic ectodermal dysplasia family: an allelic variant of Clouston syndrome? Clin Dysmorphol 4:324, 1995. Turkdogan-Sozuer D, Ozek MM, Sehiralti V, et al.: Hemimegalencephaly and Hirschsprung’s disease: a unique association. Pediatr Neurol 18:452, 1998. Hockey A: X-linked intellectual handicap and precocious puberty with obesity in carrier females. Am J Med Genet 23:127, 1986. Bagatelle R, Cassidy SB: New syndrome of macrocephaly, hypertelorism, short limbs, hearing loss, and developmental delay. Am J Med Genet 55:367, 1995. Maroteaux P, Falzon P: Hypochondroplasia: review of 80 cases. Arch Fr Pediatr 45:105, 1988. Pascual-Castroviejo I, Lopez-Rodriguez L, de la Cruz Medina M, et al.: Hypomelanosis of Ito: neurological complications in 34 cases. Can J Neurol Sci 15:124, 1988. Brown DC, Grace E, Sumner AT, et al.: ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome. Hum Genet 96:411, 1995. Spranger J, Self S, Clarkson KB, et al.: Ischiospinal dysostosis with rib gaps and nephroblastomatosis. Clin Dysmorphol 10:19, 2001. Kaler SG, Garrity AM, Stern HJ, et al.: New autosomal recessive syndrome of sparse hair, osteopenia, and mental retardation in Mennonite sisters. Am J Med Genet 43:983, 1992.

523 82. Balci S, Dagli S: Keipert syndrome in two brothers from Turkey. Clin Genet 50:223, 1996. 83. Budka H: Megalencephaly and chromosomal anomaly. Acta Neuropathol 43:263, 1978. 84. Stephen MJ, Hall BD, Smith DW, et al.: Macrocephaly in association with unusual cutaneous angiomatosis. J Pediatr 87:353, 1975. 85. Diogo L, Fineza I, Canha J, et al.: Macrocephaly as the presenting feature of L-2 hydroxyglutaric aciduria in a 5-month-old boy. J Inherit Metab Dis 19:369, 1996. 86. Hopkin RJ, Cotton R, Langer LO, et al.: Progressive laryngotracheal stenosis with short stature and arthropathy. Am J Med Genet 80:241, 1998. 87. Gregg RG, Metzenberg AB, Hogan K, et al.: Waisman syndrome, a human X-linked recessive basal ganglia disorder with mental retardation: localization to Xq27.3-qter. Genomics 9:701, 1991. 88. Le Marec B, Bracq H, Picaud JC, et al.: A complex malformation with brachymesomelia. Ann Pediatr (Paris) 30:721, 1983. 89. Clancy RR, Kurtz MB, Baker D, et al.: Neurologic manifestations of the organoid nevus syndrome. Arch Neurol 42:236, 1985. 90. Lacombe D, Bonneau D, Verloes A, et al.: Lujan-Fryns syndrome (Xlinked mental retardation with marfanoid habitus): report of three cases and review. Genet Couns 4:193, 1993. 91. Moore LA, Moore CA, Smith JA, et al.: Asymmetric and symmetric long bone bowing in two sibs: an apparently new bone dysplasia. Am J Med Genet 47:1072, 1993. 92. Sanchez O, Nastasi J, Escalona J, et al.: Two male siblings with cavum septum pellucidum, cavum vergae, macrocephaly, seizures and mental retardation. A new hereditary syndrome. Clin Dysmorphol 6:129, 1997. 93. Nokelainen P, Heiskala H, Raininko R, et al.: Two brothers with macrocephaly, progressive cerebral atrophy and abnormal white matter, severe mental retardation, and Lennox-Gastaut spectrum type epilepsy: an inherited encephalopathy of childhood? Am J Med Genet 103:198, 2001. 94. Bakker HD, Hennekam RCM: Macrocephaly, facial abnormalities, disproportionate tall stature, and mental retardation—a sib observation. Am J Med Genet 70:312, 1997. 95. Chitayat D, Moore L, del Bigio MR, et al.: Familial Dandy-Walker malformation associated with macrocephaly, facial anomalies, developmental delay and brain stem dysgenesis: prenatal diagnosis and postnatal outcome in brothers. A new syndrome? Am J Med Genet 52:406, 1994. 96. Moog U, Schoonbrood-Lenssen AMJ, Schrander-Stumpel CTRM, et al.: Spasticity, mental retardation, macrocephaly and distinct craniofacial appearance: confirmation of a new subtype of complicated spastic paraplegia? Genet Couns 9:211, 1998. 97. Russman BS, Tucker SH, Schut L: Slow tremor and macrocephaly: expanded version of the bobble-head doll syndrome. J Pediatr 87:63, 1975. 98. Mangano L, Palmeri S, Dotti MT, et al.: Macrosomia and mental retardation: evidence of autosomal dominant inheritance in four generations. Am J Med Genet 32:67, 1989. 99. Mascaro JM Jr, Ferrando J, Bombt JA, et al.: Congenital generalized follicular hamartoma associated with alopecia and cystic fibrosis in three siblings. Arch Dermatol 131:454, 1995. 100. Ben-Zeev B, Levy-Nissenbaum E, Lahat H, et al.: Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews. Hum Genet 111:214, 2002. 101. Day RE, Schutt WH: Normal children with large heads-benign familial megalencephaly. Arch Dis Child 54:512, 1979. 102. Go¨hlich-Ratmann G, Baethmann M, Lorenz P, et al.: Megalencephaly, mega corpus callosum, and complete lack of motor development: a previously undescribed syndrome. Am J Med Genet 79:161, 1998. 103. Harbord MG, Harden A, Harding B, et al.: Megalencephaly with dysmyelination, spasticity, ataxia, seizures and distinctive neurophysiological findings in two siblings. Neuropediatrics 21:164, 1990. 104. Frydman M, Berkenstadt M, Raas-Rothschild A, et al.: Megalocornea, macrocephaly, mental and motor retardation (MMMM). Clin Genet 38:149, 1990.

524

Neuromuscular Systems

105. Kantaputra PN, Kunachaichote J, Patikulsila P: Mental retardation, obesity, mandibular prognathism with eye and skin anomalies (MOMES syndrome): a newly recognized autosomal recessive syndrome. Am J Med Genet 103:283, 2001. 106. Moretti-Ferreira D, Koiffmann CP, Listik M, et al.: Macrosomia, obesity, macrocephaly and ocular abnormalities (MOMO syndrome) in two unrelated patients: delineation of a newly recognized overgrowth syndrome. Am J Med Genet 46:555, 1993. 107. Moreno HC, Zachai EH, Kaufman JH: Gigantism-advanced bone agehoarse cry. Synd Ident 11(1):22, 1974. 108. Muller F-M, Barth GM, Menger H, et al.: Cerebral malformation, seizures, hypertrichosis, distinct face, claw hands, and overlapping fingers in sibs of both sexes. Am J Med Genet 47:698, 1993. 109. al-Gazali LI, Bakalinova D: Autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance. Clin Dysmorphol 7:177, 1998. 110. Angle B, Hersh JH, Yen F, et al.: XY gonadal dysgenesis associated with a multiple pterygium syndrome phenotype. Am J Med Genet 68:7, 1997. 111. Robson WLM, Lowry RB, Leung AKC: X-linked recessive nephritis with mental retardation, sensorineural hearing loss, and macrocephaly (Case report). Clin Genet 45:314, 1994. 112. Rump P, Gruijters MY, Van der Burgt CJ: A female patient with neurological, facial, digital and renal abnormalities: another case of the neurofaciodigitorenal (NFDR) syndrome? Clin Dysmorphol 6:337, 1997. 113. Riccardi VM, Eichner JE: Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Johns Hopkins University Press, Baltimore, 1986, p 136. 114. Nokelainen P, Heiskala H, Raininko R, et al.: Two brothers with macrocephaly, progressive cerebral atrophy and abnormal white matter, severe mental retardation, and Lennox-Gastaut spectrum type epilepsy: an inherited encephalopathy of childhood? Am J Med Genet 103:198, 2001. 115. Mendez HMM, Opitz JM: Noonan syndrome: a review. Am J Med Genet 21:493, 1985. 116. Allanson JE, Van Allen MI: Noonan phenotype associated with neurofibromatosis. Am J Med Genet 21:457, 1985. 117. Hoover DL, Robb RM, Petersen RA: Optic disc drusen and primary megalencephaly in children. J Pediatr Ophthalmol Strabismus 26:81, 1989. 118. Steiner CE, Guerreiro MM, Marques-de-Faria Unicamp AP: On macrocephaly, epilepsy, autism, specific facial features, and mental retardation. Am J Med Genet 120A:564, 2003. 119. Robinow M, Unger F: Syndrome of osteopathia striata macrocephaly and cranial sclerosis. Am J Dis Child 138:821, 1984. 120. Brodie SG, Lachman RS, Jewell AF, et al.: Lethal osteosclerotic osteochondrodysplasia with platyspondyly, metaphyseal widening, and intracellular inclusions in sibs. Am J Med Genet 80:423, 1998. 121. Fryns JP, Fabry G, Remans J, et al.: Progressive anterior vertebral body fusion, overgrowth and distinct craniofacial appearance. Genet Couns 4:235, 1993. 122. Golabi M, Carey J, Hall BD: Parietal foramina clavicular hypoplasia. Am J Dis Child 138:596, 1984. 123. Lammer El, Donnelly S, Holmes LB: Pena-Shokeir phenotype in sibs with macrocephaly but without growth retardation. Am J Med Genet 32:478, 1989. 124. Mohammed MSJ: Outcome of bilateral periventricular nodular heterotopia in monozygotic twins with megalencephaly. Dev Med Child Neurol 41:486, 1999. 125. Verloes A, Massart B, Dehalleux I, et al.: Clinical overlap of BeckwithWiedemann, Perlman and Simpson-Golabi-Behmel syndromes: a diagnostic pitfall. Clin Genet 47:257, 1995. 126. Pfeiffer RA, Hirschfelder H, Rott H-D: Specific acromesomelia with facial and renal anomalies: a new syndrome. Clin Dysmorphol 4:38, 1995. 127. Humbertclaude V, Coubes PA, Leboucq N, et al.: Familial DandyWalker malformation and leukodystrophy. Pediatr Neurol 16:326, 1997. 128. Hennekam RCM, Cohen MM Jr: Hypothesis: Patient with possible disturbance in programmed cell death. Eur J Hum Genet 3:374, 1995.

129. Biesecker LG, Happle R, Mulliken JB, et al.: Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84:389, 1999. 130. Reardon W, Zhou XP, Eng C: A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association. J Med Genet 38:820, 2001. 131. Brun N, Robitaille Y, Grignon A, et al.: Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am J Med Genet 84:94, 1999. 132. Richieri-Costa A, Monteleone-Neto R, Gonzales ML: Multiple congenital anomaly syndrome: macrocephaly, arthromyodysplasia, hypoplastic digits, rib anomalies in two sibs. Rev Brasil Genet 8:569, 1985. 133. Butler MG, Wadlington WB: Robinow syndrome: report of two patients and review of the literature. Clin Genet 31:77, 1987. 134. Schorderet DF, Dahoun S, Defrance I, et al.: Robinow syndrome in two siblings from consanguineous parents. Eur J Pediatr 151:586, 1992. 135. Collins DO: Case Report 15. Synd Ident 2(1):11, 1974. 136. Cole T: Growing interest in overgrowth. Arch Dis Child 78:200, 1998. 137. Brzustowicz LM, Farrell S, Haan MB, et al.: Mapping of a new SGBS locus to chromosome Xp22 in a family with a severe form of SimpsonGolabi-Behmel syndrome. Am J Med Genet 65:779, 1999. 138. Wit IM, Beemer FA, Barth PG, et al.: Cerebral gigantism (Sotos syndrome). Compiled data of 22 cases. Analysis of clinical features, growth and somatomedin. Eur J Pediatr 144:131, 1985. 139. Goldstein DJ, Ward RE, Moore E, et al.: Overgrowth, congenital hypotonia, nystagmus, strabismus, and mental retardation: variant of dominantly inherited Sotos sequence? Am J Med Genet 29:783, 1988. 140. Blackett PR, Coffman MA, Schaeffer GB, et al.: Case report: dominantly inherited childhood gigantism resembling Sotos syndrome. Am J Med Sci 296:181, 1989. 141. Slaney SF, Winter RM: Another case of the autosomal recessive Weaver-like syndrome. Am J Med Genet 72:369, 1997. 142. Knisely AS: Megalencephaly in thanatophoric dysplasia and in achondroplasia. J Pediatr 115:1026, 1989. 143. Tollner U, Horst J, Manzke E, et al.: Heptacarpo-octatarso-dactyly combined with multiple malformations. Eur J Pediatr 136:207, 1981. 144. Toriello HV, Komar K, Lawrence C, et al.: Macrocephaly, Hirschsprung disease, brachydactyly, vertebral defects and other minor anomalies. Dymorphol Clin Genet 1:155, 1988. 145. Gardner J, Viljoen D: Aplasia cutis congenita with epibulbar dermoids: further evidence for syndromic identity of the ocular ectodermal syndrome. Am J Med Genet 53:317, 1994. 146. Turner G, Gedeon A, Mulley J: X-linked mental retardation with heterozygous expression and macrocephaly: pericentromeric gene localization. Am J Med Genet 51:575, 1994. 147. Turnpenny PD, Thwaites RJ: Dwarfism, rhizomelic limb shortness, and abnormal face: new short stature syndrome sharing some manifestations with Robinow syndrome. Am J Med Genet 42:724, 1992. 148. Dyggve H, Pedersen KE, Bonnet-Eymard J, et al.: Van Benthem syndrome: case reports. Synd Ident III(2):25, 1975. 149. Fitch N: The syndromes of Marshall and Weaver. J Med Genet 17:174, 1980. 150. Wiedemann HR, Grosse KR, Dibbern H: Syndrome of megalencephaly, distinctive facies and developmental retardation. In: An Atlas of Characteristic Syndromes: A Visual Aid to Diagnosis. HR Wiedemann, KR Grosse, H Dibbern, eds. Wolfe Medical Publications, London, 1985, p 168. 151. Wiedemann HR, Grosse KR, Dibbern H: Syndrome of megalencephaly, distinctive facies and developmental retardation. In: An Atlas of Characteristic Syndromes: A Visual Aid to Diagnosis. HR Wiedemann, KR Grosse, H Dibbern, eds. Wolfe Medical Publications, London, 1985, p 26. 152. Wiedemann HR, Opitz JM: Unilateral partial tibia defect with preaxial polydactyly, general micromelia and trigonomacrocephaly with a note on ‘‘developmental resistance.’’ Am J Med Genet 14:467, 1983. 153. Johnson JP, Nelson R, Schwartz CE: A family with mental retardation, variable macrocephaly and macroorchidism, and linkage to Xq12-q21. J Med Genet 35:1026, 1998.

Brain 154. Robertson SP, Lipp H, Bankier A: Zimmermann-Laband syndrome in an adult. Long-term follow-up of a patient with vascular and cardiac complications. Am J Med Genet 78:160, 1998. 155. Arbour LA, Watters GV, Hall JG, et al.: Multifactorial inheritance of non-syndromic macrocephaly. Clin Genet 50:57, 1996. 156. Fraser FC, Arbour LA: Association of non-syndromic macrocephaly with autism. Am J Med Genet 104:342, 2001. 157. Miles JH, Hadden LL, Takahashi TN, et al.: Head circumference is an independent clinical finding associated with autism. Am J Med Genet 95:339, 2000. 158. Petersson S, Pedersen NL, Schalling M, et al.: Primary megalencephaly at birth and low intelligence level. Neurology 53:1254, 1999. 159. Asch AI, Myers GI: Benign familial macrocephaly: report of a family and review of the literature. Pediatrics 57:535, 1976. 160. DeRosa R, Lenke RR, Kurczynski TW, et al.: In utero diagnosis of benign fetal macrocephaly. Am J Obstet Gynecol 161:690, 1989. 161. Vanderschueren WG, Demaerel PH, Smet MH, et al.: CT and MRI in infants with pericerebral collections and macrocephaly: benign enlargement of the subarachnoid spaces versus subdural collections. AJNR Am J Neuroradiol 14:855, 1993. 162. Stevenson RE, Schroer RJ, Skinner C, et al.: Autism and macrocephaly. Lancet 349:1744, 1997. 163. Bolton PF, Roobol M, Allsopp L, et al.: Association between idiopathic infantile macrocephaly and autism spectrum disorders. Lancet 358: 726, 2001. 164. Fombonne E, Roge B, Claverie J, et al.: Microcephaly and macrocephaly in autism. J Autism Dev Disord 29:113, 1999. 165. Kalifa GL, Chiron C, Sellier N, et al.: Hemimegalencephaly: MR imaging in five children. Radiology 165:29, 1987. 166. Kato M, Mizuguchi M, Sakuta R, et al.: Hypertrophy of the cerebral white matter in hemimegalencephaly. Pediatr Neurol 14:335, 1996. 167. O’Kusky JR, Akers M-A, Vinters HV: Synaptogenesis in hemimegalencephaly: the numerical density of asymmetric and symmetric synapses in the cerebral cortex. Acta Neuropathol 92:156, 1996. 168. Walters BC, Burrows PE, Musewe N, et al.: Unilateral megalencephaly associated with neonatal high output cardiac failure. Child Nerv Syst 6:123, 1990. 169. Dean ICS, Cole GF, Appleton RE, et al.: Cranial hemihypertrophy and neurodevelopmental prognosis. J Med Genet 27:160, 1990. 170. Cutting LE, Cooper KL, Koth CW, et al.: Megalencephaly in NF1: predominantly white matter contribution and mitigation by ADHA. Neurology 59:1388, 2002. 171. Marchal G, Anderman F, Tampieri D, et al.: Generalized cortical dysplasia manifested by diffusely thick cortex. Arch Neurol 46:430, 1989. 172. Prendiville JS, Cabral DA, Poskitt KJ, et al.: Central nervous system involvement in neonatal lupus erythematosus. Pediatr Dermatol 20:60, 2003. 173. Fatemi SH, Earle J, Kanodia R, et al.: Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol 22:25, 2002. 174. Sandler AD, Knudsen MW, Brown TT, et al.: Neurodevelopmental dysfunction among nonreferred children with idiopathic megalencephaly. J Pediatr 131:320, 1997. 175. Gherpelli JL, Scaramuzzi V, Manreza ML, et al.: Follow-up study of macrocephalic children with enlargement of the subarachnoid space. Arq Neuropsiquiatr 50:156, 1992. 176. Deutsch CK, Joseph RM: Breif report: Cognitive correlates of enlarged head circumference in children with autism. J Autism Dev Disord 33:209, 2003. 177. Smith RD: Abnormal head circumference in learning disabled children. Dev Med Child Neurol 23:626, 1981. 178. Smith RD, Ashley J, Hardesty RA, et al.: Macrocephaly and minor congenital anomalies in children with learning problems. Dev Behav Pediatr 5:231, 1984. 179. Neri G, Steindl K, Mazzei A, et al.: Nonsyndromal overgrowth in males with mild psychomotor delay. Am J Med Genet 79:291, 1998. 180. Moore BD 3rd, Slopis JM, Jackson EF, et al.: Brain volume in children with neurofibromatosis type 1: relation to neuropsychological status. Neurology 54:914, 2000.

525 181. Appleton RE, Bushby K, Gardner-Medwin D, et al.: Head circumference and intellectual performance of patients with Duchenne muscular dystrophy. Dev Med Child Neurol 33:884, 1991. 182. Cusmai R, Curatolo P, Mangano S, et al.: Hemimegalencephaly and neurofibromatosis. Neuropediatrics 21:179, 1990. 183. Cohen MM, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003. 184. Hartel C, Bachmann S, Bonnemann C, et al.: Familial megalencephaly with dilated Virchow-Robin spaces in magnetic resonance imaging: an autosomal recessive trait? Clin Dysmorphol 14:31, 2005.

15.3 Aprosencephaly/Atelencephaly Definition

Aprosencephaly/atelencephaly is the absence of all but remnants of structures derived from the prosencephalon or the telencephalon but with an intact cranial vault. Atelencephaly is considered a less severe form of aprosencephaly. In the latter, both telencephalic and diencephalic structures are involved (Fig. 15-6),1 whereas in atelencephaly, the diencephalic structures have developed but the cerebral hemispheres are either absent or represented by small remnants. The distinction is not absolute, and intermediate forms have been described.2 This author does not consider it useful, at present, to define those cases with a prosencephalic remnant as pseudo-aprosencephaly, thus reserving the term aprosencephaly for examples with no evidence of prosencephalic development.3 Diagnosis

The clinical presentation of aprosencephaly/atelencephaly is that of marked craniofacial disproportion due to extreme microcephaly, prominent supraorbital ridges, a sharply sloping forehead, and an intact cranium that may have redundant scalp folds. In aprosencephaly, there is involvement of structures derived from the diencephalon and of the facial components that are dependent on early prechordal mesoderm. Thus, the optic globes, mammillary bodies, hypothalamus, and posterior pituitary (hypophysis) are abnormal or absent, and the face is similar to the severe end of

Fig. 15-6. Sketch of aprosencephaly showing vestigial prosencephalon and normal cerebellum. A. Prosencephalon remnant. B,C. Cerebellum. (After Laurie et al.5)

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the holoprosencephaly spectrum,1,4,5 including cyclopia with no proboscis and extreme nasal hypoplasia with apparent absence of the ethmoid.4,5 The case reported by Goldsmith et al.6 is unusual in the lack of holoprosencephalic facial features.7 In atelencephaly the eyes are present, palpebral fissures are often upslanting, and there may be hyper- or hypotelorism.8,9 The nose is essentially normal in appearance. An exception was the patient with atelencephaly and a holoprosencephalic face described by Young et al.10 from among a series of patients with sirenomelia. Brain weights of near-term infants have ranged from 8 to 105 g. Those who survive the newborn period may have a highpitched cry, tetraparesis, vomiting, primitive reflexes, and disturbed temperature regulation.4,9 Anterior chamber dysgenesis was reported in one long surviving infant.4 The EEG may not show activity at usual amplification and consists of low-voltage thetadelta activity. Seizures, presumably originating in disorganized diencephalic remnants, have been recorded.11 It may be difficult to confirm the diagnosis with postnatal ultrasound because of a closed fontanel and the short intracranial distances. Prenatal diagnosis of atelencephaly by ultrasound is possible, and it can be distinguished from other causes of abnormal head shape and extreme microcephaly.12–14 Neuroimaging readily demonstrates the absence of cerebral structures, and autopsy can provide confirmation of the specific pathology. In atelencephaly the diencephalon is normal, with a nubbin of tissue representing more cephalad structures, whereas in aprosencephaly there is either no evidence of the prosencephalon3 or a vestigial prosencephalic remnant. The more caudad structures including the cerebellum are usually reported as normal except for some variation in size and shape and the absence of the pyramidal tracts.8,9 However, Harris et al.2 made the interesting observation in their first patient that the cerebellum, which had appeared grossly normal, was histologically virtually unrecognizable and consisted mainly of white matter. Thus, cerebellar anomalies may be more common than previously thought. The two siblings reported by Florell et al.14 both had a grossly abnormal cerebellum and may represent a specific autosomal recessive syndrome. Sergi and Schmitt3 described two cases. In one they found evidence of what they interpreted as a remnant of a collapsed forebrain vesicle, while in the second there was no evidence that the prosencephalon had ever developed, the cerebellum was absent, and there were associated gut anomalies. They argued that the

former case represents an intermediate between aprosencephaly/ atelencephaly and holoprosencephaly, to be called pseudo-aprosencephaly or vesicular forebrain, and that the second example is true aprosencephaly/atelencephaly. Certainly it is important that these types of pathological details are recorded. However, at present there does not appear to be any difference in the types of malformations associated with cases with and without a forebrain remnant, and there does not appear to be any great advantage to further complicating the nomenclature. Atelencephaly and aprosencephaly (inclusive of associated craniofacial signs) may occur in isolation or may be associated with other anomalies. Ippel et al.7 provided a tabular summary of the anomalies and malformations associated with 20 cases of aprosencephaly/atelencephaly from the literature and added one case of their own. If one discounts findings, such as adrenal hypoplasia, which may simply be secondary to the underlying brain pathology, then the types of malformations are similar for the two conditions. A possible exception is congenital heart disease that was noted in four of 11 cases of aprosencephaly but was not reported among the 10 cases of atelencephaly. The concurrence of aprosencephaly and atelencephaly with genital, gut, cardiac, and distal limb malformations has been called the XK-aprosencephaly/ atelencephaly syndrome (Table 15-3). In some cases, associated genital hypoplasia may simply be secondary to the CNS disturbance, particularly of the hypothalamic/pituitary region. In one retrospective study of children with ambiguous genitalia, a significant proportion of males were found to have associated CNS disturbance or malformations.15 Two reports of the XK-aprosencephaly syndrome yet again raise the debate over syndrome nomenclature and ‘‘lumping’’ versus ‘‘splitting.’’ Laurie et al.16 reported a term infant with hypoplastic genitalia and thumbs who had a mildly holoprosencephalic face, normal-sized hydranencephalic cranial cavity, and significant cerebellar pathology. Townes et al.17 described male twins with anencephaly and a female sibling with severe alobar holoprosencephaly. The child with holoprosencephaly was macrocephalic, lacked thumbs, and had three syndactylous digits on both hands. In neither of these reports was the brain malformation that of aprosencephaly or atelencephaly (both are included in the table of Ippel et al.7), but the cases may well represent part of the spectrum of this causally unknown syndrome. Further support for a causal overlap between atelencephaly and holoprosencephaly is provided

Table 15-3. Syndromes with aprosencephaly/atelencephaly Syndrome

Prominent Features

Causation Gene/Locus

Aprosencephalycerebellar dysgenesis14

Absent telencephalon and pyramidal tracts, rudimentary diencephalic and mesencephalic structures, primitive cerebellar hemispheres, evidence of abnormal neuronal migration, retinal dysplasia, normal optic globes, CNS perivascular mesenchymal proliferation; consanguinity

AR?

Holoprosencephaly-fetal hypokinesia18

Extreme IUGR and microcephaly by 2nd trimester, sloped forehead, micrognathia, short neck, flexed elbows, thumbs, hips; extended fingers, knees; lung hypoplasia, severe brain disorganization may include cerebellum, brain stem, and cellular architecture; one case may have had aprosencephaly

XLR

XK-aprosencephaly/ atelencephaly7

Absence deformities of upper limbs ranging from hypoplastic thumbs to absent radial ray; male genitalia hypoplastic to cloacal anogenital opening, imperforate anus, VSD, hypoplastic adrenals, diaphragmatic hernia.

Unknown, one case with r(13)6

Chromosome del(13)(q22;q31)26

One case with atelencephaly; various CNS anomalies including holoprosencephaly, cystic 4th ventricle, agenesis of caudal vermis; coloboma iris/microphthalmus

deletion

Brain

by their occurrence in two cases associated with deletions of 13q (Table 15-3). Molecular confirmation of this overlap comes from the report of a sibship with holoprosencephaly-aprosencephaly/ atelencephaly and a SIX3 gene mutation.28 Hockey et al.18 reported a sex-linked recessive syndrome of fetal hypokinesia, joint contractures, extreme microcephaly, and holoprosencephaly. The brain of one patient was described as lacking the anterior telencephalon, the prosencephalon, and the diencephalon, a condition verging on anencephaly. Labrune et al.19 considered the third of six cases they described with brain and limb defects to have the XK-aprosencephaly syndrome. The brief description described the CNS as resembling a primitive neural tube, with essentially an absent hindbrain and only a few lamellar-like cerebellar structures, again supporting the concept of a spectrum of maldevelopment. In contrast, Siebert et al.20 undertook a careful comparison of the craniofacial features of atelencephaly, anencephaly, and holoprosencephaly and concluded that they probably involved different developmental fields, perhaps related in a hierarchical fashion. They did not have a case of holoprosencephalic facies-atelencephaly for study. A case of syndromic aprosencephaly with cerebellar hypoplasia, a Rathke’s cleft cyst, and an ependymal and pigmented epithelial cyst has been reported.21 It was speculated that the ependymal cyst might be the equivalent of the dorsal cyst of holoprosencephaly. Etiology and Distribution

There has not been any attempt to determine the prevalence of aprosencephaly/atelencephaly. There have been an additional seven cases reported3,19,22–25 since the summary by Ippel et al.,7 for a total of 25, if one excludes the patients of Laurie et al.,16 Townes et al.,17 and Labrune et al.19 It is likely that not all cases are recognized and that some are mislabeled as anencephaly or microcephaly. In the series of 41 patients with prosencephalic malformations studied by Sergi and Schmitt,3 there were 36 that seem to clearly fit the holoprosencephaly spectrum, and two had aprosencephaly/atelencephaly. If holoproencephaly occurs at a rate of about 3/10,000 (see Section 15.4), then an estimate of the prevalence of aprosencephaly/atelencephaly would be 1/60,000. The embryologic origin of aprosencephaly must date from after closure of the neural plate and before division of the prosencephalon into the diencephalon and the telencephalon in the fifth week. Atelencephaly postdates this separation and thus does not involve the eyes and other diencephalic structures. Altered cranial morphology is considered secondary to the underlying brain abnormality. Pathologic studies in a 21-week-old fetus showed rounded, primitive, germinal matrix-like cells that formed rosettes and some heterotopias.12 At term the pathological findings in the prosencephalic remnants have varied. In some there have been the occasional neuron, calcospherites, and gliomesenchymal scar tissue suggestive of a destructive process of unknown etiology.8,9,21 In other cases,3,24 the findings are compatible with arrested development. Harris et al.2 described a proliferative vasculopathy in one of their cases and suggested that this could be a causative, rather than a secondary phenomenon. Most cases have been sporadic, but the presence of concurrent severe cerebellar dysplasia requires that autosomal recessive inheritance be considered. The association of two cases with deletions of 13q suggests deficiency of one or more genes in this region may result in these malformations,6,26 and there is the recent report of a causative, maternally inherited, SIX3 mutation.28 Holoprosencephaly is associated with maternal diabetes, and the fact that the mother of the patient reported by Kajantie et al.25 was a long-standing insulin-dependent diabetic raises the possibility that this illness may also be etiologic in aprosencephaly. Two further

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mothers were exposed to first-trimester radiation, and two had prior induced abortions. Sulik et al.27 provide evidence of straindependent production of holoprosencephaly/aprosencephaly anomalies in presomite mouse embryos exposed to low-dose all-trans retinoic acid, although the conclusions were based upon craniofacial appearance and brain studies were not provided. Prognosis, Treatment, and Prevention

Stillbirth or immediate postnatal death is common, but survival to age 14 months has occurred twice.4,9 Surviving infants make no significant developmental progress and may have temperature instability, seizures, a high-pitched cry, spasticity, and continuation of primitive reflexes. No treatment beyond that required for comfort is indicated. The abnormality may be detected during routine or targeted ultrasound.12–14 Good quality chromosome studies are warranted, especially in the presence of associated malformations. Given evidence for the involvement of 13q it would be of interest to look for disruption and/or deletion of ZIC2 in any subsequent cases. No direct preventive measure is known. References (Aprosencephaly/Atelencephaly) 1. Martin RS, Carey JG: A review and case report of aprosencephaly and the aprosencephaly syndrome. Am J Med Genet 11:369, 1982. 2. Harris CP, Townsend JJ, Norman MG, et al.: Atelencephalic aprosencephaly. J Child Neurol 9:412, 1994. 3. Sergi C, Schmitt HP: The vesicular forebrain (pseudo-aprosencephaly): a missing link in the teratogenic spectrum of the defective brain anlage and its discrimination from aprosencephaly. Acta Neuropathol 99:277, 2000. 4. Adkins WN, Kaveggia EG: Sporadic case of apparent aprosencephaly. Am J Med Genet 3:311, 1979. 5. Laurie IW, Nedzved MK, Lazjuk GI, et al.: Aprosencephaly-atelencephaly and the aprosencephaly (XK) syndrome. Am J Med Genet 3:303, 1979. 6. Goldsmith CL, Tawagi GF, Carpenter BF, et al.: Mosaic r(13) in an infant with aprosencephaly. Am J Med Genet 47:531, 1993. 7. Ippel PF, Breslau-Sideruius EJ, Hack WWM, et al.: Atelencephalic microcephaly: a case report and review of the literature. Eur J Pediatr 157:493, 1998. 8. Garcia CA, Duncan C: Atelencephalic microcephaly. Dev Med Child Neurol 19:227, 1977. 9. Iivanainen M, Haltia M, Lydecken K: Atelencephaly. Dev Med Child Neurol 19:663, 1977. 10. Young ID, O’Reilly KM, Kandall CH: Etiological heterogeneity in sirenomelia. Pediatr Pathol 5:31, 1986. 11. Danner R, Shewman DA, Sherman MP: Seizures in an atelencephalic infant. Arch Neurol 42:1014, 1985. 12. Siebert JR, Warkany J, Lemire RJ: Atelencephalic microcephaly in a 21 week human fetus. Teratology 34:9, 1986. 13. Tick DB, Greenberg F, Reiter A, et al.: Prenatal detection of telencephalic hypoplasia. Proc Greenwood Genet Center 9:127, 1990. 14. Florell SR, Townsend JJ, Klatt EC, et al.: Aprosencephaly and cerebellar dysgenesis in sibs. Am J Med Genet 63:542, 1996. 15. Hunter AGW: Diagnosis in persons referred for cytogenetic studies because of abnormalities of the external genitalia. Proc Greenwood Genet Center 7:136, 1988. 16. Laurie IW, Nedzved MK, Lazjuk GI, et al.: The XK-aprosencephaly syndrome. Am J Med Genet 7:231, 1980. 17. Townes PL, Reuter K, Rosquete EE, et al.: XK aprosencephaly in sibs. Am J Med Genet 29:523, 1988. 18. Hockey A, Crowhurst J, Cullitz G: Microcephaly, holoprosencephaly, hypokinesia-second report of a new syndrome. Prenat Diagn 8:683, 1988. 19. Labrune P, Trioche P, Fallet-Bianco C, et al.: Severe brain and limb defects with possible autosomal recessive inheritance: a series of six cases and review of the literature. Am J Med Genet 73:144, 1997. 20. Siebert JR, Kokich VG, Warkany J, et al.: Atelencephalic microcephaly: craniofacial anatomy and morphologic comparisons with holoprosencephaly and anencephaly. Teratology 36:279, 1987.

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21. Kim TS, Cho S, Dickson DW: Aprosencephaly: review of the literature and report of a case with cerebellar hypoplasia, pigmented epithelial cyst and Rathke’s cleft cyst. Acta Neuropathol 79:424, 1990. 22. al-Gazali LI, Bakalinova D, Bakir M, et al.: XK-aprosencephaly. Clin Dysmorphol 7:143, 1998. 23. Oostra RJ, Baljet B, Verbeeten BW, et al.: Congenital anomalies in the teratological collection of Museum Vrolik in Amsterdam, The Netherlands. III: primary field defects, sequences, and other complex anomalies. Am J Med Genet 80:46, 1998. 24. Kakita A, Hayashi S, Arakawa M, et al.: Aprosencephaly: histopathological features of the rudimentary forebrain and retina. Acta Neuropathol 102:110, 2001. 25. Kanjantie E, Ammala P, Salonen R: A fetus suggesting an extension of the XK-aprosencephaly spectrum phenotype. Clin Dysmorphol 11:299, 2002. 26. Towfighi J, Ladda RL, Sharkey FE: Purkinje cell inclusions and ‘‘atelencephaly’’ in 13q- chromosomal syndrome. Arch Pathol Lab Med 111:146, 1987. 27. Sulik KK, Dehart DB, Rogers JM, et al.: Teratogenicity of low doses of alltrans retinoic acid in presomite mouse embryos. Teratology 51:398, 1995. 28. Pasquier L, Dubourg C, Gonzales M, et al.: First occurrence of aprosencephaly/atelencephaly and holoprosencephaly in a family with a SIX3 gene mutation and phenotype/genotype correlation in our series of SIX3 mutations. J Med Genet 42:e4, 2005

15.4 Holoprosencephaly Definition

Holoprosencephaly is a spectrum of malformations of the midline of the prosencephalon that relates to varying degrees of failure of its sagittal division into the cerebral hemispheres, transverse cleavage into diencephalon and telencephalon, and the horizontal budding of the olfactory bulbs and tracts. Arhinencephaly was the term first used to describe these disorders, but it has largely been abandoned as too specific in its reference to the olfactory system and inaccurate in that the greater part of the rhinencephalon remains intact. The terms holotelencephaly1 and telencephalosynapsy 2 have been advocated, but holoprosencephaly (HPE), coined by DeMyer and Zeman,3 is generally accepted today, notwithstanding the protest that holo is inappropriate because it means ‘‘complete, entire, or perfect.’’4 Arhinencephaly connotes specific absence of the olfactory nerves, tracts, and tubercles, and it may occur as part of the HPE spectrum or as an isolated malformation. Likewise, commissural and septal defects are natural consequences of HPE but also occur on their own and in association with different syndromes and malformations unrelated to HPE. Although classic HPE shows a continuum of severity, discrete categorization into alobar, semilobar, and lobar types is helpful for diagnostic and descriptive purposes, and these terms are in wide use today. The alobar variety may be further classified into pancake, cup, or ball, depending on the degree of development of the forebrain upward to cover the dorsal surface of the holoventricle. In the interhemispheric variant of HPE (syntelencephaly), the basal forebrain, anterior frontal lobes, and occipital regions are normally separated, but there is an abnormal cerebral hemispheric fusion of the posterior frontal and parietal regions, and the Sylvian fissure connects across the midline in most cases.5 Leech and Shuman6 recognized a malformation in which there is a T-shaped telodiencephalic ventricle, agenesis of the septum pellucidum and corpus callosum and, with the exception of the hypothalamic plate, good preservation of diencephalic structures. They proposed that this holotelencephaly resulted from abnormal telencephalic rather than prosencephalic development.

It has been suggested that a classification that considers the degree of separation of the deep gray nuclei and associated CNS anomalies may provide an improved correlation with clinical outcome,7 and it is anticipated that the descriptive anatomical classification of HPE will be supplanted once the molecular basis of HPE is fully understood.8,9 Diagnosis

Holoprosencephaly is thought to occur because of defective induction of the rostral neural tube by the prechordal mesoderm and mesio-basal forebrain or as a result of excessive cell death in this region.10,11 The forebrain hypoplasia that leads to HPE is mirrored in a continuum of midline facial anomalies ranging from cyclopia without a proboscis to a small forehead with hypotelorism (Figs. 15-7 and 15-8). Kjaer and Fischer Hansen12 demonstrated that all HPE-associated craniofacial malformations were related to a triangle bounded posteriorly by the sella tursica and antero-laterally by the orbits. The severity of the facial malformations correlated with the severity of the underlying skeletal changes. The correlation of facial anomalies with HPE is not absolute but, unlike cases involving any other intracranial malformation, the majority of cases of HPE can be diagnosed by physical examination. An understanding of the facial spectrum is therefore paramount.13,14 Cyclopia is the most severe malformation and consists of a single midline orbit that can be anophthalmic, monophthalmic, or contain synophthalmic ocular structures (see Fig. 15-8A). A proboscis, representing remnants of nasal structures, is usually present and situated above the orbit. Ethmocephaly is the least common facial subtype and consists of a proboscis separating severely hypoteloric orbits, usually with marked microphthalmia (Fig. 15-9). Both ethmocephaly and cyclopia display trigonocephaly and predict alobar HPE. In cebocephaly a small, flattened nose with a single nostril is situated below hypoplastic, hypoteloric orbits (see Fig. 15-8C). Less severe in the spectrum (see Fig. 15-8D) is median cleft lip, called by some premaxillary agenesis. In fact, even in the more severe forms, in which there is no median cleft because the midface hypoplasia allows midline fusion of the maxillary processes, the lateral maxillary incisors may be present, suggesting that the lateral nasal processes participate in the midline fusion.15 In this condition the nose is small and flat, and there is hypotelorism and often trigonocephaly.

Fig. 15-7. Spectrum of facial anomalies in holoprosencephaly.

Brain

529

Fig. 15-8. A. Cyclopia with unitary ocular structure in a newborn infant. Note absence of all nasal structures. (Courtesy of Dr. C.I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.) B. Cyclopia with synophthalmia of the ocular structures and proboscis. (Courtesy of Dr. C.I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.) C. Typical

facial appearance of cebocephaly. D. Eighteen-month-old male infant with holoprosencephaly. Facial features include hypotelorism, upslanted palpebral fissures, and premaxillary agenesis. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Both cebocephaly and median cleft lip are usually associated with alobar HPE, but milder brain involvement is also seen. There are exceptions to the strong correlation between these severe (cyclopia-cebocephaly) facial anomalies and the presence of HPE. Cohen6 used the data of Roach et al.16 to state that severe HPE is associated with a diagnostic face 80% of the time. There may have been ascertainment bias in these data due to the

presence of facial anomalies, which could lead to a correlation that is somewhat higher than might occur if all cases of HPE could be ascertained. The converse, cases with craniofacial signs suggestive of HPE but with normal brains or different brain anomalies, have also been reported.7,17–19 This variability likely results from differences in the timing and/or specificity in the timing of the embryologic disturbance. For example, the three siblings with

530

Neuromuscular Systems

Fig. 15-9. Facial photograph of an infant showing the unusual combination of ethmocephaly and agnathia.

a normal facial appearance and alobar holoprosencephaly reported by Barr and Cohen20 suggest a gene acting on the prosencephalon, but either sparing the origin of the frontonasal and mesencephalic neural crest cells or acting after their separation. Several minor craniofacial anomalies may be seen alone or in combination with HPE, and although the strength of the association with HPE is less, they may still serve as important markers in family studies or to direct investigations in a child with developmental delay. Premaxillary agenesis (PMA) was discussed as part of the HPE craniofacial spectrum, but this anomaly is well described in otherwise normal, or developmentally delayed, individuals without HPE. Cohen21 has stressed that, in the absence of HPE, patients with PMA have a normal OFC and intraocular distances. The association of a single maxillary central incisor (SCMI) with HPE has received particular attention because it can occur as a form fruste of HPE in families with autosomal dominant HPE.22 SCMI is a common finding in association with congenital nasal pyriform aperture stenosis (CNPAS), which is itself often seen in HPE. SCMI and CNPAS may occur alone or together in otherwise normal individuals, although there is a strong correlation with their presence and short stature, and functional and structural pituitary anomalies.23 Of 51 cases of SMCI and/or CNPAS reviewed by Lo et al.,23 only one patient had documented HPE, although four other families (six cases) had a positive family

history of HPE. The finding of a missense mutation in sonic hedgehog (SHH), which has not been reported in full-blown HPE, raises the possibility that certain mutations may mildly disrupt this pathway and thus represent a mild expression of HPE. Kjaer et al.24 studied the palatal structure in 11, mostly alobar, fetuses with HPE who had facial signs ranging from cyclopia to mild philtral (short) anomalies. The premaxilla, including the primary portion of the hard palate, was abnormal in all cases. Although a study of brains of children ascertained through the palatal anomalies has yet to be reported, this may prove to be a useful craniofacial marker of HPE. Martin and Jones25 found that the superior labial frenulum was absent in 88% (15/17) of cases distributed across the HPE craniofacial-brain spectrum. Presence of the frenulum was associated with presence of the philtral pillars; when present in HPE, the frenulum may be abnormally thick. There are no data as to the occurrence of this anomaly in the general population or in other CNS anomalies. Other less severe facial abnormalities that may accompany HPE but are not pathognomonic include trigonocephaly, small forehead and microcephaly, hypotelorism, small and flat nose, and unilateral cleft lip.26 Hypertelorism is often mentioned as accompanying HPE, but Fitz27 states that mention of hypertelorism as being associated with HPE is based on a statement by DeMyer and Zeman3 that it might occur and that he was unaware of any actual reports. However, Jellinger et al.,28 from a retrospective review of autopsies, reported that two of eight cases of semilobar and one of nine of lobar HPE were hyperteloric. No measurements or photographs were provided, and, in the absence of some secondary phenomenon like hydrocephalus, it is difficult to account for hypertelorism with any of the current embryologic theories of HPE. One patient with HPE and hypertelorism had facial involvement with the amniotic band syndrome, which may have led to the hypertelorism.29 Some of the syndromic HPEs listed in Table 15-4 may include hypertelorism. Fitz27 has said that, in the absence of the typical facial appearance of HPE, patients with HPE and trigonocephaly do not have a closed, sclerotic, metopic suture as is seen in primary craniosynostosis. He therefore recommended against investigating otherwise normal-appearing children with craniosynostotic trigonocephaly to rule out HPE. Ben-Hur et al.18 reported relatives of patients with HPE who had midline cleft and bifid uvula. However, until relatives who have only bifid uvula are reported with recurrence of HPE, it remains speculative as to whether relatives of patients with HPE, who themselves have bifid uvula, are at risk to bear children with HPE. Hypotelorism, anosmia, and endocrine dysgenesis have also been reported in relatives of patients with HPE. Hypognathia/agnathia is a rare malformation that can occur by itself, but has some propensity to be associated with HPE and midline visceral anomalies.13 Most patients with HPE do not have agnathia, and there is no apparent correlation between the severity of the mandibular underdevelopment and that of the brain. However, the appearance of the upper midface retains its predictive value with respect to the prosencephalon. Cyclopia without a proboscis is the most common form of HPE that accompanies agnathia.13 The patient illustrated in Figure 15-9 is, thus, unusual in that he illustrates ethmocephaly, the least common form of HPE face, in association with agnathia. In the absence of clinical hypognathia, Mieden15 found abnormalities of muscle anatomy in the areas derived from the first and second branchial arches in cases of HPE, supporting the view that the overall spectrum of facial anomalies reflects the severity and

Table 15-4. Syndromes with holoprosencephaly/arhinencephaly Syndrome

Prominent Features

Causation Gene/Locus

Acalvaria-HPE-facial dysmorphism48

Absent frontal, parietal, squamous, temporal, and occipital bones above cranial fossa; short neck; hypertelorism; downslanting palpebrae; mild proptosis; oblique lateral facial cleft; abnormal auricles; no cephalic dysraphism

Unknown

Agnathia-tetrameliaholoprosencephaly49

Severe micro/tetramelia, cardiovascular anomalies, imperforate anus, cystic dysplastic kidney. Single case

Unknown (202650)

Aicardi50

Varied CNS pathology, typically agenesis of corpus callosum and heterotopias; hemivertebrae; pathognomonic chorioretinal lacunae; bilateral asynchronous hypsarrhythmia

XLD male lethal (304050) Xp22

Aqueductal-stenosis51

Single patient with cebocephaly and aqueductal stenosis; two maternal half-sibs with hydrocephalus. Chance concurrence, occasional manifestation of gene, or different gene/allele?

XLR (307000?) L1CAM?, Xq28?

Beemer-Langer: short ribbed polydactyly52

Lethal short rib dwarfism; hydrops, flat face, epicanthus, midline cleft lip, stenotic ear canals, short neck, nuchal edema, omphalocele, small penis, fused labioscrotal folds, minimal bowing femora and marked of radius and ulna; case reported with holoprosencephaly and Dandy-Walker cyst

AR (269860) 17q21?, 17q23?

Brachial amelia-cleft lip/ palate53

Large for gestational age, marked macrocephaly, right coloboma, small fixed left pupil, bilateral cleft lip, hydrocephalus, absent basal ganglia, ‘‘fused’’ cerebral hemispheres; single case

Unknown

Brancho-oto-facial-CNS54

Bilateral cleft fistulae, holoprosencephaly, encephalocele, microphthalmia, heart defect, facial anomalies; single case

Unknown

BRESHECK55

Microhydrocephaly with fused thalami, growth failure, mental retardation, alopecia, scaling skin, Hirschsprung, cleft palate, renal anomalies, microphthalmia

AR or XLR

Camptodactyly-whistling face56

Severe developmental delay, polyhydramnios, hypotonia, cleft palate (4/8), whistling face (8/8), early lethal, microscopic brain and muscle calcification, camptodactyly; case with holoprosencephaly and vermis hypoplasia

AR

Caudal regressionholoprosencephaly57

A heterogeneous spectrum of imperforate anus, sacral agenesis, sirenomelia reported associated with holoprosencephaly; see also Maternal diabetes

Chromosomal (63%), sporadic

Cerebro-oculo-nasal58

Macrobrachycephaly, craniosynostosis, low-set ears, anophthalmia, midline nasal groove, nasal skin appendages, single maxillary central incisor, agenesis of the corpus callosum, hydrocephalus, frontal encephalocele, evidence of holoprosencephaly weak

Unknown

CHARGE59

Choanal atresia, congenital heart defects, growth failure, mental retardation, hypoplastic genitalia, deafness, external ear anomalies; over half with CNS anomalies including holoprosencephaly/arhinencephaly, absent corpus callosum, septal agenesis, migrational defects

AD (214800), CHD7, 8q12.1

Chromosome abnormality60–63

Trisomy 13, 18, 20, 21, 22 X; mosaic trisomy 8, 15; duplication 3p, 6q, 11q, 14(pterq24), 22q; deletion (1)(q42/q43-qter), 2p21, (7)(pter-q32), 5q, 7(q34-qter); 11q, 13q, 14q, 18p, 21(q22.3), (22)(pter-q11), X(p11) mosaic; dup 5q del 5p; dup 5q, 9p, 11q, 13q; unbalanced t(6;18); iso 18p; ring 6, 21; triploidy. Phenotype variable depending on the chromosome imbalance.

Chromosome imbalance

Diabetes insipidus-colobomaholoprosencephaly64

Alobar holoprosencephaly, pituitary present, diabetes insipidus of unknown cause, unilateral coloboma; single case

Unknown

Ectopia cordis-embryonal neoplasms61

Complex cardiac anomalies, neuroblastoma, germ cell tumor of the ovary, cleft lip (alobar HPE)

Unknown

Familial isolated14,65

‘‘Non-syndromic’’ HPE with spectrum from normal facies to cyclopia, variation may be marked within families; lateral cleft lip suggested as microform in one kindred

AR (236100) HPE1, 21q22.3 HPE2 SIX3, 2p21 HPE3 SHH, 7q26 HPE4 TGIF, 18p HPE5 ZIC2, 13q32 HPE6, 2q37 HPE7 PTCH, 9q22.3 GLI2, 2q14 TDGF1, 3p23-p21 FAST1, 8q24.3

Holoprosencephaly þ/ Arhinencephaly

(continued)

531

Table 15-4. Syndromes with holoprosencephaly/arhinencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Microcephaly, narrow palpebrae, smooth philtrum, thin upper lip; CNS anomalies include agenesis of the corpus callosum, cavum septum pellucidum, ventriculomegaly, hypoplasia of inferior olivary eminences, small brain stem, migrational abnormalities; holoprosencephaly an occasional finding with severe abuse Unproven association; 35-week-old infant with malformed ears, microphthalmia, diaphragmatic hernia, costo-vertebral, and severe brain malformations. Immunohistochemical evidence of influenza virus antigens in the brain

In utero exposure

Genoa: holoprosencephalycraniosynostosis68

Semilobar holoprosencephaly, craniosynostosis, facial asymmetry, hypotelorism, upslanting palpebrae, nonspecific retinal pigmentation, hypoplastic terminal phalanges, cone-shaped epiphyses, slender long bones, slightly small vertebral bodies

AR? (601370)

Grote: octodactyly-cardiac anomalies69

Microphthalmia, downslanting palpebrae, median facial agenesis, microstomia, low-set and posteriorly rotated ears, tetramelic octodactyly, absent tibia, complex cardiovascular anomaly, renal hypoplasia, gut malrotation

AR? Consanguinity

Hartsfield: ectrodactyly-cleft face70

Proportional IUGR, abnormal hair pattern, cranial asymmetry, closed metopic and coronal sutures, supraorbital skull defects, hypertelorism, microphthalmia, low rotated ears, asymmetric digital absence in hands and feet (lobar HPE)

Unknown

Holoprosencephaly-DandyWalker71

Several case reports of holoprosencephaly and concurrent Dandy-Walker cyst; two in association with interstitial del 13q

Unknown, del 13q

Holoprosencephaly-endocrine dysgenesis72

Premaxillary agenesis, micropenis, absence of pituitary tissue, variable adrenal hypoplasia, hypoinsulinism; one sib with posterior ventricular cyst; may be an underdiagnosed association

AR (236100)

Holoprosencephaly-fetal hypokinesia73

Extreme IUGR and microcephaly by second trimester, sloped forehead; micrognathia; short neck; flexed elbows, thumbs, hips; extended fingers, knees; severe brain disorganization may include cerebellum, brain stem, and cellular architecture. One case with possible aprosencephaly

XLR (306990)

Holoprosencephalyhypothalamic hamartoma74

Probably heterogeneous and overlapping Pallister-Hall; hypothalamic hamartoblastoma, frontonasal dysplasia, nasal probosci, microphthalmia, megalocornea, corneal clouding, cleft palate, cardiac anomalies, absent cribriform plate, agenesis of corpus callosum, arhinencephaly to lobar holoprosencephaly

Unknown

Holoprosencephaly-NTDnerve palsy-deafness75

Three sibs, one with cyclopia, one with meningomyelocele, one hypoteloric with deafness, branchial tag, and abducens palsy. Others have reported these types of findings in relatives.

AR?

Holoprosencephaly-transverse limb defect76

Flat nasal bridge, bifid nasal tip, prominent philtral pillars, high and narrow palate, nuchal thickening, four limb terminal transverse defects, small penis, alobar holoprosencephaly, heterotopic neurons; similar to brachial amelia syndrome

Unknown

Hydantoin, prenatal77

Mild developmental delay, short nose with broad base, telecanthus, ptosis, short neck, wide mouth, developmental delay, distal digital hypoplasia. One case with holoprosencephaly may be chance concurrence.

In utero exposure

Lambotte: microcephaly-facial anomalies78

IUGR; lethal; telecanthus/hypertelorism, large pinnae, hooked nose, narrow mouth, severe mental retardation; variable anterior chamber and cardiac anomalies and polydactyly; cryptic t(2;4)(q37.1;p16.2)

Partial trisomy 2q, monosomy 4p

Lip synechia-imperforate anus79

Lobar HPE in a patient with soft tissue bands between upper and lower lips, absent external ears, cleft palate, camptodactyly of second finger, diastematomyelia, tricuspic atresia

Unknown

Majewski variant chondrodysplasia80

Micromelic lethal dwarfism, tibias especially short, narrow chest with short and horizontal ribs, flat vertebrae, hypoplastic pelvis, pre- and postaxial polydactyly hands, hexadactyly feet, short rounded long bones, visceral anomalies. Single case with cebocephaly.

AR (263520)

Martin: midline clefting skeletal anomalies81

Mental retardation, microcephaly, hypotelorism, downslanting palpebrae, high cleft palate, cleft lip, partial/complete premaxilla agenesis; nose variably flat and deviated, large or small; talipes equinovarus; vertebral fusions; scoliosis; sacral agenesis (variable with incomplete penetrance)

AD (157170) Considered to be HPE2 SIX3, 2p21

Maternal diabetes82

Higher rate of NTDs, cardiac defects (specifically transposition), sacral agenesis, proximal focal femoral deficiency; HPE a rare complication

In utero exposure

Maternal phenylketonuria83

IUGR, microcephaly, developmental delay, seizures, epicanthus, long and poorly modelled philtrum, anteverted nares, heart malformation

Poor control of maternal PKU

66

Fetal alcohol

Fetal influenza66

In utero infection

(continued)

532

Table 15-4. Syndromes with holoprosencephaly/arhinencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Spectrum of CNS anomalies; occipital encephalocele, HPE, hypoplastic cerebellum, micro/polygyria; microphthalmia, polydactyly, cystic kidneys and liver, hypoplastic genitalia, cleft palate

AR (249000) 8q24, 11q13, 17q22-q23

Meckel-like-Donnai85

Lobar holoprosencephaly, cebocephaly, encephalocele, post-axial polydactyly, renal cortical cysts, bilobed lungs, hypoplastic cerebellum; consanguinity

Unknown

Meckel-like-Fried86

Microcephaly, occipital meningoencephalocele, short neck, thumb hypoplasia/ absence, abnormal bones in forearm, unilateral 2-3 finger syndactyly, complex heart anomaly, hemiuterus, kidney normal (lobar HPE)

Unknown

Median cleft face-other anomalies87

Median cleft of nose þ/ lip and palate notched alae, nasal tip may be present in some, hypertelorism, cranium bifidum, widow’s peak. Cases reported with holoprosencephaly and with absent corpus callosum and arhinencephaly.

Unknown

Pallister-Hall88

Bathrocephaly, large fontanel, hypothalamic hamartoblastoma, hypopituitarism, auricular anomalies, multiple frenulas, natal teeth, asymmetric limb shortness, polydactyly, syndactyly; larynx, lung, heart, vertebral, and anal malformations

AD (146510) GLI3, 7p13

Pseudotrisomy 1389

HPE with postaxial hand hexadactyly, heart defects, normal kidneys, normal chromosomes; all sporadic cases

AR? (264480)

Seller: cerebellar hypoplasiafacial dysmorphism90

Varied intrafamilial spectrum; high and receding forehead, low-set ears, hypertelorism/hypotelorism, absent external nares, thick and overhanging upper lip, small jaw, cardiac defects, dilatated ileum, cerebellar hypoplasia

AR

Severe Nager-like acrofacial dysostosis91

Very small and malformed pinnae, eyelid colobomas, micrognathia, lateral oral clefts, cleft lip, short forearms with absent thumbs, lower limb phocomelia. Case with single nostril, left cryptophthalmos, absent mandible, finger-like arms, and HPE.

Unknown (154400)

Short rib-polydactyly, Martinez-Frias type92

Pre- and postaxial polydactyly, syndactyly, cleft lip, abnormal genitalia; hydrocephalus; holoprosencephaly; relationship to other SRP syndromes unclear

AR

Smith-Lemli-Opitz93

Postnatal growth failure, mental retardation, narrow forehead, ptosis, epicanthus, broad anteverted nasal tip, broad alveolar ridges, micrognathia. Severe end of spectrum has more marked genital and internal anomalies, and postaxial polydactyly.

AR (270400) DHCR7, 11q12-q13

Steinfeld: absent thumb-short forearm94

Family had consistent thumb and variable other upper limb reduction anomalies; sibs had dysplastic kidney, absent gall bladder, congenital heart defect. HPE in propositus chance or part of syndrome?

Uncertain (184705)

Trilobar holoprosencephalylimb defects95

Lobar HPE, right accessory frontal lobe containing an encephalomeningocele that protruded frontally; hypertelorism, median facial cleft; finger and toe anomalies

Unknown

Turner: XLMR-macrocephaly96

Moderate X-linked mental retardation, macrocephaly in males and some carrier females; holoprosencephaly a possible expression of the gene in males

XLD Xp21-q21

Velo-cardio-facial97

Developmental delay, long narrow face, receding chin, prominent nose with wide and prominent bridge, narrow nasal tip and hypoplastic alae, thin hands, short stature, cardiac anomalies (ventricular septal defect, tetralogy of Fallot, right-sided aorta), microcephaly (HPE rare)

Del 22q11 (192430)

Zlotogora-Dagan: thumb anomalies98

IUGR, growth and developmental delay, aplastic or malpositioned thumb, amenorrhea, azoospermia, some with skin hyperpigmentation, occasionally other anomalies, including case with holoprosencephaly

Uncertain

Acrofacial dysostosis, Rodriguez type99

Severe and lethal acrofacial dysostosis, prominent nasal bridge, severe micrognathia, microtia, severe pre- and milder postaxial limb reduction, atrial and ventricular septal defects, shoulder girdle and pelvis hypoplasia

AR

Anosmia-alopecia-deafness100

Protruding ears, microtia, atresia of the otic canal, conductive deafness, total or partial alopecia, dental caries, small jaw, retardation, congenital heart defect, some cases of anosmia

AD (147770)

Anosmia-hypogonadotropic hypogonadism101

Variable expression of the two major hypogonadotropic components of the syndrome; some evidence of increased clefting, diabetes, and perhaps renal anomalies in patients and relatives. Most families interpreted as AR but some have distant partially affected relatives (see text).

XLR (308700) KAL1, Xp22.3 AD (147950) KAL2, FGFR1, 8p11.2-p11.1 AR (244200)

Anosmia-hypogonadismbrachytelephalangy102

Square forehead, hypertelorism, small nose, thin upper lip, flat philtrum, bifid scrotum, depigmented skin spots in adolescence, short stature, short broad toes.

AD or XLD (113480)

Meckel-Gruber

84

Arhinencephaly

(continued)

533

Table 15-4. Syndromes with holoprosencephaly/arhinencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Anosmia-ichthyosishypogonadism103

Signs of hypogonadotropic hypogonadism with small penis, undescended small testes, developmental delay, decreased ACTH reserve, hypoplastic kidney. No data on brain structure.

XLR, possibly contiguous gene syndrome

Anosmia-radiohumeral synostosis61

Pierre Robin anomaly, anosmia, radiohumeral synostosis. CNS pathology unknown.

Unknown

Baller-Gerold: craniosynostosisradial aplasia104

Craniosynostosis; small and malformed ears; variable radial ray hypo/aplasia, carpal and metacarpal defects, shortness and curvature of ulna; brain abnormalities include hypoplasia of the olfactory bulbs and tracts

AR (218600)

Campomelic dysplasia105

Wide fontanels/sutures, hypertelorism, flat nasal bridge, small mouth/jaw, cleft palate, bowed femora/tibias, broad distal phalanges, small chest, 11 ribs, hypoplastic scapulae, wide spaced ischia and vertical ilia, sex reversal

AD (114290) SOX9, 17q24.3-q25.1

Campomelia-cystic renal dysplasia106

Four limb shortness and campomelia; dysplastic kidneys, pancreas, and liver; polysplenia; cervical lymphocele; short gut; cleft palate; vertebral anomalies; may be associated with polysplenia and heterotaxia

AR (211890)

Carpenter-Hunter: micromeliapolysyndactyly107

Severe short-limbed dwarfism, encephalocele, marked hypertelorism, microphthalmia, absent external nares, cleft palate, micrognathia, narrow chest, cardiac malformation, cystic dysplasia of the kidneys and pancreas, post-axial polydactyly of hands and feet, duplicated tibia, hydrocephalus, pachygyria

Unknown

Chromosome abnormality61

Duplication 1q, 6p, 6q, 16q; isochromosome 12p; 49,XXXXY

Chromosome imbalance

Cloverleaf skull-polydactyly

Low-set ears, small and downturned mouth, duplicate thumb, small fifth fingers, limited knee extension, micropenis, bifid scrotum, bilobed lungs, polymicrogyria, hypoplastic frontal lobes

Unknown

Craniosynostosis-bifid thumbmicropenis109

Craniosynostosis, clover-leaf skull, low-set ears, hypotelorism, prominent eyes, epicanthus, short and anteverted nose, bifid thumbs, small 5th finger, limited extension at the knees, bilobed lungs, polymicrogyria, hypoplastic frontal lobes, Chiari malformation

Unknown

DiGeorge association110

Variable spectrum of absent parathyroids and thymus, cardiac defects of left and right fourth branchial arch origin, persistent truncus arteriosis, hypertelorism, micrognathia, other visceral anomalies

Heterogeneity most sporadic some AD, some del 22q11,10p13, 17p13 (188400) AR?

DK-phocomelia with thrombocytopenia111

Occipital encephalocele, absent corpus callosum, variable upper limb and digital absence anomalies, hypoplastic thumbs, thrombocytopenia/reduced megakaryocytes, renal agenesis to milder defects, vaginal atresia, other variable brain anomalies

Case with del(13q) (223340)

Fitch: diaphragmatic herniacardiac anomalies112

Triangular face, hirsute forehead, low nasal bridge, absent 5th finger nails, nail hypoplasia, absent left hemidiaphragm, communicating hydrocephalus, absent corpus callosum, olfactory bulbs and tracts; consanguinity

AR?

Fryns: acral-cornealdiaphragmatic113

Coarse and hirsute face, abnormal pinnae, corneal clouding, broad and flat nasal bridge, large nose, short upper lip, cleft lip/palate, small jaw, distal phalangeal and nail hypoplasia, diaphragmatic defects, gut malrotation and/or atresia; CNS malformations include agenesis of the corpus callosum and heterotopias

AR (229850) 1q?, 6q?

Goldenhar114

Varying asymmetry of lower face, mandible hypoplasia, microtia, preauricular pits and tags, macrostomia, cervical spine and cardiac anomalies; most patients have no CNS signs or anomalies, but variety including arhinencephaly reported. Some with Townes-Brock spectrum have SALL1 mutations.

Sporadic, occasional AD (164210) 14q32

Holmes: brain malformationfetal hypokinesia115

Polyhydramnios and fetal hypokinesia in pregnancy, wide cranial sutures, telecanthus, narrow palpebrae, micrognathia. One brother with absent corpus callosum and other with arhinencephaly; spectrum of holoprosencephaly-fetal hypokinesia.73

XLR?

Hypoplastic right heart116

One of a cluster of 14 infants with right-sided heart anomalies had arhinencephaly; 10 were microcephalic; other anomalies included cleft palate, micrognathia, and low-set ears

Unknown

Hypothalamic hamartomamicrophthalmia-radial ray117

Hypothalamic hamartoma, microphthalmia, ectopic retinal pigment layer, flat nose, absent/hypoplastic thumb, gut malrotation, small stomach, asplenia, abnormal genitalia; related to microgastria-limb reduction syndrome?

Unknown

Ivemark: asplenia/ polysplenia118

Complex cardiac defects, poly/asplenia abnormal pulmonary and/or abdominal situs; cases reported with agenesis of the corpus callosum, Dandy-Walker cyst, absence of the anterior pituitary and olfactory tracts

AR (208530) AD and sporadic 12q13, 6q21-q24

108

(continued)

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Table 15-4. Syndromes with holoprosencephaly/arhinencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

170

Kallmann

Hypogonadotropic hypogonadism, anomsmia, some cases with additional somatic findings; KAL1 on Xp is anosmin; KAL2 (AD) on 8p is loss of function of FGFR1

XLSD (308700) KAL1, Xp22.3 AD (147950) FGFR1, 8p11.2 AR (244200)

Lateral proboscis-cleft lip/palate119

Unilateral absent nose with blind-ending proboscis and ipsilateral arhinencephaly; cleft lip/palate occur; may have oblique facial cleft with proboscis external to eye

Unknown

Leptomeningeal angiomatosiscleft lip120

Mild hydrops, small and posteriorly rotated ears, overfolded helices, cleft lip/palate, hypoplastic left heart, leptomeningeal angiomatosis, absent septum pellucidum, absent olfactory tracts, hypoplastic corpus callosum. Single case.

Unknown

Melnick-Needles121

Small facial bones, prominent eyes, small chest, thin ribs, short arms and distal phalanges, males severely affected and stillborn; case reported with arhinencephaly, ocular dysplasia, skull hypoplasia

XLD (309350) FLNA, Xq28

Microgastria-upper limb reduction122

Microgastria, variable upper limb defects, asplenia/splenogonadal fusion; case reports in association with iris coloboma, orbital cyst, fused thalami, arhinencephaly, agenesis of corpus callosum, several internal anomalies, hypothalamic hamartoma; anophthalmia and porencephalic cyst

Unknown (156810)

Mohr-Majewski: oro-facialdigital type IV123

Severe abnormalities of epiglottis, tongue, and larynx; cystic kidneys, gut malrotations, hepatic fibrosis, arhinencephaly, neuronal migrational defects in patient within gamut of OFD II and short rib-polydactyly II

AR (258860)

Ptosis-coloboma-mental retardation124

Arhinencephaly, prominent nose, hypertelorism, microphthalmia, aniridia, retinal dysplasia, persistent primary vitreous, cleft palate, omphalocele, accessory spleen; cousin with some signs

AR/XLR

Rubinstein-Taybi125

Mental retardation, short stature, downslanting palpebrae, hypoplastic maxilla, narrow palate, beaked nose with extended septum, abnormal pinnae, broad angulated thumbs and halluces; arhinencephaly appears an uncommon occurrence

AD (180847) CREB binding protein, 16p13.3

Varadi: oro-facial-digitallike126

Pre- and postnatal growth failure, duplex hallux, bifid third metacarpal, cleft lip/ palate, lingual nodule, renal hypoplasia, cryptorchidism, absent cerebellar vermis, absent olfactory bulbs and tracts

AR (277170)

Winter-Wigglesworth127

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, poorly formed hemispheres; microscopic renal changes

Unknown

Wollcot-Rallison: epiphyseal dysplasia-diabetes128

Spondyloepiphyseal dysplasia, onset of diabetes mellitus in early infancy, shortened middle and distal phalanges, cone-shaped epiphyses of the proximal phalanges, small irregular carpal centres with ivory epiphyses; autopsied case showed endocardial fibroelastosis, laryngeal stenosis, hypoplastic pancreas

AR (226980)

X-linked laterality sequence129

Variable situs inversus of viscera and heart; congenital heart anomalies, polysplenia, asplenia, sacral/anal malformation. One of eight studied had arrhinencephaly, and one a meningomyelocele. Also autosomal dominant and recessive forms.

XLR (306955) ZIC3, Xq26.2 AD (601086), AR (605376) EBAF, 1q42.1 CFC1. Chr 2 CRELD1, 3p25.3 ACVR2B, 3p22-p21.3 NKX2-5, 5q34

Chromosomal130

Hypertelorism and ectrodactyly in a child with a de novo, apparently balanced translocation

t(2;4)(q14.2;q35)

Ectrodactyly-cleft lip/palate131

Bilateral cleft lip/palate, hypertelorism, microtia. Reported as a case of Hartsfield syndrome,70 but latter cases stated to have lobar HPE.

Unknown

Midline Inter-hemispheric Variant

scope of interference with the facial neural crest derivatives. With the exception of the two siblings reported by Pauli et al.,30 who likely both had an unbalanced 46,XX,der(18)(6;18) karyotype, all cases of agnathia have been sporadic, and it has yet to be included in the spectrum of HPE of known etiology. The majority of patients with HPE have some facial dysmorphia that suggests the diagnosis and leads to appropriate neuroimaging studies. In those with a normal face or nonspecific

signs, developmental delay and/or seizures lead to further investigation. Neuroimaging with MRI or good quality CT (slices  5 mm) will demonstrate the single ventricle (holosphere) and allow delineation of the severity of the HPE. The arterial pattern in arhinencephaly is normal, whereas in HPE the circle of Willis is incomplete with the anterior component replaced by uni- or bilateral branches from the internal corotids.31 Expected angiographic findings have been summarized by Fitz.27 Routine skull

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Fig. 15-10. The pathologic subtypes of alobar holoprosencephaly.

radiographs may demonstrate hypotelorism, absent nasal septum and ethmoid sinuses, and a small sella turcica.27 In alobar HPE no midline fissure separates the cerebral hemispheres, and there is no evidence of temporal or occipital horns; the third ventricle is absent, although it may be represented by a midline groove in the fused thalami. Brain weight is in the range of 100 g, but microcephaly is less common than in the less severe forms of HPE, probably because of a frequent accompanying hydrocephalus.7 A small case study has suggested a correlation between the size of the middle cerebral peduncle and the presence or absence of the cortico-ponto-spinal tract (CPST) with the severity of HPE; the CPST is absent in the alobar form.32 The specific radiologic appearance is further modified by the relative development of the frontal lobe (Fig. 15-10). In the pancake form (the most severe) the dorsal ventricular surface consists of a thin membrane and generally a dorsal cyst (vide infra). With further growth of the brain, the fused thalami are larger and the more developed brain partially covers the dorsal cyst, giving rise to the ‘‘cup’’ variant (Figs. 15-10 and 15-11). In the ball variety there is no dorsal cyst, and the prosencephalon is covered by cortex. The subarachnoid space may be very large (Fig. 15-10).27 In semilobar HPE a partial interhemispheric fissure separates the posterior cerebral hemispheres, and temporal horns have developed. However, the inferior monoventricle adjacent to the fused thalami in the alobar form may give the impression of temporal Fig. 15-11. Cup-type alobar holoprosencephaly.

horns; thus, accurate distinction between semilobar and alobar forms is based on other findings. These include a rudimentary third ventricle, the beginning of sagittal separation as evidenced by a downward indentation of the dorsal roof, separate occipital horns, and variably developed posterior fissure and falx.27 The cerebral cortex is continuous across the midline below the interhemispheric fissure.8 Lobar HPE is most likely to be misdiagnosed or missed because the interhemispheric fissure can be deep and virtually complete. Shallowness anteriorly may be detectable, and there is an area, which may be small, of visible continuity of the frontal cortex at the extreme rostral/ventral region.8,27 The lateral ventricles are closely apposed and have a narrow appearance. When adequately visualized in a coronal view, the fused anterior horns have somewhat squared borders and a flat roof. In some cases there may be a well-developed corpus callosum contiguous with a small posterior portion of normally divided cerebral hemispheres, but most of the antero-posterior axis continues to show continuity of the cerebral cortex across the midline with absence of the corpus callosum.8 The septum pellucidum is absent. Abnormalities of gyral, sulcal, and basal ganglia appear to show broad correlation with the severity of HPE. Cortical thickness appears to be normal across the spectrum of HPE.33 Gyral pattern and sulcal depth are normal in most patients with lobar and semilobar HPE; but with increasing severity (alobar) there is an increasing prevalence of shallow sulci, often associated with subcortical heterotopias, and abnormal gyral patterning.8,33 With increasing severity the Sylvian fissure becomes displaced in an antero-medial direction and is absent in the most severe cases.33 There is a decreasing gradient of gyral and cytoarchitectural abnormality in an antero-medial to postero-lateral direction.8,9 There is a consensus that primary defects of radial cell migration are uncommon, and it has been suggested that the more commonly observed anomalies of cortical organization are secondary to injury or result from abnormal cortical neuronal connections.8 Judas et al.34 found a normal six-layered neocortex in a patient with semilobar HPE due to 18pbut subtle changes in the cytoarchitecture were seen. The most striking change was an increased cell-body size and total basal dendritic length in the layer III pyramidal neurons. Modern neuroimaging is adding to our understanding of the involvement of the deep gray nuclei in HPE.8,35 It appears that the hypothalmus is always, and the caudate nucleus almost always, non-cleaved. There is a descending prevalence of non-cleavage from thalami, to lentiform, to caudate nuclei.35 Although there is a general correlation between the extent of nuclear fusion and the severity of HPE, there are notable exceptions, with cases of alobar and semilobar HPE showing essentially normal thalamic and lentiform nuclei.35 In alobar and semilobar HPE, the posterior supratentorial cerebrum is usually replaced by a large fluid-filled midline dorsal sac/cyst (Figs. 15-12 to 15-14).8,9 These prosencephalic cysts arise from, and lie behind, the holosphere and are continuous with its horse-shoe shaped, dorsal lip. They contain CSF, have a thin transparent membrane, abut the cerebellum and the parieto-occipital area of the cranial cavity, connect directly to the midline ventricular system, and may protrude through the anterior fontanel. Dorsal cysts vary in their specific pathology and in the spectrum of associated cerebral anomalies. There is some agreement that the membranous covering of the dorsal cyst represents the posterior roof of the holosphere,8 but its direct cause remains a source of conjecture. Simon et al.36 found a strong correlation between the occurrence of a dorsal cyst and the

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Fig. 15-12. Inferior view of a brain with holoprosencephaly (HC) in an infant with trisomy 13. The cerebellar hemispheres (C) and the brain stem (B) are well developed. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

presence and extent of thalamic non-cleavage. They speculated that the uncleaved thalamus blocked exit of CSF from the third ventricle, resulting in cystic expansion of the posterior holosphere. Sarnat and Flores-Sarnat9 posited that the supraspinal recess reFig. 15-13. Gross pathologic view of alobar holoprosencephaly. The dorsal sac has been opened. (Courtesy of Dr. C. Jime´nez, Department of Pathology, Children’s Hospital of Eastern Ontario.)

537

presents the path of least resistance to expansion, and is the sight of origin of the cysts. They suggest that the uncleaved thalamus contributes through reducing the volume of the third ventricle. Yokota et al.37 suggest that two additional types of dorsal cysts should be distinguished. An interhemispheric dorsal cyst arises from the third ventricle and extends between the hemispheres, displacing, rather than replacing, cerebral tissue. The wall is considered to derive from the diencephalic roof, and common associated findings include a complete or partial absent corpus callosum and falx and a midline parietal encephalocele. These primary interhemispheric cysts are distinguished from secondary interhemispheric cysts by the defective falx.37 Cases with associated absent olfactory bulb and tract have been used to argue that this lesion is part of the holoprosencephaly spectrum. However, the cerebellar tentorium is present, and the complete interhemispheric fissure and the course of the pericallosal artery indicate normal hemispheric separation.37,38 The second cystic lesion they discuss is congenital midline porencephaly, which is characterized by congenital hydrocephalus, a midline scalp defect or encephalocele, and a symmetric defect of the midline posterior cerebral mantle and the midline septae. There is no evidence of midline fusion of telencephalic or diencephalic structures or absence of the olfactory system, and the cyst walls contain neural remnants. Several authors have noted that the neuroimage of a dorsal cyst, behind a semi or lobar HPE, is reminiscent of an ‘‘arrowhead’’ and may be a useful diagnostic sign. Absence of the corpus callosum (ACC) with an interhemispheric cyst must be distinguished from HPE with the dorsal cyst lying behind the holosphere. The ‘‘bat wing’’ appearance of the ventricles on coronal view and their widely separated and parallel orientation on axial view, together with the presence of the falx and complete interhemispheric fissure, allows the differentiation to be made. Cohen21 has suggested that isolated ACC can be considered as part of the HPE spectrum when it occurs in syndromes that do include HPE. However, even within a single syndrome the specific embryopathology of the ACC could differ between cases with isolated ACC and those with HPE-associated ACC. Pituitary dysfunction is common in HPE but, although true absence does occur, careful histopathologic study will reveal presence of the gland in most cases.21 Simple absence of the septum pellucidum shows more normal ventricular borders, and hydranencephaly is distinguished by the presence of dysplastic brain remnants and the falx.27 The MRI and CT appearance of the middle hemispheric variant of HPE is distinctive.5 By definition it is the mid-portion of the cerebral hemispheres that is continuous across the midline, and in over 85% the Sylvian fissures also connect over the vertex. Furthermore, the hypothalamus and lentiform nuclei are always separated by a third ventricle, and the cerebral ventricles almost always separate the caudate nuclei. Dorsal cysts, associated with thalamic noncleavage, occur in about one-fourth of cases, and hypotelorism is not characteristic. Although abnormal maturation of white matter can be seen in up to half of the cases of standard HPE, there is evidence that it does not occur in the middle hemispheric variant.39 HPE has often been detected by routine and targeted prenatal ultrasound (PUS), although there continues to be difficulty in both specifying that the malformation is HPE, and in assigning the sub-type of HPE. Bullen et al.40 reported a retrospective study of 68 patients with HPE born between 1985 and 1998 and reported to a congenital malformation registry from among a population that had routine PUS available. The detection rate for HPE was 37/45 (88%) of alobar, 12/18 (58%) of semilobar, 1/3 of lobar, and 3/8 of an unclassified group. The detection rate of 71%

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Neuromuscular Systems

Fig. 15-14. Superior view and coronal section of the holoprosencephalic brain of the infant shown in Fig. 15-12. A. In the superior view, the hemispheres are completely fused on the surface anteriorly (A), but a shallow midline (arrows) can be seen posteriorly. B. In the coronal section, a single ventricle (V) is shown beneath the midline groove (arrows). (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

for the entire study period improved to 86% for the years 1992 to 1998. However, in only 30 of the 45 PUS-detected cases was a specific diagnosis of HPE made; other diagnoses included ventriculomegaly (5), brain cysts (4), microcephaly (2), encephalocele (2), and other non-CNS anomalies (2). As expected, associated craniofacial and non-craniofacial malformations and chromosome studies were important aides to diagnosis. Detection rates as high as 100% have been reported for alobar HPE in more recent and selected populations.41 Alobar HPE has been subject to firsttrimester diagnosis, and transvaginal and/or 3-D PUS have been useful to better define the CNS and craniofacial pathology.42–44 Prenatal MRI may not be as useful for the clarification of large and complex lesions such as HPE.45 In alobar and semilobar HPE, the diagnosis is made through demonstration of a single sickle-shaped ventricle. In the axial plane, the cortex is crescent shaped without evidence of fissure or midline structures, and posteriorly the protruding fused thalami can usually be visualized.41 The presence of a dorsal sac may aid the differential diagnosis, although visualization of its connection to the ventricle in some cases requires a meticulous search. In hydrocephalus the separation of the ventricles is demonstrable, and hydranencephaly can be excluded if the crescent-shaped frontal cortex can be demonstrated. A careful search for the facial features, such as hypotelorism, cyclopia, a single nostril, and midline cleft, are essential parts of any assessment for HPE. Pilu et al.46 have proposed that the fused and rudimentary fornices are seen as a single fascicle within the third ventricle and are specific for lobar HPE. Congenital midline porencephaly has also been detected by PUS.47 Given the current lack of specificity of PUS, it is important that appropriate post-termination or postnatal examinations and

diagnostic tests are performed in order to detect or confirm HPE and any associated syndrome or etiology. HPE with or without characteristic facial changes can occur as an isolated malformation or as part of a broad range of chromosomal, single gene, and unknown genesis syndromes (Table 15-4). Leech and Shuman6 proposed that there is a spectrum of midline defects ranging from aprosencephaly, which may have an HPE face (see Section 15.3), through typical HPE, to commissural plate agenesis, septo-optic dysplasia, agenesis of the septum pellucidum, and absent corpus callosum. The hypothesis drew on the fact that several of these anomalies are simple epiphenomena in the presence of HPE. However, Cohen13 stressed that the spectrum of brain defects tends to be specific and limited for each known genesis syndrome and that overemphasis of the concept of a continuum may be misleading when counseling families. Examples include the broad range from alobar HPE to isolated arhinencephaly seen in trisomy 13 and the contrasting narrow range of arhinencephaly seen in Kallmann syndrome. The point is further made by comparing the different patterns of associated malformations in isolated ACC with HPE when ACC is an epiphenomenon.28 It is for this reason that Table 15-4 continues to separate syndromes that may have HPE and/or arhinencephaly from those that have only been reported with arhinencephaly. Well-delineated syndromes where there has been a single reported case with HPE have been excluded. Distribution and Etiology

Estimates of the prevalence of HPE can be influenced by sample size, sources and timing of ascertainment, rates of autopsy, the inclusion or exclusion of cases with chromosome anomalies and of pregnancy terminations or losses, and whether isolated arhinencephaly

Brain

is included. However, recent population-based reports of birth prevalence have been fairly constant, ranging from 0.48/10,000 to 0.88/10,000.40,132–134 Inclusion of fetal losses and stillbirths has obtained rates in the range of 1.2/10,000.40,133 The prevalence of HPE is much higher early in pregnancy, and Matsunga and Shiota reported a prevalence of 40/10,000 in early induced abortions.135 Calculation of the contribution of chromosome abnormality to the prevalence of HPE is compromised by the fact that such cases, notably trisomy 13, more often have craniofacial and other malformations, and this makes both ascertainment and karyotyping more likely. Indeed major epidemiologic studies have deliberately used craniofacial signs associated with HPE and trisomy 13 as aids to ascertainemnt.40,132 There has yet to be an epidemiologic study in which all cases of HPE have been karyotyped. Similarly, non-chromosomal syndromes may be over-represented because their associated malformations bias their ascertainment. With those caveats in mind, 63/82 (77%) of the cases reported by Olsen et al.132 were karyotyped, of which 15/63 (24%) were abnormal and 8/15 (53%) were trisomy 13. The comparable figures reported by Bullen et al.40 were 53/68 (78%), 20/53 (38%), and 15/20 (75%); and by Croen et al.133 were 92/121 (76%), 43/92 (46%), and 38/43 (88%). The latter authors considered that the additional seven cases, which were not karyotyped, had clinically recognizable trisomy 13. As would be expected, the studies that included fetal losses and/or stillbirths report a higher proportion of chromosome abnormality and trisomy 13. It is probable that a study limited to early fetal loss would show an even higher contribution from chromosome abnormality. Trisomy 13 is by far the most important chromosome abnormality in terms of its frequency of occurrence and its high rate and broad spectrum of HPE anomalies. Taylor136 estimated that 70% of cases of trisomy 13 have some expression of HPE. In contrast, HPE is an infrequent finding in several of the abnormal karyotypes listed in Table 15-4, and many have a narrower HPE spectrum; indeed several have thus far only been reported with arhinencephaly.13,61 The non-random association of specific cytogenetic abnormalities with HPE has suggested at least 12 loci on 11 chromosomes may contribute to HPE.137 These data have played an important role in the discovery of several non-syndromic HPE genes (Table 15-4). Of the numerous syndromes listed in Table 15-4, most are individually rare or express HPE in a minority of cases. Thus nonchromosomal syndromes appear to account for a relatively small proportion of HPE. Such syndromes were recognized in 4/68 (5.9%) of the series reported by Bullen et al.,40 3/82 (3.7%) reported by Olsen et al.,132 and 18/121 (14.9%) ascertained by Croen et al.133 A somewhat higher rate of syndromic and familial isolated-HPE may be reported from genetic centers, perhaps because of a greater expertise in syndrome diagnosis and more opportunity to fully explore family history; some bias of ascertainment may also be in play.138 Thus, a significant proportion of cases of HPE is unexplained, and progress toward identifying specific etiologies is frustrated by the relatively low background frequency of the malformation and its etiologic diversity. In 1989 Cohen13 listed a number of potential human teratogens that were supported by anecdotal data and required further study. He concluded that maternal diabetes was the only proven environmental cause of HPE in humans. Indeed, maternal diabetes has been the most consistently identified risk factor, occurring in 10/273 cases from population-based studies.40,132,133 Martinez-Frias et al.139 obtained an odds ratio (OR) for HPE of

539

3.27 (95% CI 1.29–7.77), and Croen et al.140 of 10.2 (95% CI 1.9– 39.4), for infants born to diabetic mothers. Several cases of HPE/arhinencephaly have been reported following alcohol abuse during pregnancy, and animal experiments indicate that alcohol can produce the HPE spectrum and other malformation associations.141 An OR of 2.0 (95% CI 0.9– 4.5) for alcohol exposure reported by Croen et al.140 did not quite attain significance, but it did appear to have an additive effect upon cigarette smoking; OR smoking alone was 4.1 (95% CI 1.4– 12.0), and for smoking and alcohol was 5.4 (95% CI 1.9–20.0). HPE can result from experimental exposure to retinoic acid in animals,141 and a human case of HPE associated with excess in utero exposure has also been reported.142 The case-control study by Matsunaga and Shiota135 showed no effects of maternal or paternal ages, parity, acute or chronic maternal illnesses, or menstrual irregularities on HPE. They suggested a borderline significant increase in the mean number of prior abortions, but this requires further study, especially in light of the number of statistical tests applied. The mean maternal and paternal ages recorded by Bullen et al.40 did not differ from the general population, but Olsen et al.132 reported an approximate two-fold greater prevalence in mothers under 18 years of age. An excess of females with HPE has been reported from a number of studies,16,61,132,133,140 and, at least in part, this may result from a greater survival of female infants with trisomy 13.133 The absence of a sex difference in the study by Bullen et al.,40 which included fetal loss, is consistent with this interpretation. Unfortunately there was no information as to the sex ratio of the abortuses studied by Matsunaga and Shiota135 and, hence, their study does not shed light on this question. Roach et al.16 found a significant increase in matrilineal dizygotic twinning in their families. There is perhaps some evidence of a slight excess of twins, discordant for the anomaly, among cases with HPE,40,132 but the finding is inconsistent.133 Croen et al.140 noted a significantly increased OR for children born to Mexican and non–U.S.-born mothers. However, their excess risk to Hispanic-white mothers was not seen in the New York data of Bullen et al.,40 perhaps reflecting a different origin for the Hispanic groups. Other variables showing increased but not quite significant ORs included early age at menarche, medication use for upper respiratory tract infections, and use of aspirin.140 Roach et al.16 reported that of their 32 families, 12 had mental illness and 16 had mental retardation among near relatives. They considered this to be an extremely high rate, although the relatives did not display characteristics consistent with mild expression of the dominant or recessive forms of HPE. Unfortunately, the denominator of the number of individuals counted was not provided, and there was no control group. The latter is of particular importance in light of the poverty status of 30 of the 32 families. It is similarly difficult to assess the possible relationship of neural tube defects to HPE. The spectrum of the ‘‘holoprosencephalic’’ face is seen in association with anencephaly, and affected siblings concurrent for these two anomalies have been reported.13 Similarly, more distant relatives have been reported to have neural tube defects, but these are common malformations and there are as yet no data to show if the rate among relatives is greater than expected by chance. On the other hand, some syndromes, as well as human and animal teratogens, have a spectrum of reported anomalies that include both HPE and neural tube defects. Until such time as all genes causing non-syndromic HPE are isolated and can be tested on a population-based sample, it will

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remain difficult to gauge the contribution of single genes to this disorder. Mutations in the genes presently known account for a relatively small fraction of cases (Table 15-4, vide infra). Roach et al.16 found two recurrences among 35 siblings, a rate of 6%. However, many of their patients were not karyotyped, and those who were, as well as a number of familial cases reported in the literature, were studied in the prebanding era. Recurrent derivative chromosome anomalies remain a possibility in some cases. Bullen et al.40 identified 5 (7.4%) familial cases among their 68 population-based index cases. Starting with an initial series of 258 cases, Odent et al.138 found 97 cases of non-syndromic, nonchromosomal HPE distributed in 79 families. From a segregation analysis they concluded that transmission fit an autosomal dominant model with 82% penetrance for the major HPE phenotype. The proportion of sporadic cases was estimated at 68%, and a recurrence risk of 13% was calculated for sporadic, isolated HPE. The embryologic disturbance that results in HPE occurs early, and the strong association between midline facial malformations and HPE suggests an intimate embryologic relationship between the developing prosencephalon and the neural crest cells that populate the frontonasal process. The neural plate appears by the third week post conception; by the time it begins to fuse at 22 days, the forebrain has two subdivisions and bilateral optic sulci.132,143 As opposed to the midbrain and hindbrain, which are induced by the notochord, forebrain induction is dependent on the prechordal plate and mesoderm. The inducing tissues express sonic hedgehog (SHH), a gene that is subsequently turned on in the CNS floorplate. Current evidence favors a primary defect in the induction and/ or patterning of the rostral neural tube by the prechordal mesoendoderm as the underlying cause of HPE.11,144 Non-random structural cytogenetic abnormalities provided the initial clues as to the potential location of genes that could be involved in these developmental processes, and SHH, at 7q36, was the first gene to be implicated in the pathogenesis of non-syndromic HPE.22 Forebrain expression of SHH is initially restricted to the tuberal and mamillary hypothalamic primordia, and later to a region of the rostrobasal telencephalon, termed the lamina terminalis. It is within the lamina terminalis that the commissural plate forms.11 The key role of the Shh pathway has been confirmed in animal models. Shh / mice have perinatal lethal HPE and cyclopia; in contrast, ectopic expression of Shh leads to ectopic development of the previously mentioned hypothalamic primordia.8 Shh activation of its target genes is suppressed by Gli3-R, and further evidence of the importance of Shh signaling is that the double knockout (Shh /, Gli3-R /) mouse is rescued from HPE.145 The causative role in humans has been confirmed by the demonstration that two HPEassociated SHH mutations decrease in vivo SHH activity in the CNS, and that they fail to induce ventrally expressed genes, and to repress dorsally expressed genes.146 There is evidence that the bone morphogenetic proteins (BMPs) play a role in dorsal patterning of the brain, and that their expression can induce or repress genes normally expressed in the dorsal forebrain.8 Golden et al.147 showed that introducing recombinant BMP4- or BMP5-soaked beads into chick forebrain caused HPE, cyclopia, and loss of ventral midline structures. Markers of dorsal gene expression were present, but those for ventral gene expression were lost. The loss of the basal telencephalon was shown to be due to excess cell death, a finding compatible with the overall decrease in brain size seen in severe HPE spectrum anomalies. This experiment was also important in demonstrating that HPE can be induced at a time when the neural tube has closed.

Mapping and candidate gene approaches have lead to the discovery of causative mutations in other genes in the SHH signaling pathway, as well as in other pathways that may not interact directly with SHH signaling. To date these include PTCH and GLI2 (sonic hedgehog signaling), TDGF1, FAST1, and TGIF (Nodal/ TGF-b signaling), SIX3, and ZIC2 (a dorsally expressed gene).65,148,149 Other genes implicated in mice include Smoothened (Smo) in the Shh-signaling pathway150 and the homeobox genes Nkx2.1151 and Vax1.152 An interesting sidebar to the SHH story is that patients with Smith-Lemli-Opitz syndrome (Table 15-4) have low cholesterol levels due to their defect in 7-dehydrocholesterol reductase, and about 5% of them have HPE. Inhibitors of cholesterol synthesis can also cause HPE.153 SHH signaling may be directly impaired because SHH requires a cholesterol-related processing to attain its functional state.145 Additionally, hypocholesterolemia may act further down the pathway on PTCH, or on caveolin- containing, cholesterol-rich vesicles themselves, to interfere with the intracellular movement of SMO,145 which is a key step in signaling.65 Notwithstanding progress in finding single genes related to the pathogenesis of HPE, surveys of large numbers of patients have found a relatively low rate of mutations.154,155 The four genes available for clinical testing may account for up to 37% to 48% of families showing autosomal dominant inheritance, and less than 5% of sporadic non-syndromal cases.156 Testing of all currently known genes has only found mutations in 15–20% of cases.65 Although there may be a single predominant major gene yet to be discovered, this seems unlikely, and thus there remain questions as to the cause of most sporadic cases of HPE. Also unexplained is the dramatic variation in the expression of HPE, which is seen61 even in families with a known mutation.22 This has lead Ming and Muenke65 to propose that in most instances the occurrence of HPE in humans requires a double hit, either genetically, or genetically and environmentally. They point out that Shh þ/ mice (unlike Shh /) are unaffected by HPE, and they provide three examples of affected children who were heterozygous for mutations at two different HPE loci (biallelic inheritance); parents who were available were heterozygous and unaffected. Indeed there is the potential that a combination of environmental factors (e.g., alcohol, retinoids, low cholesterol) and polymorphisms at multiple HPE loci, each resulting in subtle variation in timing and gradient of gene signaling, might combine to cause sporadic HPE. Concurrent face and brain malformations in HPE point to maldevelopment of a shared precursor or inducer. For example, malformations of the HPE spectrum have been produced in a number of experimental systems by interference with the prechordal mesoderm and/or gastrulation.142,158 Variation in severity suggests differing magnitude or timing of an insult, or of fetal susceptibility. Discordant monozygotic twins would indicate that the insult may be local and quite random. Cases of HPE showing lack of correlation between the face and the brain, either where the face is normal and the brain abnormal or the brain is normal and the face abnormal, suggest that at times the pathogenic process may be specific, and probably later in time than when concurrent effects are induced. Sulik and Johnston10 showed that an insult during gastrulation results in a narrow forebrain and the HPE spectrum. By varying the timing and intensity of alcohol exposure during gastrulation, they produced the entire gamut of malformations, from virtual aprosencephaly through HPE, to the typical prenatal alcohol syndrome. Notable was the production of agnathia/HPE, pointing to damage to the early mesoderm.

Brain

These above data can support variability of timing as a cause for variations in HPE. However, Sarnat-Flores and Sranat9 have proposed that the degree of midface hypoplasia that presents in association with HPE is due to a rostrocaudal gradient in the genetic defect. They note that others19 have shown such a gradient in the rate of non-cleavage, with 96% non-cleavage of the caudate, 67% of the thalamus, and 27% of the midbrain. Failed separation of the inferior and superior colliculi, hypoplasia of the periaqueductal gray matter, and aqueductal stenosis/atresia evidence midbrain non-cleavage. Furthermore, there is a greater dorsal than ventral non-cleavage. Siebert159 implicated the degree of integrity of the ethmoid bone with respect to the occurrence of the ‘‘holoprosencephalic’’ face. The ethmoid derives from the cartilagenous mesethmoid, which is the major component of the nasal capsule and which would be expected to be deficient in proportion to the degree of neural crest cell abnormality. There is not consensus as to whether the middle interhemispheric variant (MIH) is truly part of the HPE specrum.21 However, there is genetic evidence that there are at least some common pathogenic factors. ZIC2, which acts in both closure of the neural tube and differentiation of the dorsal midline to form the roof plate, has been found to play a role in one of 16 cases with MIH.161 MIH has also been described in five fetuses with 13q-, a deletion that includes the ZIC2 locus.162 The primary involvement of a dorsal acting gene would account for the general lack of ventral midline CNS involvement in MIH. Prognosis, Treatment, and Prevention

As would be expected for any severe CNS malformation, HPE carries a high mortality rate and poor prognosis for development in those who survive. However, not all patients die, and some individuals show meaningful development. It is therefore paramount that parents be provided with as accurate information as possible about what can be expected. Data from more recent population-based studies are more likely to reflect the impact of current prenatal diagnosis and perinatal practice. Of the 68 cases reported by Bullen et al.,40 four were lost spontaneously at <24 weeks gestation, 38 pregnancies were terminated following prenatal diagnosis, two were stillborn, and 24 were born alive. Eight of the liveborn infants died within 24 hours, and 14 (58%) within a month; 29% (35% of the euploid) survived to 1 year. Survival rates are affected by the severity of the HPE, the presence of a cytogenetic or syndrome diagnosis, and the occurrence of associated lethal anomalies. Among their 78 liveborn cases, Olsen et al.132 recorded an overall mortality of 32% within 48 hours and of 38.5% within a week. The 48-hour mortality rate for syndromic (including chromosomal) cases was 57%, and the 1week survival was 50% for alobar HPE. At 1 year, 54% of patients with isolated, 14% of those with syndromic, and 25% of those with non-syndromic HPE with multiple associated defects were alive. Of the 121 Californian cases reported by Croen et al.,133 80% of the chromosomal and 32% of the euploid cases died within 1 week, and 2% and 30%, respectively, were alive at 1 year. All euploid patients with cyclopia or ethmocephaly died within a week, whereas 57% of those with less severe facial anomalies were alive at 1 year. Thus, in both of the latter studies the severity of the facial anomalies in the euploid cases allowed some prediction of survival. The cause of death in children with HPE who do not have an associated lethal malformation is not always clear, but may often relate to brainstem dysfunction, manifest as unstable cardiac and respiratory rates, and thermolability. Barr and Cohen163 stress that prolonged episodes of respiratory and cardiac instability are ominous, and parents should

541

be forewarned as to their potential consequence. Recurrent infections, to which the infants often respond poorly, and which may be exacerbated by dehydration due to diabetes insipidus, may also cause death. Although uncommon, survival beyond childhood does occur with alobar HPE and becomes more common as the severity of the HPE diminishes. Additional non-facial malformations are the rule in patients with a chromosome abnormality. Up to 90% of patients with euploid HPE have facial anomalies; 60% involve the eyes and nose, and 33% involve the lips and palate.40 In general, the severity of the facial anomalies does correlate with the severity of the HPE, but there are important exceptions. Plawner et al.7 had three patients with alobar HPE and a normal face, and this pattern may run true in families.20 The euploid group has a 70% incidence of additional non-facial anomalies, which include the skeletal, renal, and cardiovascular systems as well as the gut and lung.28,40 There are a number of medical problems common to children who survive with HPE, and Plawner et al.7 have looked for correlations between their rate and severity and the degree of HPE and involvement of the deep gray nuclei. They reviewed 68 patients, 13 with alobar, 43 with semilobar, and 12 with lobar HPE, whose respective mean ages at the time of study were 0.86, 3.8, and 5.8 years. Where appropriate, the evaluations were limited to the 46 children who were over 1 year of age. Seizures occurred in 33/68 (49%) of cases, and their presence did not correlate with the type of HPE. However, the seizures were judged difficult to control in 17/33 (52%), which did correlate with the severity of the HPE and the presence of cortical malformations. Barr and Cohen,163 whose study was limited to alobar HPE, state that the frequency and intensity of seizures may vary over time, and that they often respond to a standard medical approach, although several medications, alone or in combination, may have to be tried in order to gain control. Diabetes insipidus, treatable with replacement antidiuretic hormone, is common in HPE, affecting 49/68 (72%) of the patients in one series,7 and additional pituitary anomalies including panhypopituitarism can occur. Plawner et al.7 did not find a good correlation between the presence of an endocrine disturbance and the appearance of the pituitary as assessed by neuroimaging; there was some correlation with the severity of the HPE, and a good correlation with the degree of hypothalamic non-cleavage. However, Sarnat-Flores and Sarnat9 do not accept that the endocrinopathies are explicable solely on the basis of hypothalamic non-cleavage and have hypothesized that down-regulation of the OTP homeobox gene, or an interrelated downstream gene, causes a lack of differentiation and/or functional maturity of the magnocellular neurons of the hypothalamus. Temperature instability, unrelated to infection and ranging from 368C to 38.68C, is common and occurred in 22/68 (32%) cases studied by Plawner et al.,7 of which six were judged to be severe. Again they noted a correlation with the degree of hypothalamic non-cleavage. The presence of hydrocephalus is strongly correlated with the severity of the HPE and the presence of a dorsal cyst; the latter two are of course strongly interrelated. In the series by Plawner et al.,7 CSF shunts were required in 62% of patients with alobar, 7% of those with semilobar, and 9% of those with lobar HPE. Dorsal cysts were found respectively in 11/12, 12/43, and 1/11 cases; shunts were needed in 9/23 patients with, and only in 2/41 without, a dorsal cyst. Hercig et al.164 reported a 28-year-old unemployed women, who had been in a common-law relationship for 6 years, and who developed a delusional psychosis. The psychosis, but not her poor short-term memory, responded to antipsychotic medication, and

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a MRI showed lobar holoprosencephaly. The authors posited a causal relationship. Serious developmental delay is the rule in HPE, and its severity shows a general correlation with the degree of HPE. In their review of survivors with alobar HPE, Barr and Cohen163 speak of some infants being able to bat objects, occasionally being able to bring objects to the midline, and the absence of any expressive language. Hearing is usually normal, and the authors state that the children may develop specific sounds for some needs, respond consistently to certain sounds and tones, and, if vision is normal, recognize familiar faces. Plawner et al.7 did not observe sitting in any of their patients with alobar HPE, a minority of those with semilobar HPE had succeeded, and about half with lobar HPE could walk independently or with assistance. The relative ages of the groups should be kept in mind. Use of the upper limbs in patients with alobar HPE was limited to reaching and batting objects, whereas 4/30 patients with semilobar and half of those with lobar HPE had normal or only mild upper limb dysfunction. Development of language was limited to vowel sounds in patients with alobar HPE, while two of those patients with semilobar and two with lobar HPE had multi-word sentences or better. There was a high inverse correlation between development of language and the degree of non-cleavage of the caudate, lentiform, and thalamic nuclei. Plawner et al.7 developed a composite motor scale (CMS), composite clinical severity scale (CCSS), and deep gray nuclear scale (DGS). The CMS for alobar and semilobar HPE did not differ but both were significantly greater than that for lobar HPE. The CCSS was greater for alobar than for semilobar, which was greater than that for lobar HPE, and there was a strong correlation between the CCSS and DGS. The authors proposed that the latter might provide additional predictive clinical/developmental information as compared with the simple measure of HPE severity. The cases reported by Hercig et al.,164 Shanks and Wilson,165 and Moulinger et al.166 serve to emphasize the degree of normalcy that can occur in lobar HPE, and there is likely a bias toward the ascertainment of severe cases. Feeding difficulties are common and often marked, especially at the severe end of the HPE spectrum. They include poor suck and swallowing, gagging, choking, vomiting with its risk of aspiration, airswallowing, and colic, and may be exacerbated by constipation.163 Gastrostomy may be the logical solution in some cases. Postnatal growth failure is frequent. Behavior may cycle between calm and irritable without apparent reason, and does not always respond to the usual approaches. Barr and Cohen163 suggest that continual background noise (e.g., radio) may help and may also restore a normal sleep pattern, which can itself be extremely disturbed. There is no treatment for HPE, and aggressive intervention is not indicated in light of the poor prognosis for both survival and development. In children who do survive, consideration should be given to treatment of non–life-threatening malformations to increase the benefits of routine care. Persing167 discussed some of the ethical issues surrounding surgical treatment of patients with HPE. He argued for a high benefit-to-risk ratio, such as cleft lip/ palate repair, which would aid management and also reduce social isolation of the patient and family. Cleft repair will not correct a feeding difficulty that has a central cause.163 In experienced hands the risks of surgery should not be significantly different from that in the general population. With the possible exception of improved management of diabetic pregnancies, there is no means of primary prevention of HPE. Greater use of routine prenatal ultrasound screening means that a significant majority of cases of HPE can be detected in utero, early

enough to provide parents with the option of terminating the pregnancy.49 However, some couples when presented with this unexpected information elect to continue the pregnancy. RedlingerGross et al.168 have discussed this decision-making process and stress the need of the parents for informational, emotional, and general support from their family, friends, and health care professionals. The increasing recognition of individual syndromes and the genes responsible for both syndromic and isolated HPE means that there is a growing potential for prenatal diagnosis in high-risk families, both through application of ultrasound for the detection of HPE and the syndrome-associated malformations, and through specific mutation analysis. Direct mutation analysis is available clinically for four of the genes causing isolated HPE,156 and preimplantation diagnosis has been applied in a case of HPE due to a SHH mutation.169 All affected infants (or fetuses), not only those who appear to have trisomy 13, should be karyotyped. This is not simply to document the cause of the HPE and to enable more precise counsel regarding its risk of recurrence, but because young couples who give birth to a child with standard trisomy have a nonspecific (about 1%) risk of recurrent trisomy. Specific chromosome findings in an affected patient may of course lead to further family studies and, in the case of a familial rearrangement, identification of a higher recurrence risk and the potential for prenatal karyotyping. High-resolution studies are indicated in cases in which the clinical syndrome diagnosis is not apparent. The potential risk for autosomal recessive and autosomal dominant forms of HPE, and with it the importance of assessing close relatives for microforms such as absent or single maxillary central incisors, hypotelorism, anosmia, and endocrine dysfunction, has been discussed previously. Any such relative should be counseled as to potential risk. The counseling of individuals found to have these ‘‘microforms’’ in the absence of a family history is more problematic; they are probably at low risk, but offering prenatal ultrasound would be prudent.

References (Holoprosencephaly) 1. Yakovlev PT: Pathoarchitectonic studies of cerebral malformations. J Neuropathol Exp Neurol 18:22, 1959. 2. De Morsier G: Etude sur les dysraphies cranioencephaliques. VII. Telencephalosynapsis hemispheres cerebraux incompletement separes. Psychiatr Neurol (Basel) 141:239, 1961. 3. DeMyer W, Zeman W: Alobar holoprosencephaly (arhinencephaly) with median cleft lip and palate: clinical electroencephalograhic, and nosologic considerations. Confin Neurol 23:1, 1963. 4. Warkany J: Congenital Malformations. Year Book, Chicago, 1971, p 201. 5. Simon EM, Hevner RF, Pinter JD, et al.: The middle interhemispheric variant of holoprosencephaly. AJNR Am J Neuroradiol 23:742, 2002. 6. Leech RW, Shuman RM: Holoprosencephaly and related midline cerebral anomalies: a review. J Child Neurol 1:3, 1986. 7. Plawner LL, Delgado MR, Miller VS, et al.: Neuroanatomy of holoprosencephaly as a predictor of function. Beyond the face predicting the brain. Neurology 59:1058, 2002. 8. Golden JA: Towards a greater understanding of the pathogenesis of holoprosencephaly. Brain Dev 21:513, 1999. 9. Sarnat HB, Flores-Sarnat L: Neuropathologic research strategies in holoprosencephaly. J Child Neurol 16:918, 2001. 10. Sulik K, Johnston MC: Embryonic origin of holoprosencephaly: interrelationship of developing brain and face. Scan Electron Microsc 1:309, 1982. 11. Muller F, O’Reilly R: Mediobasal prosencephalic defects, including holoprosencephaly and cyclopia, in relation to the development of the human forebrain. Am J Anat 185:391, 1989.

Brain 12. Kjaer I, Fischer Hansen B: Human fetal pituitary gland in holoprosencephaly and anencephaly. J Craniofac Genet Dev Biol 15:222, 1995. 13. Cohen MM Jr: Perspectives on holoprosencephaly: part III. Spectra, distinctions, continuities, and discontinuities. Am J Med Genet 34:271, 1989. 14. Cohen MM Jr, Jirasek JE, Guzman RT, et al.: Holoprosencephaly and facial dysmorphia: nosology, etiology and pathogenesis. Birth Defects Orig Artic Ser VII(7):125, 1971. 15. Mieden GD: An anatomical study of three cases of alobar holoprosencephaly. Teratology 26:123, 1982. 16. Roach E, De Myer W, Conneally PM, et al.: Holoprosencephaly: birth data, genetic and demographic analysis of 30 families. Birth Defects Orig Artic Ser XI(2):294, 1975. 17. Fryns J, Van den Berghe H: Single maxillary central incisor and holoprosencephaly. Am J Med Genet 30:943, 1988. 18. Ben-Hur N, Ashur H, Murreri M: An unusual case of median cleft lip with orbital hypotelorism: a missing link in the classification. Cleft Palate J 15:365, 1978. 19. Golden J, Holmes L: The face-brain relationship: a case of the face not predicting the brain. Clin Dysmorphol 3:164, 1994. 20. Barr M Jr, Cohen MM Jr: Autosomal recessive alobar holoprosencephaly with essentially normal facies. Am J Med Genet 112:28, 2002. 21. Cohen MM Jr: Problems in the definition of holoprosencephaly. Am J Med Genet 103:183, 2001. 22. Roessler E, Belloni E, Gaudenz K, et al.: Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357, 1996. 23. Lo F-S, Lee Y-J, Lin S-P, et al.: Solitary maxillary central incisor and congenital nasal pyriform aperture stenosis. Eur J Pediatr 157:39, 1998. 24. Kjaer I, Keeling J, Russel B, et al.: Palate structure in human holoprosencephaly correlates with the facial malformation and demonstrates a new palatal developmental field. Am J Med Genet 73:387, 1997. 25. Martin RA, Jones KL: Absence of the superior labial frenulum in holoprosencephaly: a new diagnostic sign. J Pediatr 133:151, 1998. 26. Ardinger HH, Bartley JA: Microcephaly in familial holoprosencephaly. J Craniofac Genet Dev Biol 8:53, 1988. 27. Fitz CR: Holoprosencephaly and related entities. Neuroradiology 25: 225, 1983. 28. Jellinger K, Gross H, Kaltenback E, et al.: Holoprosencephaly and agenesis of the corpus callosum: frequency of associated malformations. Acta Neuropathol 55:1, 1981. 29. Hunter AGW, Carpenter BF: Implications of malformations not due to amniotic bands in the amniotic band sequence. Am J Med Genet 24:691, 1986. 30. Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255, 1989. 31. van Overbeeke JJ, Hillen B, Vermeij-Keers C: the arterial pattern at the base of arhinencephalic and holoprosencephalic brains. J Anat 185:51, 1994. 32. Albayram S, Melhem ER, Mori S, et al.: Holoprosencephaly in children: diffusion tensor MR imaging of white matter tracts of the brainstem-initial experience. Radiology 223:645, 2002. 33. Barkovich AJ, Simon EM, Clegg NJ, et al.: Analysis of the cerebral cortex in holoprosencephaly with attention to the sylvian fissure. AJNR Am J Neuroradiol 23:143, 2002. 34. Judas M, Rasin M-R, Kruslin B, et al.: Dendritic overgrowth and alterations in laminar phenotypes of neocortical neurons in the newborn with semilobar holoprosencephaly. Brain Dev 25:32, 2003. 35. Simon EM, Hevner R, Pinter JD, et al.: Assessment of the deep gray nuclei in holoprosencephaly. AJNR Am J Neuroradiol 21:1955, 2000. 36. Simon EM, Hevner RF, Pinter J, et al.: The dorsal cyst in holoprosencephaly and the role of the thalamus in its formation. Neuroradiology 43:787, 2001. 37. Yokota A, Oota T, Matsukado Y: Dorsal cyst malformations. Part 1. Clinical study and critical review of the definition of holoprosencephaly. Child Brain 11:320, 1984. 38. Probst FP: The Prosencephalies: Morphology, Neuroradiological Appearances and Differential Diagnosis. Springer, Berlin, 1979. 39. Barkovich AJ, Simom EM, Glenn OA, et al.: MRI shows abnormal white matter maturation in classical holoprosencephaly. Neurology 59:1968, 2002.

543 40. Bullen PJ, Rankin JM, Robson SC: Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England. Am J Obstet Gynecol 184:1256, 2001. 41. Lai TH, Chang CH, Yu CH, et al.: Prenatal diagnosis of alobar holoprosencephaly by two-dimensional and three-dimensional ultrasound. Prenat Diagn 20:400, 2000. 42. Hsu TY, Chang SY, Ou CY, et al.: First trimester diagnosis of holoprosencephaly and cyclopia with triploidy by transvaginal threedimensional ultrasonography. Eur J Obstet Gynecol Reprod Biol 96:235, 2001. 43. Blass HG, Eik-Nes SH, Vaino T, et al.: Alobar holoprosencephaly at 9 weeks gestational age visualized by two- and three-dimensional ultrasound. Ultrasound Obstet Gynecol 15:62, 2000. 44. Stagiannis KD, Sepulveda W, Bower S: Early prenatal diagnosis of holoprosencephaly: the value of transvaginal ultrasonography. Eur J Obstet Gynecol Reprod Biol 61:175, 1995. 45. Vimercati A, Greco P, Vera L, et al.: The diagnostic role of ‘‘in utero’’ magnetic resonance imaging. J Prenat Med 27:303, 1999. 46. Pilu G, Ambrosetto P, Sandri F, et al.: Intraventricular fused fornices: a specific sign of fetal lobar holoprosencephaly. Ultrasound Obstet Gynecol 4:65, 1994. 47. Vintzileos AM, Hovick TJ, Escoto DT: Congenital midline porencephaly: prenatal sonographic findings and review of the literature. Am J Perinatol 4:125, 1987. 48. Sperber GH, Honore´ LH, Johnson ES: Acalvaria, holoprosencephaly, and facial dysmorphism syndrome. J Craniofac Genet Dev Biol (Suppl) 2:319, 1986. 49. Ades LC, Sillence DO: Agnathia-holoprosencephaly with tetramelia (case report). Clin Dysmorphol 1:182, 1992. 50. Menezes AV, MacGregor DL, Buncic JR: Aicardi syndrome: natural history and possible predictors of severity. Pediatr Neurol 11:313, 1994. 51. Lambert JC, Ferrari M, Donzeau M, et al.: Association d’une hydrocephalie he´re´ditaire et d’une holoprosencephalie. Arch Fr Pediatr 40:397, 1983. 52. Yang SS, Roth JA, Langer LO Jr: Short rib syndrome, Beemer-Langer type with polydactyly: a multiple congenital anomalies syndrome. Am J Med Genet 39:243, 1991. 53. Thomas M, Donnai D: Bilateral brachial amelia with facial clefts and holoprosencephaly. Clin Dysmorphol 3:266, 1994. 54. Hing AV, Torack R, Dowton SB: A lethal syndrome resembling branchio-oculo-facial syndrome. Clin Genet 41:74, 1992. 55. Reish O, Gorlin RJ, Hordinsky M, et al.: Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/ BRESHECK). Am J Med Genet 68:386, 1997. 56. Stoll C, Benoit F, Peter MO, et al.: Familial association of camptodactyly, mental retardation, whistling face and Pierre Robin sequence. Clin Dysmorphol 8:247, 1999. 57. Martinez-Frias ML, Bermejo E, Garcia A, et al.: Holoprosencephaly associated with caudal dysgenesis: a clinical-epidemiological analysis. Am J Med Genet 53:46, 1994. 58. Ercal D, Say B: Cerebro-oculo-nasal syndrome: another case and review of the literature. Clin Dysmorphol 7:139, 1998. 59. Lin AE, Siebert JR, Graham JM Jr: Central nervous system malformations in the CHARGE association. Am J Med Genet 37:304, 1990. 60. Norman M, McGillivary B, Kalousek D, et al.: Holoprosencephaly: defects of the mesobasal prosencephalon. In: Congenital Malformations of the Brain. Pathological, Embryological, Clinical, Radiological and Genetic Aspects. Norman MG, McGillivray BC, Kalousek DK, et al., eds. Oxford University Press, New York, 1995, p 187. 61. Cohen MM: Perspectives on holoprosencephaly: part I. Epidemiology, genetics, and syndromology. Teratology 40:211, 1989. 62. Lurie IW, Ilyina HG, Podleschuk LV, et al.: Chromosome 7 abnormalities in parents of children with holoprosencephaly and hydronephrosis. Am J Med Genet 35:286, 1990. 63. Estabrooks LL, Rao KW, Donahue RP, et al.: Holoprosencephaly in an infant with a minute deletion of chromosome 21 (q22.3). Am J Med Genet 36:306, 1990.

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64. Van Gool S, de Zegher F, de Vries LS, et al.: Alobar holoprosencephaly, diabetes insipidus and coloboma without craniofacial abnormalities: a case report. Eur J Pediatr 149:621, 1990. 65. Ming JE, Muenke M: Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Med Genet 71: 1017, 2002. 66. Bonnemann C, Meinecke P: Holoprosencephaly as a possible embryonic alcohol effect: another observation . Am J Med Genet 37:431, 1990. 67. Conover PT, Roessmann U: Malformational complex in an infant with intrauterine influenza viral infection. Arch Path Lab Med 114:535, 1990. 68. Camera G, Lituania M, Cohen MM Jr: Holoprosencephaly and primary craniosynostosis: the Genoa syndrome. Am J Med Genet 47:1161, 1993. 69. Grote W, Rehder H, Weisner D, et al.: Prenatal diagnosis of a probable hereditary syndrome with holoprosencephaly, hydrocephaly, octodactyly, and cardiac malformations. Eur J Pediatr 143:155, 1984. 70. Hartsfield JK, Bixler D, De Myer WE: Hypertelorism associated with holoprosencephaly and ectrodactyly. J Clin Dysmorphol 2:27, 1984. 71. Kurokawa Y, Tsuchita H, Sohma T, et al.: Holoprosencephaly with Dandy-Walker cyst: rare coexistence of two major malformations. Child Nerv Syst 6:51, 1990. 72. Begleiter ML, Harris DJ: Holoprosencephaly and endocrine dysgenesis in brothers. Am J Med Genet 7:315, 1980. 73. Hockey A, Crowhurst J, Cullity G: Microcephaly, holoprosencephaly, hypokinesia-a second report of a new syndrome. Prenat Diagn 8:683, 1988. 74. Iafolla K, Fratkin JD, Spiegel PK, et al.: Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (PallisterHall syndrome). Am J Med Genet 33:489, 1989. 75. Burck U, Held KR, Kitschke HJ: Occurrence of cyclopia, myelomeningocele, deafness, and abducens paralysis in siblings. Am J Med Genet 11:443, 1982. 76. Slavotinek A, Stahlschmidt J, Moore L: Transverse limb defects, holoprosencephaly and neuronal heterotopia - a new syndrome? Clin Dysmorphol 6:365, 1997. 77. Kotzot D, Weigl J, Huk W, et al.: Hydantoin syndrome with holoprosencephaly: a possible rare teratogenic effect. Teratology 48:15, 1993. 78. Verloes A, Dodinval P, Beco L, et al.: Lambotte syndrome: microcephaly, holoprosencephaly, intrauterine growth retardation, facial anomalies, and early lethality-a new sublethal multiple retardation syndrome in four sibs. Am J Med Genet 37:119, 1990. 79. Rowlatt U, Pruzansky S: Premaxillary agenesis, ocular hypotelorism, holoprosencephaly, and extracranial anomalies in an infant with a normal karyogram. Cleft Palate J 17:197, 1980. 80. Prudlo J, Stoltenburg-Didinger G, Jimenez E, et al.: Central nervous system alterations in a case of short-rib polydactyly syndrome, Majewski type. Dev Med Child Neurol 35:158, 1993. 81. Martin AO, Perrin JCS, Muir WA, et al.: An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly. Clin Genet 12:65, 1977. 82. Barr M, Hanson JW, Currey K, et al.: Holoprosencephaly in infants of diabetic mothers. J Pediatr 102:565, 1983. 83. Keller K, McCune H, Williams C, et al.: Lobar holoprosencephaly in an infant born to a mother with classic phenylketonuria. Am J Med Genet 95:187, 2000. 84. Lurie IW, Prytkov AN, Meldere LV: Meckel syndrome in different populations. Am J Med Genet 18:661, 1984. 85. Meinecke P: Holoprosencephaly, polydactyly, and lethal outcome— another observation. Proc Greenwood Genet Center 8:78, 1989. 86. Fried K: A Meckel-like syndrome? Clin Genet 5:46, 1974. 87. Bomelburg T, Lenz W, Eusterbrock T: Median cleft face syndrome in association with hydrocephalus, agenesis of the corpus callosum, holoprosencephaly and choanal atresia. Eur J Pediatr 146:301, 1987. 88. Hall JG, Pallister PD, Clarren SK: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly-a new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Genet 7:47, 1980. 89. Moerman P, Fryns JP: Holoprosencephaly and postaxial polydactyly: another observation. J Med Genet 25:501, 1988.

90. Seller MJ, Pal K, Moscoso G, et al.: Cerebellar hypoplasia, facial dysmorphism and internal abnormalities: a new recessive syndrome? Clin Dysmorphol 7:41, 1998. 91. Christianson AL, Kruger H, Dini L: Atypical acrofacial dysostosis syndrome. Am J Med Genet 51:32, 1994. 92. Martinez-Frias ML, Bermejo E, Urioste M, et al.: Short rib-polydactyly syndrome (SRPS) with anencephaly and other central nervous system anomalies: a new type of SRPS or a more severe expression of a known SRPS entity? Am J Med Genet 47:782, 1993. 93. Kelley RI: RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. Am J Hum Genet 63:322, 1998. 94. Nothen MM, Knopfle G, Fodisch H-J, et al.: Steinfeld syndrome: report of a second family and further delineation of a rare autosomal dominant disorder. Am J Med Genet 46:467, 1993. 95. Mazal PR, Schuhfried G, Budka H: Trilobar holoprosencephaly (‘‘triprosencephaly’’) a unique type of cerebral malformation. Acta Neuropathol (Berl) 89:567, 1995. 96. Turner G, Gedeon A, Mulley J: X-linked mental retardation with heterozygous expression and macrocephaly: pericentromeric gene localization. Am J Med Genet 51:575, 1994. 97. Meinecke P, Beemer FA, Schinzel A, et al.: The velo-cardio-facial (Shprintzen) syndrome. Eur J Pediatr 145:539, 1986. 98. Zlotogora J, Dagan J, Ganen A, et al.: A syndrome including thumb malformations, microcephaly, short stature, and hypogonadism. J Med Genet 34:813, 1997. 99. Wessels MW, Den Hollander NS, Cohen-Overbeek TE, et al.: Prenatal diagnosis and confirmation of the acrofacial dysostosis syndrome type Rodriguez. Am J Med Genet 113:97, 2002. 100. Johnson VP, McMillin JM, Aceto T Jr, et al.: A newly recognized neuroectodermal syndrome of familial alopecia, anosmia, deafness, and hypogonadism. Am J Med Genet 15:497, 1983. 101. White BJ, Rogol AD, Brown KS, et al.: The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review. Am J Med Genet 15:417, 1983. 102. Hunter AGW, Feldman W, Miller J: Characteristic craniofacial appearance and brachytelephalangy in a mother and son with Kallmann syndrome in the son. Am J Med Genet 24:527, 1986. 103. Perrin JCS, Idemoto JY, Sotos JF, et al.: X-linked syndrome of congenital ichthyosis, hypogonadism, mental retardation and anosmia. Birth Defects Orig Artic Ser XII(5):267, 1976. 104. Nwokoro NA, Jaffe R, Barmada M: Baller-Gerold syndrome: a postmortem examination. Am J Med Genet 47:1233, 1993. 105. Hall BD, Spranger JW: Campomelic dysplasia. Am J Dis Child 134:285, 1980. 106. Cumming WA, Ohlsson A, Ali A: Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:783, 1986. 107. Carpenter BF, Hunter AGW: Micromelia, polysyndactyly, multiple malformations, and fragile bones in a stillborn child. J Med Genet 19:311, 1982. 108. Cohen MM Jr: The Child with Multiple Birth Defects. Raven Press, New York, 1982, p 78. 109. Cohen MM Jr: Craniosynostosis: Diagnosis, Evaluation, and Management. Raven Press, New York, 1986. 110. Conley ME, Beckwith JM, Mancer JFK, et al.: The spectrum of Di George syndrome. J Pediatr 94:883, 1979. 111. Bamforth JS, Lin CC: DK-phocomelia phenotype (von Voss-Cherstvoy syndrome) caused by somatic mosaicism for del(13q). Am J Med Genet 73:408, 1997. 112. Fitch N, Sorolovitz H, Robitaille Y, et al.: Absent left hemidiaphragm, arhinencephaly, and cardiac malformations. J Med Genet 15:399, 1978. 113. Fryns JP: Fryns syndrome: a variable MCA syndrome with diaphragmatic defects, coarse face, and distal limb hypoplasia. J Med Genet 24:271, 1987. 114. Wilson GN: Cranial defects in the Goldenhar syndrome. Am J Med Genet 14:435, 1983. 115. Holmes LB, Schoene WC, Benacerraf BR: New syndrome: brain malformation, growth retardation, hypokinesia and polyhydramnios in two brothers. Clin Dysmorphol 6:13, 1997. 116. Baetz-Greenwalt B, Ratliff NB, Moodie DS: Hypoplastic right-sided heart complex: a cluster of cases with associated congenital birth defects. A new syndrome? J Pediatr 103:399, 1983.

Brain 117. Verloes A, Narcy F, Fallet-Bianco C: Syndromal hypothalamic hamartoblastoma with holoprosencephaly sequence, microphthalmia, pulmonary malformations, radial hypoplasia and mu¨llerian regression: further delineation of a new syndrome? Clin Dysmorphol 4:33, 1995. 118. Sultan Z, Gnanaratnam J, Sharief N: Isolated aplasia of the anterior pituitary gland with unusual associations. Clin Dysmorphol 5:347, 1996. 119. Antoniades K, Baraister M: Proboscis lateralis: a case report. Teratology 40:193, 1989. 120. Hurst JA, Hallam LA, Hockey KA: Leptomeningeal angiomatosis, absent olfactory tracts, hypoplasia of the cerebellar vermis, cleft lip and palate and congenital heart disease in a stillborn infant. Clin Dysmorphol 1:168, 1992. 121. Barr M, Cohen MM Jr: The kidney-skull connection: is selective or general hypotension a teratogenetic mechanism? Proc Greenwood Genet Center 10:61, 1991. 122. Meinecke P, Bonnemann CG, Laas R: Microgastria-hypoplastic upper limb association: a severe expression including microphthalmia, single nostril and arhinencephaly. Clin Dysmorphol 1:43, 1992. 123. Ades LC, Clapton WK, Morphett A, et al.: Polydactyly, campomelia, ambiguous genitalia, cystic dysplastic kidneys, and cerebral malformation in a fetus of consanguineous parents: a new multiple malformation syndrome, or a severe form of oral-facial-digital syndrome type IV? Am J Med Genet 49:211, 1994. 124. Le Marec B, Odent S, Urvoy M: A new syndrome with ptosis, coloboma and mental retardation. Genet Couns 3:119, 1992. 125. Kimura H, Ito Y, Koda Y, et al.: Rubinstein-Taybi Syndrome with thymic hypoplasia. Am J Med Genet 46:293, 1993. 126. Mattei J-F, Ayme S: Syndrome of polydactyly, cleft lip, lingual hamartomas, renal hypoplasia, hearing loss and psychomotor retardation: variant of the Mohr syndrome or a new syndrome? J Med Genet 20:433, 1983. 127. Winter RM, Wigglesworth JS: Unusual association of cerebral and renal abnormalities. Clin Dysmorphol 2:71, 1993. 128. Stewart FJ, Carson DJ, Thomas PS, et al.: Wolcott-Rallison syndrome associated with congenital malformations and a mosaic deletion 15q11-12. Clin Genet 49:152, 1996. 129. Mathias RS, Lacro RV, Jones KL: X-Iinked laterality sequence: situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:111, 1987. 130. Corona-Rivera A, Corona-Rivera JR, Bobadilla-Morales L, et al.: Holoprosencephaly, hypertelorism, and ectrodactyly in a boy with an apparently balanced de novo t(2;4)(q14.2;q35). Am J Med Genet 90:423, 2000. 131. Imaizumi K, Ishii T, Masuno M, et al.: Association of holoprosencephaly, ectrodactyly, cleft lip/palate and hypertelorism: a possible third case. Clin Dysmorphol 7:213, 1998. 132. Olsen CL, Hughes JP, Youngblood LG, et al.: Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York state, 1984–1989. Am J Med Genet 73:217, 1997. 133. Croen LA, Shaw GM, Lammer EJ: Holoprosencephaly: epidemiologic and clinical characteristics of a Californian population. Am J Med Genet 64:465, 1996. 134. Urioste M, Valcarcel MA, Gomez I, et al.: Holoprosencephaly and trisomy 21 in a child born to a nondiabetic mother. Am J Med Genet 30:925, 1988. 135. Matsunaga E, Shiota K: Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology 16:261, 1977. 136. Taylor AI: Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. J Med Genet 5:227,1968. 137. Roessler E, Muenke M: Holoprosencephaly: a paradigm for the complex genetics of brain development. J Inherit Metab Dis 21:481, 1998. 138. Odent S, Le Marec B, Munnich A, et al: Segregation analysis in nonsyndromic holoprosencephaly. Am J Med Genet 77:139, 1998. 139. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al.: Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers. Am J Med Genet 78:140, 1998.

545 140. Croen LA, Shaw GM, Lammer EJ: Risk factors for cytogenetically normal holoprosencephaly in California: a population-based casecontrol study. Am J Med Genet 90:320, 2000. 141. Sulik KK, Cook CS, Webster WS: Teratogens and craniofacial malformations: relationship to cell death. Development (Suppl) 103:213, 1988. 142. Lammer EJ, Chen DT, Hoar RM, et al.: Retinoic acid and embryopathy. N Engl J Med 313:837, 1985. 143. O’Rahilly R, Muller F: Human Embryology and Teratology. WileyLiss, New York, 1992, p 3. 144. Siebert J, Cohen MM Jr, Sulik K, et al.: Holoprosencephaly. An Overview and Atlas of Cases. Wiley-Liss, New York, 1990. 145. Roessler E, Muenke M: How a Hedgehog might see holoprosencephaly. Hum Mol Genet 12 (Supp 1):R15, 2003. 146. Schell-Apacik C, Rivero M, Knepper JL, et al.: SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Hum Genet 113:170, 2003. 147. Golden JA, Bracilovic A, McFadden KA, et al.: Ectopic bone morphogenetic proteins 5 and 4 in the chicken forebrain lead to cyclopia and holoprosencephaly. Proc Nat Acad Sci USA 96:2439, 1999. 148. Melhuish TA, Wotton D: The interaction of the carboxyl terminusbinding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF. J Biol Chem 275:39762, 2000. 149. Ming JE, Kaupas ME, Roessler E, et al.: Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 110:297, 2002. 150. Zang XM, Ramalho-Santos M, McMahon AP: Smoothened mutants reveal redundant roles for shh and ihh signaling including regulation of l/r asymmetry by the mouse node. Cell 105:781, 2001. 151. Sussel L, Marion O, Kimura S, et al.: Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular specification within the basal telencephalon: evidence for transformation of the pallium into the striatum. Development 126:3359, 1999. 152. Hallonet M, Hollemann T, Pieler T, et al.: Vax1, a novel homeoboxcontaining gene, directs development of the basal forebrain and visual system. Genes Dev 13:3106, 1999. 153. Cooper MK, Porter JA, Young KE, et al.: Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280:1603, 1998. 154. Aguilella C, Dubourg C, Attia-Sobol J, et al.: Molecular screening of the TGIF gene in holoprosencephaly. Hum Genet 112:131, 2003. 155. Nanni L, Croen LA, Lammer EJ, et al.: Holoprosencephaly: molecular study of a California population. Am J Med Genet 90:315, 2000. 156. Muenke M, Gropman A: Holoprosencephaly overview. In: GeneReviews: Genetic Diseases Online Reviews at GeneTests-GeneClinics [database online]. Copyright University of Washington, Seattle. Available at http:// www.geneclinics.org, 2003. 157. Chiang C, Litingtung Y, Lee E, et al.: Cyclopia and defective axis patterning in mice lacking sonic hedgehog gene function. Nature 383: 407, 1996. 158. Lieuw Kie Song SH, Been W: Median facio-cerebral anomalies in chick embryos resulting from local destruction on the anterior-most parts of the early neural plate and neural crest. Acta Morphol Neerl Scand 18:231,1980. 159. Siebert JR: The ethmoid bone: implications for normal and abnormal facial development. J Craniofac Genet Dev Biol 1:381, 1981. 160. Braddock SR, Grafe MR, Jones KL: Development of olfactory nerve: its relationship to the craniofacies. Teratology 51:252, 1995. 161. Brown LY, Odent S, David V, et al.: Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum Mol Genet 10:791, 2001. 162. Marcorelles P, Loget P, Fallet-Bianco, et al.: Unusual variant of holoprosencephaly in monosomy 13q. Pediatr Dev Pathol 5:170, 2002. 163. Barr M Jr, Cohen MM Jr: Holoprosencephaly survival and performance. Am J Med Genet 89:116, 1999. 164. Hercig D, Bau A, Resnek L: Psychosis associated with lobar holoprosencephaly. Can J Psychiatry 39:449, 1994. 165. Shanks DE, Wilson WG: Lobar holoprosencephaly presenting as spastic diplegia. Dev Med Child Neurol 30:378, 1988. 166. Moulignier A, Fenelon G, Aubin ML, et al.: Holoprosencephalie lobaire associe´e a des he´te´rotopies de substance grise. Rev Neurol 146:51, 1990.

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167. Persing JA: Craniofacial surgery and the ethics of decision-making. Cleft Palate Craniofac J 39:357, 2002. 168. Redlinger-Grosse K, Bernhardt BA, Berg K, et al.: The decision to continue: the experiences and needs of parents who receive the prenatal diagnosis of holoprosencephaly. Am J Med Genet 112:369, 2002. 169. Verlinsky Y, Rechitsky S, Verlinsky O, et al.: Preimplantation diagnosis for sonic hedgehog mutation causing familial holoprosencephaly. N Eng J Med 348:1449, 2003. 170. Parr JH: Midline cerebral defects and Kallmann’s syndrome. J R Soc Med 81:355, 1988.

15.5 Malformations of Cortical Development: Disorders of Neuronal and Glial Formation, Migration, and Maturation; Lissencephaly, Pachygyria, Polymicrogyria, Heterotopias, Ectopias, and Cortical Dysplasias Malformations of cortical development are any significant disturbance to the embryogenesis of the cellular architectonics of the six-layered cerebral cortex, which will result in a quite predictable alteration in the gross morphologic appearance of the brain. Careful neuroimaging and attention to clinical-pathologic correlation has led to a greater ability to make the reverse prediction, and in some situations, to suggest the gene that is most likely to have been involved. However, it remains true that the same gross pathology can result from markedly different underlying histopathology. Furthermore, several morphologic, and therefore cellular architectonic, abnormalities can coexist within the same brain. Distinct and recognizable patterns of cellular disturbance may result from diverse genetic and environmental causes. Specific recognition of extrinsic etiologies may be hampered because the brain is incapable of mounting a glial scarring response during the first and second trimesters of pregnancy. A general understanding of the normal pattern of the origin and migration of the neurons and glia is helpful when considering cortical malformations. The reader is referred to the original referenced papers for a more complete discussion of cortical development than is provided in this brief overview. Morphogenesis of the cerebral cortex can be divided into the three distinct, but overlapping, stages of neurogenesis, migration, and organization. Neurons develop from about 40 to 125 days gestation in subependymal proliferative zones that are present along the entire maturing neural tube.1 There are peaks of neuronal production between 8 to10 weeks and at 12 to 14 weeks, with a maximum at 13 weeks.1 In this ventricular zone (VZ), cells in the deeper regions prepare for mitosis and migrate toward the luminal surface, where they divide.2 The daughter cells move to the more superficial VZ, and the process continues back and forth until the cells cease to divide, and migrate to their ultimate cortical positions as neuroblasts and glioblasts, which are initially indistinguishable.2 In some regions a subventricular zone develops in which cells divide, and later migrate, without initially moving to the ventricular lumen.2,3 Some 30% to 50% of young neurons may undergo programmed cell death. A decrease in cell proliferation, excessive cell death, or an alteration in determination of cellular fate at this stage will have a profound impact upon cortical morphogenesis. Mutations in the transcription factor EMX2 have been found in a few cases of open-lipped schizencephaly (see Section 15.11).4 Emx2 is normally produced at the VZ, and mice lacking Emx2 fail to produce radial glial cells (RGC) and lose the ability to produce reelin, thus preventing the next stage of cortical development, which is neuronal migration.5

Cell migration begins by 7 weeks gestation, shortly after neuroblast histiogenesis begins, and continues to about 25 weeks gestation, although the exact endpoint is unknown. At the outset, the cerebrum is limited to the VZ and a narrow marginal zone (MZ) between it and the pia.3 Studies in mice, in which migration occurs between E11 and E18, show that the initial wave of cells that moves toward the pial surface forms a ‘‘preplate’’ neuronal layer.6 A second wave of cells at E13, which forms the cortical plate, splits the preplate into the superficial marginal (plexiform) layer and the subplate, through which all subsequent migrating cells must pass. The marginal zone produces an early synaptic network, mainly of Cajal-Retzius (CR)–like neurons and contains a transient subpial granular cell layer.7,8 The origin of these initial cells remains under study, 7,8 but they are known to secrete reelin, which plays a critical role in cell migration and cortical lamination (vide infra). The subplate neurons are thought to play a role in the early patterning of the internal capsule and commissural fibers of the hippocampus.8 Migration to the cortical plate occurs either by nuclear translocation, which is glial independent, or by locomotion, which requires the presence of specialized radial glial cells (RGC). RCG arise from the VZ before the neuroblasts, and bipolar and monopolar forms produce a radial array of processes, resulting in an intermediate zone (IZ), along which the neuroblasts maintain an intimate contact as they migrate. Bergmann glial cells are the monopolar equivalent in the cerebellum. Radial cells in the superficial ventricular zone (SVZ) or the IZ maintain contact through their descending processes with the basal processes of cells in the VZ.3 RGC remain mitotically active and give rise to further generations of RGC. Important features of the RGC architecture are: 1) they are gathered into bundles as they cross the IZ, and 2) these fascicles become split in a stepwise fashion across the cortical plate until they are ultimately single fibers. The migrating neuroblasts appear to contact multiple RGC fibers as they move up the fascicle; but, as they reach their cortical destination, they move between and separate the fascicle fibers and thus may play a role in controlling the destination of future neuroblasts.3 The initial migrating neurons need only travel a relatively short distance, which permits their own cellular processes to extend to the final destination, and migration can occur by the smooth and continuous process of nuclear translocation to that site.6 As distances become greater, migration becomes dependent upon the integrity of, and interaction with, the RGC. There is evidence that neurons can leave the RGC as they approach their destined lamina and complete the journey by nuclear translocation. Locomotion along the RCG is an intermittent process requiring production of a ‘‘leading process’’ to which the remainder of the cell catches up. The mature cortex consists of six layers (Fig. 15-15): the superficial, relatively acellular, marginal layer (I) and five cellular neuronal layers (II-VI), which are formed embryologically in order from deepest to most superficial but which are named in reverse order from outside in. Cortical lamination is apparent by 23 to 25 weeks gestation, and the outermost layers, II and III, have reached the cortical plate by 26 weeks gestation.1 Layers II and III contain small to medium-sized pyramidal cells; layer IV, stellate cells; layer V, large pyramidal cells; and layer VI, polymorphic cells.3 After the cells reach their destination, there is some orthogonal migration, and growth continues with the development and organization of dendrites, axons, and glial cells. In addition to this predominant radial migration, there is evidence of non-radial migration of cells from the medial ganglionic eminence, and that

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orders according to their presumed pathogenic pathway with subdivision according to clinical and/or genetic detail, and potential but as yet undescribed categories, is attractive and to some extent followed in this section: 1. abnormal neuronal and glial proliferation, 2. abnormal neuronal migration, and 3. abnormal cortical organization. These groups provide a useful framework for thinking about these disorders. However, as emphasized by the authors, our understanding of the detail of underlying pathogenesis is limited, and major shifts are to be expected between major categories and subgroups. As an example, schizencephaly is listed under ‘‘cortical disorganization,’’ whereas the Emx2 mouse model would suggest some cases result from decreased proliferation of RGC. 15.5.1 Lissencephaly

Fig. 15-15. Section through cortex showing the normal six-layered appearance. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

Lissencephaly is a generalized failure of the normal pattern of cortical neuronal migration resulting in a smooth cerebral cortex with absent gyral formation (agyria). Some authors prefer the term agyria/pachygyria to lissencephaly because agyria of the entire cortex is relatively uncommon. Lissencephaly is used in this section because the term has become firmly associated with welldefined subtypes of generalized neuronal migration disorders, in several cases due to mutations in known genes. Children with a birth OFC < 3 SD and a lissencephalic brain are classified as having microcephaly with simplified gyral pattern (MSG). Originally called microlissencephaly and classified by Barkovich et al.10 under ‘‘abnormal neuronal and glial proliferation,’’ this condition is discussed in Section 15.1. In fact, our present knowledge does not provide a biologic basis on which to define this demarcation. Diagnosis

these cells are an important source of GABA-staining cortical neurons.9 Cells in the cerebellum migrate from germinal zones over the surface, thus forming the external granular cell layer; they then move inward to form the internal granular cell layer. Over a dozen genes in man, mouse, and other animal models are now known to play a role in migration, and there is little doubt that more will be discovered.4 Specific human genes that have been associated with defined clinical-pathological cortical malformations will be included in the discussion of those conditions that follow. Animal models have also been instructive. For example, mouse studies have shown that Reln (reeler mouse), Dab1 (scrambler and yotari mice), Vldlr (very low density lipoprotein receptor), and ApoER2 (Apolipoprotein E receptor 2) are all part of the same signaling pathway, which when disrupted causes a failure of splitting of the preplate, with the cortical layers remaining below this level and in an inverted order.6 The cells responsible for splitting of the subplate normally arrive at E13 by nuclear translocation, and the histopathology observed with these mutations differs from that seen in other signaling pathways that more closely relate to locomotion and/or the RGC. As our knowledge of the pathogenesis of cortical malformations increases, there is need for a nosology that takes us beyond the purely descriptive. The clinician requires an approach that logically connects the clinical and neuroimaging presentation of the patient with the growing array of DNA diagnostic tests that are becoming available. It is reasonable to assume that genes and teratogens that act at a particular time and on a specific process will have a similar effect upon the histopathology and thus the gross pathology of the cortex. Thus, the effort by Barkovich et al.10 to group these dis-

Lissencephaly may be suspected on the basis of neonatal behavior, appearance, and the presence of commonly associated malformations. Neonates usually present with moderate microcephaly, poor responsiveness and feeding, hypotonia, and often early-onset seizures. Confirmation is readily provided by neuroimaging, which demonstrates a smooth, thick cortex with smooth subsurface lines and an early fetal pattern of the ventricular system resembling colpocephaly (see Section 15.9). With lack of development and operculization, the sylvian fissure is replaced by a fossa and results in a ‘‘figure 8’’ appearance of the brain (Fig. 15-16). Dobyns et al.11 used the specific microscopic pathologic findings to define subtypes of lissencephaly and have further subdivided the classic form (type I) according to the degree of gyral abnormality12 and cerebellar involvement.13 The gyral gradations are grade 1 (diffuse agyria), grade 2 (diffuse agyria with a few shallow sulci over the frontal or occipital pole), grade 3 (mixed agyria and pachygyria), grade 4 (pachygyria only), grade 5 (pachygyria with subcortical band heterotopia (SBH), and grade 6 (SBH only). The classification appears to have validity in that there is good correlation between specific subtypes and certain syndromes and/or specific genes. Classic (type I) lissencephaly is characterized by a smooth neocortex, which may spare the hippocampus and the temporal and limbic cortex (Fig. 15-17). The head circumference at birth usually lies between 1 SD and 2 SD, falling to about 2 SD as the child grows, but microcephaly does not occur in a significant proportion of cases. A majority of children will have treatmentresistant seizures, and both spastic quadriparesis and hypotonia with increased tendon reflexes are common. Although patients with isolated classic lissencephaly have been considered to be

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Fig. 15-16. CT image of a patient with Miller-Dieker syndrome showing the characteristic ‘‘figure 8’’ appearance of lissencephaly. (Courtesy of Dr. W.B. Dobyns, Indiana University School of Medicine, Indianapolis, and Dr. A.E. Chudley, Children’s Hospital, Winnipeg)

normal in appearance, minor facial dysmorphia are not uncommon, and they have been shown to have a similar facial pattern profile to patients with Miller-Dieker syndrome (Fig. 15-18).14 There is hypoplasia of the corticospinal tract and lateral rhombic lip derivatives. When the cerebellum is involved the hypoplasia is maximal in the midline, affecting the vermis, sometimes including mild hypoplasia of the hemispheres, but folia are maintained.13 This midline cerebellar involvement is considered characteristic of classic lissencephaly by Ross et al., and

Fig. 15-17. Gross lissencephaly brain specimen showing smooth cortical surface with shallow sylvian fissure. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

Fig. 15-18. Photograph of patient showing the typical facial appearance of Miller-Dieker syndrome. (Courtesy of Dr. A.E. Chudley, Children’s Hospital, Winnipeg.)

is classified as type LCHa in their discussion of lissencephaly with cerebellar involvement (LCH).13 The overall cortical thickness is increased with more gray matter and less white (Fig. 15-19). This increase varies from moderate levels of 5–10 mm to more marked values of 10–20 mm depending upon the particular syndrome/ gene involved. The MRI detection of a thin cortical band with a high T2-weighted signal may be helpful in distinguishing classic lissencephaly. This band represents a partially myelinated layer with reduced cell numbers, which lies beneath the true cortex.15 Microscopically the cortex consists of four, rather than the normal six, layers (Fig. 15-20): an outer, abnormally wide molecular layer; a relatively thin superficial layer of neurons oriented perpendicular to the surface; a plexus of myelinated fibers horizontal to the cortex and containing few nerve cells; and a thick, poorly organized, deep cellular layer joining the thin layer of white matter and representing neurons that failed to migrate. The third layer may not be apparent in the very young, and the fourth layer may become subdivided by myelinated fibers in older children.16 The four cortical layers do not blend into normal adjacent cortex and are thus distinguished from the findings in true polymicrogyria. The combination of gross cerebral and cerebellar pathology, and histopathologic differences, can be combined to better define subtypes of classic lissencephaly, and these in turn show useful clinical-genotype correlation (Table 15-5). In a preliminary study,

Brain

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Fig. 15-19. Lateral gross view and parahorizontal section from a fetus at 34 weeks gestation with lissencephaly and dilatation of the posterior lateral ventricles (V). The surface of the cerebral cortex is smooth (arrows). Other findings include heterotopic foci of gray matter and septum cavum pellucidi defect. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Viot et al.298 have proposed that lissencephaly due to mutations in DCX (vide infra) result in a roughly ordered ‘‘six-layered’’ cortex. Cobblestone (type II) lissencephaly is thought to represent the migration of neurons beyond the cortical plate and marginal zone, through a disrupted pial-glial limitans, and into the leptomeninges. This results in a pitted, verrucous (cobblestone) layer over the surface of the cortex (Fig. 15-21). This type of lissencephaly does not occur as an isolated malformation, but rather is accompanied by additional abnormalities of the brain, eyes, and muscles in specific syndromes (Fig. 15-22; Table 15-5). The clinical and pathologic severity varies with the specific syndrome, and most cases have been associated with Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), or Fukuyama congenital muscular dystrophy (FCMD), which are listed in descending order of severity. In its most severe expression, the cerebrum is void of gyri except for a shallow sylvian fissure. A few patients may have some areas of abortive gyri with shallow, distorted fissures. The cortex is relatively thickened (7–10 mm), and the third and lateral ventricles are grossly dilated. Obstructive hydrocephalus due to gliovascular and mesodermal overgrowth can usually be demonstrated. Hydrocephalus may obscure the characteristic smooth surface of lissencephaly in neuroimaging sections (Fig. 15-22), and diagnosis depends on recognition of the smooth subsurface lines. Associated neuropathologic findings may include a small, dysplastic cerebellum with a simple foliar pattern, absent posterior vermis, and hypoplastic anterior vermis. The cerebellar cortex is usually thickened but may be absent in small areas. Olfactory elements may be absent or hypoplastic, and the optic pathway (in association with malformations of the eye) is often hypoplastic.

The cerebral hemispheres, notably the frontal areas, may be fused by a gliosis; the septum pellucidum is absent and the corpus callosum absent or hypoplastic. The claustrum is absent, and most deep nuclei are present but small. A variety of brain stem structures may be affected, largely related to lack of their usual cortical and cerebellar connections.17 Dandy-Walker cysts or posterior cephaloceles may occur. The cerebral white matter has a spongy edematous appearance, and subependymal cavitations have been observed. Microscopic examination shows clear differences from type I.17 The cortex lacks normal lamination, and two broad laminations may be recognized.9 An outer band is broken into pockets of cells and acellular zones by ingrowing gliovascular bundles that show extensive proliferation near the surface and in the subarachnoid space (Fig. 15-23). Glial fibrous bands may interrupt the gray matter. Cell columns are sparse and disoriented, as are neurons that have reduced axons. Oligodendrocytes and myelin are reduced. A deeper layer of disorganized neurons may represent the original cortical plate.9 Neuronal heterotopias are present in the deeper cortex and white matter. Adjacent areas of pachygyria and polymicrogyria show similar pathology but with greater acellular areas and are thus distinct from classic pachygyria and polymicrogyria. The pathologic cortical findings in Neu-Laxova syndrome, although not unique to that syndrome (Table 15-5), have been referred to as type III lissencephaly.18 Findings vary somewhat but are characterized by virtual agyria and by a granular-appearing cortex. The corpus callosum is generally absent, the cerebellum very hypoplastic; olfactory and optic tracts, quadrigemina, basal ganglia, and thalami are hypoplastic or absent. Identifiable nuclei tend to show immature forms. The third and fourth ventricles

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Fig. 15-20. Section from cortex of a patient with Norman-Roberts type lissencephaly showing three to four layers. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

may have an open roof; the cortex is thin, and there is poor gray matter/white matter distinction. In most studied cases there are six cortical layers with many immature neurons, and glial elements are seen in the periventricular area. Within the same case, the small cerebellum may consist of two to four layers. Immature neurons are found in the white matter, especially the wall of the fourth ventricle. Patients whose pathologic findings in the brain are less clearly defined have been described and are included in Table 15-5. Etiology and Distribution

Lissencephaly is the endpoint of causally heterogeneous abnormalities of neuronal migration (Table 15-5). Details of the embryology of neuronal migration have been published by Sidman and Rakic58 and summarized in a number of recent reviews4,6,9,59 (see also Fig. 15-24). The discovery of a number of genes in which mutations cause lissencephaly is leading to a greater understanding of the gene interactions and processes that are required for neurons to migrate along the RGC and to successfully settle at their appropriate lamina. In classic (type I) lissencephaly, early layering of the cerebral cortex and relative preservation of the cerebellum and specific areas affected are compatible with arrest of development at 11 to 13 weeks gestation and with primary involvement of the pallial and rhombic lip pathways (Fig. 15-24). In what Dobyns et al.11 have called the cerebrocerebellar lissencephaly variant of type I (Table 15-5), changes are most compatible with disrupted development at 8 to 9 weeks gestation; the cerebellar pathway is also

involved and results in extreme cerebellar hypoplasia. In some patients, the absence of cortical layering suggests an earlier occurrence of developmental arrest than in those who have a fourlayered cortex.11,21 Haploinsufficiency of LIS1 was the first gene to be identified as causing classic lissencephaly.60 It is deleted in all patients with Miller-Dieker syndrome and accounts for 40% of isolated classic lissencephaly. The gene product, a non-catalytic alpha subunit of intracellular 1b isoform platelet activating factor acetylhydrolase (PAFAH1b1), is widely distributed from early fetal to adult life in the brain and spinal cord.61 More recently, patients with a milder lissencephaly phenotype have been found to have missense mutations in LIS1, raising the potential for under-ascertainment of patients with milder migrational defects caused by mutations in this gene.62 From a series of patients it has been noted that those with LIS1 deletions or null mutations in the coded coil domain (exons 2–5) had a grade 2–3 cortical severity; those with null mutations more distally generally were grade 3–4, whereas missense mutations, with the exception of those involving a critical amino acid, were even less severe.12 Studies of null and hypomorphic conditional knockout mice6,9 have shown that Lis1/ is a trophoblast stage lethal, and that cortical disruption in heterozygotes is Lis1 dose dependent. The primary embryopathology is a slowing of cell migration. In mild Lis1 deficiency, the cortical lamination proceeds in its normal inside-out direction but the layers are indistinct; more severe reduction of Lis1 results in failed subplate splitting and a complete loss of lamination.63 PAFAH is an inactivator of platelet activating factor (PAF), and it is not clear whether or not LIS1, in its role as a subunit of PAFAH, has a direct effect upon neuronal migration, but altered signal transduction could act upon the neuronal cytoskeleton. The current consensus is that the critical role of LIS1 is its microtubule-associated regulation of dynein activity. This system is highly conserved from yeast, to flies and mammals. Work with NudF (aspergillus nidulans equivalent of LIS1) has shown that it interacts with a tyrosine kinase (NudC) and a cytoplasmic dynein (NudA), with additional involvement of NudE (mouse Nudel), which binds to NudF and the dynein light chain.64,65 Findings are similar in drosophila and mammals. LIS1, dynein, and the dynein-regulatory complex localize to the VZ and cortical plate, and play a key role in microtubular organization in the cell periphery.4 Disruption might well affect production or function of the leading process or ‘‘catch up’’ of the cell body, thus impairing locomotion during RGC-related neuronal migration. The LIS1-dynein complex may also have a direct effect on cell division and nuclear translocation. LIS1 is localized to the kinetocores and the mitotic spindle, and varying LIS1 levels can cause in vitro disruption of mitosis.66 Diminished cell number, and delayed production of cells and altered interkinetic nuclear migration, which would both alter the timing of migration, would be expected to disrupt normal cortical lamination. The gene 14-3-3e (YWHAE) lies 40kb telomeric of LIS1 on 17p13.3, and its concurrent deletion in patients with MillerDieker syndrome appears to account for the greater severity of lissencephaly (grade 1) in that syndrome, as compared to patients with deletions restricted to LIS1 (grades 2–3).67 The gene product of 14-3-3e binds to and prevents the dephosphorylation of CDK5/ p35 phosphorylated NUDEL, and is necessary for localization of NUDEL, and for the functioning of the dynein complex.22 Mice deficient in 14-3-3e have brain pathology equivalent to heterozygous Lis1 deficient mice, whereas compound heterozygotes for Lis1 and 14-3-3e are more severely affected.22

Table 15-5. Syndromes with lissencephaly Syndrome

Prominent Features

Causation Gene/Locus

Microlissencephaly-cardiacspinal urogenital19

Severe growth and developmental delay, quadriparesis, roving eye movements, early death, ventricular septal defect, distal arthrogryposis, urethral valves, hypospadias; consanguinity

AR/XLR?

Microcephaly-simplified gyri20

Severe congenital microcephaly, early onset seizures, normal tone to mild spasticity, simplified gyral pattern on neuronal imaging

AR (603802) Not linked to 17p, 8p22

Barth: cerebro-cerebellar I21

No extracranial anomalies, very small brain, extreme neopallial and cerebellar hypoplasia, failure of mesencephalic flexure, absence of rhombic lip and cortico-spinal structures

Probable AR

Miller-Dieker22,23

Microcephaly usually of postnatal onset, prominent occiput, bitemporal narrowing; low, rotated ears, upturned nares, long, thin upper lip, micrognathia, postnatal growth failure, genital and heart anomalies, absent corpus callosum, calcification between lateral ventricles, profound mental retardation (Figs. 15-16 and 15-18)

(247200) del 17p13.3; may be sub-microscopic LIS1, 14-3-3e

Norman-Roberts24

Microcephaly, small forehead, wide-set eyes, micrognathia, flat nasal bridge, chordee, clinodactyly 5th finger, high number of whorls on finger-tips, low brain:total weight ratio; some consider this is LCHb and due to RELN mutations but unproven

AR (257320) RELN, 7q22?

Isolated lissencephalygeneral23,25

Extracranial anomalies other than deformations rare: agenesis of the corpus callosum less common than in Miller-Dieker; when present, calcifications are scattered and may be periventricular; ~75–80% associated with known genes

Heterogeneity AD/XLR/AR

Isolated lissencephaly-LIS1 associated12,26

Cortex 10–20 mm, posterior ! anterior gradient, cell sparse zones in agyric areas, midline cerebellar involvement, grades 2–4 severity; deletions (40%) and point mutations

AD (607432) LIS1, 17p13.3

Isolated lissencephaly-DCX associated12,13,27

Cortex 10–20 mm, anterior ! posterior gradient, cell sparse zones in agyric areas, SBH in female heterozygotes, grade of severity variable but 3 uncommon

XLD (300121) DCX, Xq22.3q23

Isolated lissencephaly-RELN associated (LCHb)12,86

Cortex 5–10 mm, anterior ! posterior gradient, no cell sparse zones in agyric areas, abnormal hippocampus, cerebellar hypoplasia

AR (605140) RELN, 7q22

Isolated lissencephaly-14-3-3e associated12,22

Posterior ! anterior gradient, grade 1 severity when deleted with LIS1

AD/biallelic, 17p13.3

Lissencephalyhypomyelinating neuropathy29

Arthrogryposis, severe developmental delay, microcephaly, axonal neuropathy with hypomyelination. Single case

Unknown

X-linked-abnormal genitalia (XLAG)12,30

Cortex 5–10 mm, posterior ! anterior gradient, no cell sparse zones in agyric areas, deficient small cortical granular cells, immature white matter, poorly demarcated basal ganglia that may have small cysts, agenesis corpus callosum (includes 50% of females), neonatal onset of seizures, hypothalamic dysfunction, ambiguous male genitalia

XLR (300382, 300215) ARX, Xp22.13

Microlissencephaly

Classic (Type I) Lissencephaly

Cobblestone (Type II) Lissencephaly

Cobblestone lissencephalynormal eyes and brain31

Moderate to severe developmental delay, mild axial hypotonia and lower limb spasticity, Dandy-Walker, ventriculomegaly, brain stem hypoplasia, normal eye examination including ERG, normal CK

AR

Cobblestone lissencephalyretinal atrophy32

Profound mental retardation, abnormal cerebellum, severe myopia; sectors of retina of varied thickness with gliosis and disordered layers, gliotic optic nerve; normal muscle; eye pathology considered distinctive

Unknown

Dobyns: cephalocele-retinal elevation11

Large fontanels, cephalocele, mild microcephaly, abnormal ears, myopia, peripheral retinal elevation, low nasal bridge, epicanthus, ptosis, small jaw; one case

Unknown

Dobyns: facio-oculo-aural33

Microcephaly, mild trigonocephaly, short nose and jaw, flat philtrum, low-set ears with absent crura and antihelix, microcornea, ectopic pupils, choroidal coloboma, finger contractures, absent corpus callosum

Unknown

Fukuyama: cerebro-oculomuscular4,34,35

Less severe than Walker-Warburg, developmental delay, small areas of agyria, pachygyria/ polymicrogyria microscopically as in type II lissencephaly, mild cerebellar foliation defects, minor or absent eye defects, progressive facial and limb muscular dystrophy and contractures, raised CK; founder mutation in Japanese

AR (253800) Fukutin, FCMM, 9q31-q33

Muscle-eye-brain4,36

Early onset severe hypotonia, delayed development, frontal pachygyria, occiput less severe, agenesis of the corpus callosum, hypoplasia of the pons and cerebellar vermis, white matter abnormalities patchy or absent, mild hydrocephalus, nystagmus, anterior chamber defects, glaucoma, myopia, preretinal glial membrane, ERG abnormal after age 1 year, cataracts, myopathy with elevated CK levels; common in Finland

AR (253280) POMGnT1, 1p32-p34.1

(continued)

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Table 15-5. Syndromes with lissencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Seidahmed: congenital muscular dystrophy37

Profound prenatal and postnatal hypotonia, generalized joint contractures, biopsy evidence of muscular dystrophy, lack of ocular involvement differentiates from cerebrooculo-muscular and Fukuyama congenital muscular dystrophy, probable cerebellar hypoplasia, type II lissencephaly with a cobblestone appearance

AR

Walker-Warburg (HARDþ/E)4,17,38

Diffuse agyria, cobblestone appearance may be obscured by hydrocephalus, abnormal white matter, laminar heterotopia below cortex, absent septum pellucidum, severe midline to lateral cerebellar hypoplasia, brain stem hypoplasia, Dandy-Walker malformation, cephalocele, retinal dysplasia/nonattachment; microphthalmia, cataract, corneal opacity, hyaloid vessels, retinal corneal opacity, abnormal face; myopathic skeletal muscle with variable size and splitting of fibres with endomysial fibrosis

AR (236670) POMT1, 9q34.1

Neu-Laxova18

Sloping forehead, hypertelorism, abnormal ears, extreme microcephaly, absent corpus callosum, flexion contractures, syndactyly, phalangeal hypoplasia, subcutaneous edema, ichthyosis, hypoplastic genitalia, pulmonary hypoplasia

AR (256520)

Stippled epiphyses-loose skin-lissencephaly type III39

Microcephaly, arthrogryposis, craniofacial edema with onset in utero; stippled cervical vertebrae, feet and sacrum; short metacarpals and distal phalanges, agenesis of corpus callosum, agyria, hypoplastic brain stem, diffuse severe neuronal loss

AR

3-hydroxyisobutyric acid40

Poor neonatal behavior, triangular face, short and sloping forehead, narrow bitemporal distance, shallow supraorbital ridges, epicanthus, micrognathia, adducted thumbs, clinodactyly of toes 4 and 5, intracerebral calcification, cerebellar hypoplasia, agenesis of the corpus callosum, lissencephaly, pachygyria

AR (236795)

Abnormal lymph nodes-Tcell deficiency41

Early onset of infections, rheumatoid symptoms, postnatal growth failure, hypertonia, dysmature lymph nodes, hypodontia, micrognathia

Unknown

Cerebro-cerebellar II11

Similar to that reported by Barth et al.,9,12 but without four-layered cortex

Unknown

Choi: subarachnoid neuronal ectopia42

Early lethal, recurrent apnea, posteriorly rotated ears, prominent supraorbital ridges, high palate, smooth brain, including cerebellum, massive ectopic neurons and glial cells in the subarachnoid space; single case

Unknown

Craniotelencephalic dysplasia43

Craniosynostosis, frontal bone protrusion, encephalocele, microphthalmia, hydrocephalus, absent corpus callosum, grade 2 lissencephaly, incomplete lamination, no mature neuronal organization, cerebellar heterotopias

Probably AR (218670)

Dental anomaliespolyarthritis44

Hypodontia, polyarthritis, flared ribs, T-cell dysfunction, probably type I lissencephaly; one case

Unknown

Fontaine: craniosynostosislimb defects45

IUGR, craniosynostosis, wormian bones, broad forehead, downslanting palpebrae, overfolded helix, disorganised posterior hair patterning, especially at the back, small hands, hypoplastic distal phalanges, hypoplastic abdominal muscles, small genitalia, patchy lipodystrophy, ventricular septal defects, lissencephaly; single case

Unknown

Goldenhar46

Variable asymmetric and hypoplastic lower face, microtia, preauricular tags and pits, macrostomia, upper vertebral anomalies, epibulbar dermoids, variety of CNS defects in low frequency

Sporadic: occasionally AD (164210), 14q32

Kozlowski-Tsuruta: cortical hyperostosis47

Stillborn, hydrops, hypoplastic lungs with incomplete lobation, bone cortical thickening most marked in long bones and ribs, narrow proximal metacarpals and metatarsals, vertebral coronal clefts, may have had lissencephaly

Unknown

Lissencephaly-cleft palatecerebellar hypoplasia48

IUGR, cleft palate, ventriculomegaly, long thumbs and halluces, absent distal digital creases, variable brain stem involvement, absent corpus callosum, absent cerebellum, thick and disorganized cortex, no cortical lamination, severe cerebellar hypoplasia, LCHc of Ross et al.13

Uncertain

Majoor-Krakauer: Seckel like49

IUGR, extreme micrognathia, dysplastic low-rotated ears, beak-like nose, prominent eyes, absent gyral pattern and abnormal neuronal migration, not further described

AR

Micro50

Severe mental retardation, microcephaly, prominent ears, beaked nose with a prominent root, microcornea, cataracts, optic nerve atrophy, retinal dystrophy, small pupils, posterior synechiae, hypertrichosis, agenesis of the corpus callosum, one of three patients stated to have lissencephaly

AR (600118) RAB3GAP, 2q21.3

Type III Lissencephaly

Undefined Lissencephaly

(continued)

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Brain

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Table 15-5. Syndromes with lissencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Osteogenesis imperfectamicrocephaly-cataracts

Type II osteogenesis imperfecta, IUGR, hypertelorism, cataracts, cardiac anomaly, ambiguous genitalia, single umbilical artery, marked microcephaly, ‘‘smooth cortex without convolutions,’’ cerebellum hypoplastic; one family of three siblings

Probably AR (259410)

Pena-Shokier I: fetal hypokinesia52,53

Restriction at major joints, camptodactyly, decreased dermal ridges and digital flexion creases, IUGR, micrognathia, abnormal pinnae, small mouth, pulmonary hypoplasia, cryptorchidism, polyhydramnios

Heterogenous, many AR (208150)

Prenatal alcohol54

Growth deficiency, short palpebral fissures, midface hypoplasia, joint restriction, abnormal dermatoglyphics, developmental delay, brain heterotopias, ectopias, and, in the most severe cases, lissencephaly

In utero alcohol exposure

Prenatal cytomegalovirus24

Microcephaly, retinopathy, deafness, periventricular calcification. Severe cases have lissencephaly with no differentiation of cortex, unmyelinated parenchyma, and central nuclei, large leptomeningeal vessels, astroglial scarring, disorganized cortex, heterotopias, and cell loss

In utero infection exposure

Prenatal isoreinoin55

Neural crestopathy with craniofacial and cardiac anomalies. Some patients have areas of pachygyria or agyria with histology most like type I lissencephaly

In utero exposure

Prenatal valproic acid56

High and narrow forehead, infraorbital skin creases, telecanthus, short nose, midface hypoplasia, cardiac malformations. Neural tube defects are the most common CNS lesion, but abnormal corpus callosum, colpocephaly, and lissencephaly have been reported.

In utero exposure

Sedaghatian: lethal metaphyseal dysplasia57

Mild rhizomelia of the arms, narrow chest, mild platyspondyly, lacy iliac crests, severe metaphyseal dysplasia, relatively few reports, one with lissencephaly

AR (250220)

Winter: osteodysplastic primordial dwarfism86

IUGR, sloped forehead, prominent occiput, alopecia, low-rotated abnormal ears, largebeaked nose, disproportionate short limbs, redundant skin, joint dislocations and limited extension, platyspondyly, delayed ossification of vertebrae, short long bones, broad metaphyses, hypoplastic vermis, absent corpus callosum, few gyri, loss of cortical layers

Unknown

Doublecortin (DCX) was the second major isolated lissencephaly gene to be found, and it accounts for about 35% of cases.27,68 Most mutations are missense and cause classic lissencephaly in hemizygous males and subcortical band (sometimes called laminar) heterotopia (SBH) in heterozygous females (Fig. 15-25). Females have a normal laminar cortex, except for somewhat shallow sulci, and a bilateral, symmetrical band of gray matter within the central white matter. The relative thickness of the band shows some correlation with clinical severity, which can range from normal intelligence to significant mental retardation with

Fig. 15-21. External surface of the brain from a patient with type II lissencephaly showing smooth verrucous surface. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

seizures. Random X-inactivation accounts for the mixed population of normal cells migrating to the cortical plate, and the abnormal cells that fail to migrate and form the SBH. The severity of lissencephaly in the male is quite variable (grades 1–4), and in general, males with grade 1 lissencephaly have symptomatic heterozygous female relatives with thick SBH, whereas those with grade 4 lissencephaly have female relatives with SBH limited to the

Fig. 15-22. Coronal CT image from a patient with WalkerWarburg syndrome illustrating how hydrocephalus obscures the brain surface. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario.)

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Neuromuscular Systems

Fig. 15-23. Section of cortex from a patient with cobblestone lissencephaly taken through a verrucous area showing lack of lamination and having a polymicrogyric appearance with vertically descending blood vessels (arrows). (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

Fig. 15-24. Summary of the embryologic milestones relevant to the occurrence of lissencephaly.

frontal region and/or thin bands and a more favorable outcome.12 MRI changes may be subtle and discontinuous in some cases.69 Normal carrier women have been seen with mutations that cause only frontal SBH in males.70 Somatic mosaicism appears relatively common in both sexes, again resulting in a milder phenotype. Thus, a high index of suspicion may be necessary when considering mutation in this gene. DCX is a mammalian gene that has two tandem conserved repeats (doublecortin domains) that bind to a- and g-tubulin, but

not directly to microtubules per se.6,12 Expression is exclusive to the fetal brain, and in vitro and mouse brain extract it acts in concert with LIS1 to maintain stability of microtubular polymerization.6 Thus, it may be related to the LIS1 pathway. Clinicalgenotype correlation shows that truncating mutations in exons 1–7 cause severe disease, while those in exon 9 are milder; missense mutations cluster in the doublecortin domains of exons 4–6.12 Mutations in RELN have been reported in a small number of patients with LCHb,13,28 which some consider to include the

Brain

Fig. 15-25. T1-weighted MRI, axial sequence, supraventricular region. Note the simplified gyral pattern with several large gyri (left anterior, bilateral occipital). The posterior hemispheres show an extensive bilateral subcortical band of heterotopic gray matter. Anteriorly the pachygyric cortex shows increased thickness of the gray matter layer. The left hemisphere is on the reader’s right. (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario)

Norman-Roberts phenotype. These patients have a moderately increased cortical thickness of 5–10 mm, with an anterior-toposterior gradient of severity, involvement of the hippocampus, and a cerebellum with virtually no folia. RELN is a 388 kd protein with 8 EGF repeats that is secreted into the extracellular matrix by the CR cells of the preplate, MZ, cerebellar EGL, and hippocampal pioneer cells.4 RELN was initially cloned as Reln, the gene responsible for the mouse reeler phenotype, which shows failed preplate splitting and a poorly laminated inverted cortex. Further work with the scrambler and yotari mice that have different mutations in Dab1 (disabled), and a double null knockout for Vldlr and ApoER2, all of which share a phenotype similar to reeler, have demonstrated the relationships of this signaling pathway.4,6,12 RELN acts as an extracellular ligand for Vldlr and ApoER2, thereby directing tyrosine phosphorylation of Dab1, which binds on the cytoplasmic side of the cell membrane. Reeler mice and double null homozygotes for Vldlr and ApoER2 have elevated levels of Dab1, and knock-in mice with absent Dab1 tyrosine phosphorylation sites have a reeler phenotype,71 thus proving the key role of this phosphorylation pathway. Dab1 is known to interact with a number of other mouse proteins (Abl, Enah, fax, prospero) that have been implicated in neuronal migration and neurite outgrowth.6 The fact that Dab1, Vldlr, and ApoER2 are secreted by

555

the radially migrating neurons and that RELN is secreted by the CR cells of the MZ suggests that a RELN gradient may play a role in radial migration. Reln also binds to other signaling components such as a3b1-integrin and the cadherin related neuronal receptor family, possibly suggesting a role in determining when neurons detach from the RGC.6 Kitamura et al.30 have demonstrated that mutations in ARX (aristaless-related homeobox) cause abnormal forebrain and testicular development in mice and the X-lissencephaly abnormal genitalia (XLAG) syndrome in humans. This condition represents the first clear example of human lissencephaly that primarily affects the tangential migration of interneurons from the medial ganglionic eminence (MGE). The lissencephaly in this syndrome is characterized by a moderately increased cortical thickness, a posterior-to-anterior gradient of severity, a normally oriented 3-layered cortex with immature white matter, absent corpus callosum, basal ganglion cysts, and a deficiency of small granular neurons in the cerebral cortex.12,30 Males with XLAG have null or non-conservative missense mutations, whereas heterozygous females may have a normal phenotype with absent corpus callosum or suffer variable mental retardation and seizures. Other types of ARX mutations are responsible for a broad syndromic spectrum with poor genotype phenotype correlation, including X-linked infantile spasms, non-syndromic XLMR, Partington syndrome, hydranencephaly, and/or agenesis of the corpus callosum with abnormal genitalia.12,72 The mouse model of XLAG shows decreased proliferation throughout the VZ, normal radial neuronal migration, and severely disturbed migration from the MGE to the cortical intermediate zone. Interestingly, neurons from the MGE show normal migration to the cortical subventricular zone.30 Normally, intercortical neurons are scattered throughout the cortical plate, but in Arx mutant mice, those cells that do migrate are restricted to the subplate; GABAergic interneurons that are normally found in layer V are scattered in the cortical plate of mutant mice. Thus, there is disruption of a two-stage migrational process; step one from the MGE to the intermediate zone, and step two from there to the appropriate cortical lamina. As already discussed, cobblestone (type II) lissencephaly appears to be due to migration of neurons and glial cells beyond the cortical plate and a disrupted glia-limitans. It is largely associated with WWS, MEB, and FCMD (Table 15-5), which show varying severity of brain and muscle disease, with or without eye involvement. All three syndromes share a common pathogenesis involving defective glycosylation of a-dystroglycan (a-DG). Dystrophin at the inner cell surface binds with the transmembrane b-subunit of dystroglycan, which binds to extracellular a-DG.73 The latter then binds other proteins such as laminin, agrin, and neurexin, also engaging integrins and perlecan in the incorporation of laminin into larger clusters that are important to the integrity of the glia-limitans. Dystroglycan binding requires that glycosyltransferases add sugar moieties to both the a and b subunits.73 Michelle et al.74 demonstrated reduced glycosylation of aDG in MEB and FCMD, as well as in the naturally occurring myodystrophy (myd) mouse, which has similar brain pathology. a-DG, but not b-DG, was absent from muscle biopsies in both diseases, and in the mouse, which also had a disrupted glia-limitans. Moore et al.75 created a conditional knockout mouse, with absent aDG limited to neurons and glial cells. The mouse demonstrated brain changes compatible with cobblestone lissencephaly, but, as expected, had normal muscle. The MEB gene, O-mannosyl-b-1,2N-acetylglucosaminyltransferase (POMGnT1), which was isolated

556

Neuromuscular Systems

by Yoshida et al.,76 adds an N-acetylglucosamine residue to a protein O-linked mannnose.38 The FCMD gene, Fukutin, was found by Kobayashi et al.77 The disease is rare outside of Japan, where a significant majority of cases are attributable to an ancient insertion of a retrotransposon in the 30-untranslated region. Recently, Beltran-Valero de Bernabe´ et al.,38 using a candidate gene approach with homozygous mapping in consanguineous families, have shown that WWS is due to a deficiency of O-mannosyltransferase (POMT1). This enzyme catalyzes the first step in O-mannosylglycan synthesis, a process limited to the brain, peripheral nerves, and muscle, perhaps accounting for the greater severity of WWS, as compared to MEB and FCMD. The current consensus is that abnormal glycosylation of a-DG causes impaired stability of the basement membrane and dystrophin complex causing muscular dystrophy, and that diminished binding and clustering of laminin causes a defective glia-limitans. Abnormal glycosylation may act through other pathways, including dysfunction of neuromuscular junctions and synapses. Other potential causes for cobblestone lissencephaly are suggested by the production of similar brain pathology in a presenilin-1 deficient mouse model.78 Presenilin-1 is transiently expressed in leptomeningeal fibroblasts, and its role in the maintenance of CR cells was illustrated by the loss of the majority of cells in the MZ, including most of the CR cells. Type III lissencephaly (Neu-Laxova) is suggestive of inadequate migration of neurons, with incomplete maturation and differentiation corresponding to arrested development at 12 to 16 weeks gestation; but responsible genes have yet to be discovered.18 There do not appear to have been any systematic determinations of the incidence of lissencephaly. Although research groups may assemble reasonable numbers of cases for study, true lissencephaly appears to be uncommon. Prognosis, Treatment, and Prevention

The outlook for all children with lissencephaly is extremely grave, more so for those with the identifiable syndromes. An occasional patient with isolated lissencephaly may sit or roll, and a rare patient with mild, mixed agyria and pachygyria will walk.79 The majority of patients show no significant development beyond the 3- to 5-month level.23 The neonate is hypotonic and feeds poorly; feeding may improve, but development of spasticity in type I may compromise both feeding and respiration. Seizures begin shortly after birth in most patients and frequently are, or evolve into, infantile spasms. While the overwhelming majority of patients, regardless of the type of lissencephaly, will die before age 2 years, parents should be informed that occasionally there will be survival to late childhood. Leventer et al.87 estimate survival to age 10 years for lissencephaly due to mutations in DCX. As discussed, certain mutations may give rise to milder cortical changes and be compatible with a significantly better prognosis, but such children do not have lissencephaly per se. The same is true of SBH. The severe underlying malformations of the brain are not amenable to treatment, but normal supportive care is appropriate to facilitate comfort and nursing requirements. Seizures should be controlled, significant progressive hydrocephalus shunted, and, if feeding proves difficult, a gastrostomy tube should be considered. Aspiration and respiratory disease are the most common terminal events. The fact that the normal fetal brain is lissencephalic in the first half of the second trimester, and that many children with lissencephaly are born with an OFC that falls within the normal range, means that early recognition of isolated lissencephaly during

standard prenatal ultrasound is unlikely. Early microcephaly or associated cerebellar hypoplasia may be detected in some cases, although generally this has occurred in the late second or early third trimester.21,80 With improved prenatal imaging and greater attention to the subtle details of normal evolution of cortical sulcation, earlier diagnosis may prove possible.81 Toward that end, Abe et al.82 have studied and classified normal fetal gyral and sulcal development from 18 to 39 weeks gestation. In syndromic lissencephaly (Table 15-5), brain malformations or anomalies in other systems may allow for earlier prenatal detection of fetal anomaly. Prenatal diagnosis of Walker-Warburg syndrome is possible through recognition of associated hydrocephalus, absent corpus callosum, posterior fossa cysts, clefting, and even retinal detachment.83,84 Thus, except for the chance recognition of abnormalities on a routine ultrasound, prevention is based on the recognition of specific etiologies, provision of appropriate genetic counseling, cytogenetic and molecular diagnostics, and prenatal diagnosis for specific syndromes. Careful pregnancy and family histories should be obtained. All patients with Miller-Dieker syndrome will be found to have either a cytogenetically visible or submicroscopic deletion of 17p13.3, and appropriate counsel will depend on parental karyotypes. Patients without visible deletions should be studied with appropriate molecular probes.85 In the absence of a parental chromosome rearrangement, most families of patients with this syndrome have a low recurrence risk. Attention to the details of clinical and pathological examination, as well as neuroimaging studies, will allow the most appropriate choice of cytogenetic and/or DNA diagnostic testing. Current knowledge is such that abnormalities in known genes account for a significant majority of affected children, both those with non-syndromic classical and with syndrome-associated cobblestone lissencephaly. Thus, a majority of families should be able to benefit from this knowledge as they consider having additional children. The relatively high frequency of somatic mosaicism in DCX should be kept in mind. The presence of marked cerebellar involvement in association with classic lissencephaly probably raises a greater concern for autosomal recessive inheritance. The possibility of a contiguous gene syndrome should be considered in cases of syndromic classic lissencephaly, especially if the clinical and neuroimaging pattern is suggestive of any of the known genes. In cases where marked microcephaly has been present at birth, it is reasonable to screen for microcephaly with prenatal ultrasound in subsequent pregnancies, but with the understanding that the onset of microcephaly may occur relatively late in gestation. 15.5.2 Pachygyria Definition

Pachygyria is an area of cerebral cortex that shows a reduced number of gyri, which are unusually broad and in which the cortical mantle is abnormally thick (Figs. 15-26, 15-27). The affected cortex is generally four layered and is similar to, but reflects a slightly later embryologic timing than, agyria. The subdivision and nomenclature of the neuronal layers differ slightly between authors and are summarized in Fig. 15-28. The molecular or marginal layer is normal. The outer or cellular layer consists of large, medium, and small neurons and of polymorphic cells that have reached their normal location but that occur in reduced quantity in the cortex.2,87 Many of the neurons have abnormal orientation of their apical dendrites, and other

Brain

557

Fig. 15-26. T1-weighted MRI, coronal sequence, parieto-occipital region. The left panel shows a normal brain. The right panel is an image from a mentally handicapped individual with severe congenital microcephaly. Note the enlarged lateral ventricles, the thin cerebral mantle, and the simplified gyral pattern. There are abnormally broad gyri in the parasagittal convexity and virtual absence of gyri in the cortex apposed to the tentorium cerebelli. Cortical gray matter thickness is relatively normal. (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario.)

Fig. 15-27. Macrogyria (black lines) in a fetus at 33 weeks gestation with asphyxiating thoracic dystrophy. C, cerebellum; BS, brain stem; A, anterior; P, posterior. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

disoriented organization.88 It is less defined and marked than in classic lissencephaly, and the differences in Fig. 15-28, therefore, are more a question of timing and severity with respect to this third layer. The inner or thick cell layer consists of neurons, poorly arranged in broad radial columns, whose migration has been arrested. The subcortical white matter is thinned and may contain heterotopias. Diagnosis

Disorders of neuronal migration and cortical layering can be found under diverse circumstances, either alone or in combination with each other or with additional intracranial and extracranial

malformations, including those of the cerebellum and brain stem. The first edition of this book, and several other volumes and reviews, considered pachygyria and polymicrogyria together, primarily because they were so often reported in the same patient and were therefore thought to represent a spectrum of abnormality. They are now treated separately because there are differences in the histopathology, as well as a growing consensus that, unless MRI slices of < 4 mm or other neuroimaging adaptations such as curvilinear reconstruction are used, the fusion of the molecular layer over the sulci in polymicrogyria can be misinterpreted as pachygyria.4,89 Furthermore, genes thus far discovered to cause cortical malformations generally cause agyria/pachygyria or polymicrogyria, but not both. There may be exceptions.90 Cortical malformation with pachygyria is a continuum from agyria/pachygyria (lissencephaly) to focal areas of pachygyria. Indeed, grade 4 lissencephaly, as defined by Dobyns et al.,12 is generalized pachygyria. Unilateral involvement, except in the context of hemimegalencephaly, appears to be uncommon. Focal involvement has been divided into bilateral posterior and bilateral parietal by Barkovich et al.,10 to which frontoparietal could logically be added. Although the severity of clinical presentation can be expected to vary with the degree of cortical involvement, pachygyria is a severe cortical malformation. Patients are likely to present with some combination of severe developmental delay, failure to thrive, variable anomalies of tone, pyramidal signs, seizures, microcephaly or hydrocephalus, and EEG changes. Caraballo et al.91 have suggested that a combination of developmental delay, motor deficits, and seizures, together with a posterior interictal polyspikewave paroxysms and diffuse ictal 10-11Hz EEG changes, may be suggestive of bilateral posterior agyria/pachygyria. Liang et al.92 have stated that evoked potential and EEG may provide some useful correlation with the clinical severity of CNS dysfunction. It is apparently unusual for pachygyria to be an incidental finding at autopsy.1

Fig. 15-28. Variations in terminology of layers.

558

Neuromuscular Systems

With MRI the abnormal gyration is readily visible, and the gray–white matter ratio is reversed. On T2-weighted MRI images, a high intensity circumferential band, believed to represent the cell-sparse layer, may be seen.87 The brain stem may appear small because of underdeveloped spinocerebellar tracts. Distribution and Etiology

There are no systematic studies of the prevalence of either syndromic or isolated pachygyria. It is only with the development of modern neuroimaging methods that in vivo diagnosis has become possible, and even recently there may be failure to distinguish some cases of polymicrogyria from pachygyria. Autopsy series clearly select cases at the severe end of the spectrum, and unfortunately, they have also often failed to distinguish the different types of cortical malformation.93,94 However, it seems probable that the rates of significant pachygyria would be even lower among patients with milder delay or less intractable seizures. More restricted and less severe anomalies might occur in patients with focal neurologic disturbances. With the exception of cases representing the mild spectrum of genetic lissencephaly, the etiology of pachygyria remains largely unexplained. Migrational disorders are common to a number of peroxisomal disorders, non-ketotic hyperglycinaemia, and glutaric acidemia type II (Table 15-6). A common pathway might be energy production systems on which the actively developing brain is dependent. A prominent hypothesis was that a hypoxic/hypoperfusion episode, about the time the cells in layers V and VI had completed their migration, led to laminar necrosis and the cell sparse layer. This layer was thought to inhibit neuronal migration to the cortical plate. However, cortical freezing experiments, which mimic production of this layer, do not prevent the later transmigration of neurons, so that it is necessary to postulate more direct damage to the neurons or RGC in human pachygyria.95 Cells whose processes are trapped in the cell sparse zone may undergo degeneration. The architectonic changes in classic lissencephaly and in pachygyria differ only in degree, and within the same brain lissencephaly can be seen at the extremes of arterial supply, whereas pachygyria is seen in the more proximal areas. Thus, hypoperfusion/hypoxia remains a viable hypothesis for some cases of pachygyria. The timing of the teratogenic insult is considered to be the fourth month. Abnormal development and thickness of the cortex presumably inhibits normal gyral formation. Twin studies and cross-correlation comparisons between twins and non-twins have shown that while the heritability of brain size is high (94%), gyral patterning is predominantly non-genetic.144 Familial recurrence of focal pachygyria appears to be uncommon, suggesting that a genetic etiology is infrequent. However, pachygyria is seen in a number of the lissencephaly syndromes included in Table 15-5, and the possibility of milder mutations or polymorphisms of the lissencephaly genes, perhaps only acting in the face of an environmental stress, and/or on cells at arterial watersheds, remains a consideration. In their study of factors associated with malformations of cortical development, Montenegro grouped patients with agyria/pachygyria and heterotopia together and found a history of prenatal events in 42% compared with 5% of controls.96 They also noted a 32% family history of seizures and a 32% family history of neurologic impairment, which likely was due in part to some of the recognized genetic lissencephaly syndromes. Somatic mosaicism affecting a limited area of the VZ or MGE is also possible, although without any supportive evidence to date. Table 15-6 lists a number of syndromes and case reports with

pachygyria. Many include other CNS lesions, including polymicrogyria, and were described without benefit of modern neuroimaging. Thus, some of the syndromes listed may not actually demonstrate pachygyria, but until there is experience with further cases that have been subject to adequate imaging, no distinction can be made. It is also clear that in some cases pachygyria and polymicrogyria do occur together and represent the expression of a single etiology with varied timing, degree of exposure, and/or location in the brain resulting in the differing pathology. Some such cases appear to be genetic.90,140 Prognosis, Treatment, and Prevention

Notwithstanding a bias toward selection of cases with neurologic signs and symptoms, it is rare that pachygyria is an unexpected finding at autopsy. This finding is consistent with the significant disruption of normal CNS development and function. Golgi studies have shown that neurons that have reached their normal destination have abnormal orientation and interconnections.3,88,216 In general, neurologic development is profoundly delayed, and intractable seizures and microcephaly are common. Initial hypotonia often evolves into hypertonia. Titlebaum et al.217 studied 23 children with pachygyria-like changes on CT or MRI. The malformations were isolated in seven cases, syndromic in nine, and due to infection in seven. Patients were divided into unilateral diffuse and bilateral nondiffuse and had been ascertained through investigation of seizures and developmental delay. Eighteen had developmental quotients (DQ) of 20 and failed to obtain any milestones. Three patients had DQs between 50 and 70 and were ambulatory and communicative, and in two of these the lesion was nondiffuse and nonsyndromic. One had unilateral megalencephaly. Eight of 10 with nondiffuse pachygyria had frontotemporal predominance. In the study by Montenegro et al.,96 all of the patients with pachygyria/agyria were retarded, and this contrasted dramatically with their patient groups with focal cortical dysplasia and those with polymicrogyria in which retardation was the exception (vide infra). Developmental delay with or without seizures appear as constant features of the pachygyriaassociated syndromes in Table 15-6. Treatment is supportive in such patients and includes attempts to control seizures and thus facilitate care. Prevention must be directed at primary causes. Cytomegalovirus infection, and in endemic areas, toxoplasmosis, may contribute a proportion of cases, and prevention and/or recognition of maternal gestational infection would represent an important preventive measure. Recognition and appropriate counseling in the case of specific syndromes is also important. Some have no significant recurrence risks; others do and may be subject to prenatal diagnosis because of known specific biochemical anomalies or associated malformations (Table 15-6). The challenge of prenatal diagnosis of gyral abnormalities has been discussed in the section on lissencephaly. 15.5.3 Polymicrogyria Definition

Polymicrogyria (PMG) are areas of the cerebral cortex characterized by an excessive number of gyri that are small and may give the appearance of a wrinkled walnut (Figs. 15-29, 15-30). The depth of the sulci is variable, and fusion of the molecular layer between the gyri may result in a glandular or, paradoxically, smooth appearance.2,87 The cortex is abnormally thick, but the reversal of the grayto-white ratio is not as marked as in pachygyria.

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias Syndrome

Prominent Features

Causation Gene/Locus

Acrofacial dysostosisintermediate severity97

Malar, maxillary, and mandibular hypoplasia; downslanting palpebrae, absent eyelashes; lateral and typical facial clefts; macrostomia; abnormal ears; mesomelic dysostosis; congenital heart; hydrocephaly, polymicrogyria

Unknown

Adams-Olivercortical dysplasia98,99

Cutis aplasia congenita of the scalp, terminal limb reduction defects, short digits, hypoplastic nails, may have constriction rings; case with unilateral cortical dysplasia and sibs with polymicrogyria

AD (100300) AR?

Ades: campomeliapolydactyly-dysplastic kidney100

Cleft epiglottis and tongue, dysplastic larynx, coloboma, cystic dysplastic kidneys, periportal hepatic fibrosis, mesomelia, absent corpus callosum, abnormal gyri

Unknown

Agonadism-CNS anomalies101

Agonadism with urogenital sinus and 46,XY karyotype, severe mental retardation, absent corpus callosum, cerebellar agenesis, pachygyria. Single case

Unknown

Agyria-pachygyria-absent corpus callosum102

Normencephaly, hypertonia, apnea, neonatal death, absent corpus callosum, cortical dysplasia–probably agyria/pachygyria

AR

Aicardi103

Pathognomonic retinal lacunae, absent corpus callosum, infantile spasms, hypsarrhythmia, vertebral segmentation defects, polymicrogyria, heterotopias, colpocephaly, hypoplastic cerebellar vermis

XLD, male lethal (304050) Xp22

Alcohol, prenatal104

Short stature, microcephaly, short palpebral fissures, hypoplasticphiltrum, thin vermillion border, mental impairment Macrocephaly, microophthalmia, bilateral cleft lip/palate, myoclonic seizures, hypotonia, posterior midline cyst, frontal polymicrogyria, absence of the corpus callosum. Single case; could be part of the oculocerebrocutaneous spectrum.

In utero exposure

Apert106

Severe craniofacial synostosis, marked syndactyly; developmental delay is common; CNS includes corpus callosum (5/113), limbic system, microgyria, polymicrogyria, heterotopia, ventriculomegaly

AD (101200) FGFR2, 10q25.3-q26

Arena: XLMR-spasticity-iron in basal ganglia107

Mental retardation, severe spastic paraplegia, hypoplasia of white matter with poor myelination, macrogyria, cerebellar hypoplasia, possible iron deposits in the basal ganglia

XLR Xq22-q25

Autosomal dominant microcephaly-pachygyria108

Mildly retarded woman with moderate microcephaly, small cerebellum, and mild pachygyria; child with severe microcephaly, horizontal scalp folds, small cerebellum and brain stem, pachygyria greatest over frontal and parietal area

AD

Baller-Gerold: craniosynostosis-radial ray109

Craniosynostosis; variable radial ray, carpal and metacarpal hypoplasia/aplasia; small anomalous ears, hypertelorism, epicanthus, prominent nasal bridge; anal abnormalities; thin corpus callosum, crowded and small gyri, abnormal hippocampi, hypothalamic heterotopias

AR (218600)

Baraitser-Winter: iris coloboma-pachygyria110

Mental retardation, short stature, ptosis, iris colobomata, hypertelorism, marked epicanthus inversus, flat nasal bridge, pachygyria; two cases with similar inversion 2p12;q14

AR, microdeletion? 2p12-q14

Bohring-Opitz111

Trigonocephaly, microcephaly, prominent eyes, broad nasal bridge, micrognathia, cleft lip/palate, flexion deformities at elbows and wrists, postnatal growth failure; small brain stem, reduced white matter, focal nodular heterotopia

AR (605039)

Bo¨rjeson-ForssmanLehmann112

Central obesity, narrow palpebrae, large ears, short stature, moderate to severe retardation, kyphosis, short neck, post-pubertal hypogonadism

XLR (301900) PHF6, Xq26.3

Carnitine palmitoyltransferase II deficiency113

Neonatal lethal, hypoglycemia, hepatic decompensation, cardiomyopathy, cystic renal dysplasia; CNS degeneration with gliosis, neuronal migrational defects

AR (600649) CPT2, 1p32

Carpenter-Hunter: micromelia-polysyndactyly114

Severe short-limbed dwarfism, encephalocele, marked hypertelorism, microphthalmia, absent external nares, cleft palate, micrognathia, narrow chest, cardiac malformation, cystic dysplasia of the kidneys and pancreas, post-axial polydactyly of hands and feet, duplicated tibia, hydrocephalus, pachygyria

Unknown

Cataracts-contracturescortical dysplasia115

Postnatal growth and developmental failure, prominent supraorbital ridge, cataracts, large joint contractures, osteoporosis, cavum septum pellucidum, right temporal arachnoid cyst, cerebellar atrophy, multiple foci of cortical dysplasia in frontal and parietal lobes

AR

Cerebellar hypoplasialymphedema116

Mental retardation, hypotonia, ataxia, clonic/tonic seizures, pale fundi and poor VEP, variable duodenal atresia, cerebellar hemisphere and vermis hypoplasia, poor cerebral white matter, abnormal neuronal migration, pachygyria

AR (600514) RELN, 7q22

Cerebral calcificationleukodystrophy117

Microcephaly and cerebellar hypoplasia variable, seizures, cerebral calcification is most marked in the periventricular area, generalized delay in myelination. Case with microphthalmia. Case reported with pachygyria was the offspring of first cousins.

AR

Anophthalmia-cranial cystscleft lip/palate105

Unknown

(continued)

559

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Cerebro-oculo-faciallymphatic118

Acrobrachycephaly, trigonocephaly, thick hair, hypertelorism, ptosis, bushy and arched eyebrows, broad nasal bridge and tip, epicanthus, macrostomia, broad and webbed neck, abnormal nipples, contractures, short and wide hands, frontal agyria/pachygyria

Unknown

Cerebro-oculo-hepato-renal (Arima)119

Leber congenital amaurosis, telecanthus, blepharoptosis, polycystic kidneys and renal failure, hepatic fibrosis, hypotonia, mental retardation, aplasia inferior vermis, micropolygyria of dentate and pachygyria inferior olivary nuclei

AR

Chromosomal120

A number of karyotypic anomalies are listed as associated with cortical malformations but such malformations are often not mentioned in reviews of recurrent cytogenetic anomalies, and neuroimaging studies are lacking. See reference for specifics.

Chromosome deletion/ duplication

Coad: agenesis of cortical tracts121

Cortical spinal tract aplasia due to cortical migration or proliferation defect, hypertelorism, flat nose, micrognathia, arthrogryposis, cortical thumbs, hypospadias

Unknown

Congenital alopecia-seizuresmental retardation122

Microcephaly, congenital alopecia, neonatal seizures, profound mental and growth retardation, spastic quadriparesis; microgyria over frontal, parietal and occiput with pachygyria in temporal and orbitofrontal regions; reduced neurons, mostly in 3rd and 4th layers

AR (203600)

Congenital extraocular muscle fibrosis-brain anomalies123

Mother and two children with congenital extraocular muscle fibrosis, unilateral hypoplasia of body and tail of caudate with ipsilateral ventriculomegaly; children had bilateral cortical dysplasia

AD (135700) CFEOM1?, 12p11.2-q12

Cortical dysplasia-anterior horn arthrogryposis124

Bilateral symmetrical cortical dysplasia maximal in the sylvian region, infolded cortex, abnormal gyri, seizures, lower limb contractures, short right leg with muscle atrophy

Unknown

Cranio-carpo-tarsal dystrophy125

Usually normal intelligence, deep-set eyes, small nose; puckered, H-shaped, and small mouth; long philtrum, camptodactyly with ulnar deviation; reported with delayed myelination, dysplastic corpus callosum, agenesis of inferior vermis, cortical dysplasia

AD (193700)

Craniofacial dysostosis-limbomphalocele126

Frontal bossing, severe hypertelorism, thin and small mouth, philtral skin tag, lower lid colobomas, hypoplastic nasal alae, cleft palate, asymmetric limb anomalies, syndactyly, short sternum, omphalocele, internal anomalies, ‘‘polygyria’’

Unknown

Craniosynostosis-bifid thumb-micropenis127

Craniosynostosis, low-set and posteriorly rotated ears, hypotelorism, prominent eyes, epicanthus, short and anteverted nose, flat nasal bridge, bifid thumbs, limited extension at the knees, small 5th finger, bilobed lungs, small penis with bifid scrotum, polymicrogyria, hypoplastic frontal lobes, arhinencephaly, cerebellar herniation, hydrocephalus

Unknown

Cutis marmoratamacrocephaly295

Congenital reticular vascular pattern seen in association with hemihypertrophy, hemiatrophy, aplasia cutis congenita, cavernous hemangiomas of the skin, and developmental delay; macrocephaly, seizures, and other associations are uncommon and include digital and congenital heart defects. Case with cortical dysplasia.

Unknown (602501)

Cutis verticus gyrata-Lennox Gastaux128

Developmental delay, early onset of seizures, most characteristically tonic and akinetic; EEG slow with irregular spike and wave complexes, usually at less than 3 cps. Case with polymicrogyria reported.

Unknown

Cytomegalovirus infection, prenatal129

In symptomatic cases: microcephaly, deafness, chorioretinitis, intracranial calcification, mental retardation, paraventricular cysts, pachygyria, polymicrogyria, cerebellar hypoplasia

In utero infection

Desmosterolosis130

IUGR, downslanting palpebral fissures, low nasal bridge, thick alveolar ridges, gingival nodules, congenital heart defect, ambiguous genitalia. Case with macrocephaly and another with microcephaly, ‘‘immature gyral pattern,’’ cholesterol biosynthesis.

AR (602398) Sterol-delta 24-reductase, 1p33-p33.1

Diffuse cortical dysplasiafamilial131

Generalized tonic/clonic and atonic seizures; pachygyria, with underlying cell-sparse zone, over the parietal area with less involvement over the temporal and occipital regions; sparing of the perisylvian region of the temporal lobe

AR/XLR

Diffuse pachygyria-cerebellar hypoplasia132

Diffuse broad gyri and severe hypoplasia of cerebellar vermis and hemispheres but with normal birth OFC, which remained normal in 3 of 4 cases; severe developmental delay, seizures, early hypotonia, truncal ataxia, action tremor; non-dysmorphic

AR

Disorganization-like133

Various malformations, generally affecting the craniofacial area and limbs, in association with aberrant digits/skin tags thought to resemble the mouse mutation. Case with periventricular heterotopias.

Unknown (223200)

Duchenne muscular dystrophy134

Mean IQ is reduced compared with those of sibs. Initial report of pachygyria and heterotopias not confirmed in recent studies, which have revealed abnormal dendritic arborization

XLR (310200) dystrophin, Xp21.2 (continued)

560

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Ehlers Danlos

Heterogeneous connective tissue disorder with hyperelasticity/friability most apparent in skin and joints; CNS not limited to a specific type and include cortical dysplasia, heterotopias, bilateral perisylvian polymicrogyria

Most AD

Ellis: microcephaly-heartrenal136

IUGR, severe microcephaly, small ears, pre-auricular pits, short palpebral fissures, hypoplastic alae, cleft palate, redundant neck skin folds, varied congenital heart defects, lung segmentation defects, unilateral renal agenesis, high lethality. One sib had small brain with reduced gyri, malformed cortical areas; other hydrancephaly-like.

AR (601355)

Encephalocele-radial anomalies137

Esophageal atresia, abnormal lung lobulation, congenital heart, radial ray defects, visceral anomalies, partial absent corpus callosum, hypoplastic cerebellum, encephalocele, ‘‘cortical microgyria’’

Fetal akinesia (PenaShokeir)138

IUGR, depressed nose, micrognathia, ankylosis, camptodactyly, pulmonary hypoplasia, variable CNS pathology, polymicrogyria with four-layered and unlayered cortex, heterotopias

Heterogeneity some AR (208150)

FG syndrome139

Megalencephaly, mental retardation, hypotonia, contractures, congenital heart defects, anal anomalies, constipation, pyloric stenosis, hypertelorism, short palpebrae, epicanthus, high palate, mouth breathing, absent corpus callosum, pachygyria, heterotopias of nerves 7 and 8

XLR (305450) Xq12-q21.3

Focal occipital neuronal migration defect140

Profound mental retardation, seizures, polymicrogyria/pachygyria/agyria limited to the occipital region; male siblings from an isolate

Uncertain

Frontal pachygyriaautosomal recessive141

Non-dysmorphic, mental retardation, mild seizures, pyramidal and cerebellar signs, shallow sulci mostly anterior to the sylvian fissures, pachygyria in the frontal lobes, less abnormality in the occipital area

AR

Fryns142

Coarse face, hypertelorism, anteverted nares, eye anomalies, macrostomia; genital, renal, gut, and cardiac anomalies; diaphragmatic hernia; high lethality; absent corpus callosum, cerebellar heterotopia and hypoplasia, gyral anomalies

AR (229850)

Fuhrmann143

Dislocated hips, angulated femora, absent/hypoplastic fibulas, hypoplastic fingers and nails, metacarpal and metatarsal coalescence and hypoplasias; cortical dysplasia in one of six cases

AR (228930)

Galloway-Mowat: abnormal gyri-glomerulopathy145

Floppy ears, minor dysmorphia, increased/decreased tone, lethal nephrosis onset from birth to age 2 years, variable pathology with pachygyria, polymicrogyria, marginal glioneuronal heterotopias

AR (251300)

Genitopatellar146

Coarse face, prominent nasal root and bulbous tip, micrognathia, high palate, soft skin, flexion contractures, dislocated/absent patellae, variable skeletal changes. Case with absent corpus callosum and periventricular neuronal heterotopias.

AR (606170)

Glutaric aciduria type 2147

Macrocephaly early sign, cryptorchidism, hypospadias; most show initial normal health and development; signs can include respiratory distress, hypoketotic hypoglycemia, sweaty-foot odor, seizures, dystonic cerebral palsy; aliphatic mono- and dicarboxylic acids, sarcosine, glycine conjugates in blood and urine; abnormal electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-dehydrogenase)

AR (231680) multiple acyl-CoA dehydrogenase defects; ETFA, 15q23-q25 ETFB, 19q13.3 ETFDH, 4q32qter

Goldberg-Shprintzen148

Microcephaly, short stature, developmental delay, hypertelorism, submucous cleft palate; diminished white matter, hypo/partial absence corpus callosum, pachygyria, cerebellar hypoplasia

AR (235730) SMADIP1, 2q22

Hayashi: leprechaunismlike149

Megalencephaly, hydrocephaly, unusual appearance, severe growth failure, hypoglycemia, no hyperinsulinemia, cardiac defect, decreased cortical neuronal density, fronto-parietal dysplasia. Single case

Unknown

Heptacarpo-octatarsodactyly-plus150

Lethal, hypertelorism, hydrocephalus, ependymal cysts, ‘‘polygyria,’’ cleft lip/palate, macroglossia, abnormal lung lobulation, complex heart malformation, genitourinary anomalies, complex polydactylies all four limbs

Unknown

Holmes: brain malformationfetal hypokinesia151

Polyhydramnios, fetal hypokinesia, wide cranial sutures, telecanthus, narrow palpebrae, micrognathia. One sib had agenesis of the corpus callosum, slightly broad gyri, focal cerebellar disorganisation; other sib had arhinencephaly, hypoplastic gyri, regions of persistent external cerebral granular layer

Uncertain

Hypochondroplasia297

Disproportionate short stature; milder but clinical and radiologic resemblance to achondroplasia; case report with inadequate white/gray differentiation and abnormal gyri in temporal lobe

AD (146000) FGFR3, 4p16

135

(continued)

561

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Irregular congenital hypopigmented streaks follow lines of Blashko; may be otherwise asymptomatic or have skeletal, eye, or brain anomalies; cortical dysplasia, brain atrophy, increased Virchow-Robin spaces

Chromosome mosaicism (300337)

Hypothalamic hamartomamicrophthalmia-radial ray153

Hypothalamic hamartoma, microphthalmia, ectopic retinal pigment layer, flat nose, absent/hypoplastic thumb, gut malrotation, small stomach, asplenia, abnormal genitalia. Case with agenesis of the corpus callosum, meningeal dysplasia, abnormal gyral pattern

Unknown

Joint contractures-renalfacies154

Brachycephaly, large fontanel, upswept anterior hair, short palpebrae, flat face, thin nares, cystic pinnae, camptodactyly, small kidneys with dysplastic foci, pachygyria with atypical histology

Uncertain

Kabuki155

Developmental delay, long palpebrae with ectropion of outer 3rd lower lid, arched eyebrows, broad nasal tip, large ear lobes, cardiac defects, brachydactyly, prominent finger-tip pads; reported with polymicrogyria

AD (147920)

Larson-like-brain dysplasia156

Severe mental retardation, tetraplegia, intractable partial seizures, laryngotracheomalacia, multiple joint dislocations, bilateral perisylvian cortical dysplasia with zonal heterotopia of pyramidal and granule neurons in molecular layer, brain protrusion in subarachnoid space

Unknown

Lurie: cerebro-renal-digital157

Microcephaly, short and webbed neck, renal dysplasia, polysplenia, microgyria (family ‘‘L’’ in report)

AR (200995)

Linear nevus sebaceous158

Papular/verrucous lesions with atrophic scars over craniofacial area, pigment changes, ipsilateral brain anomalies, hemimegalencephaly, pachygyria heterotopias, porencephalies, mental retardation, seizures

Unknown (163200)

Majewski: short ribpolydactyly159

Lethal short ribbed micromesomelic dwarfism, short tibiae, pre- and postaxial polydactyly, median cleft lip, genital anomalies, hypoplastic epiglottis and larynx, glomerular cysts, tortuous cerebral vessels, cerebellar vermis hypoplasia, posterior fossa arachnoid cysts, agenesis or hypoplasia of the corpus callosum, pachygyria, neuronal heterotopia

AR (263520)

Marshall-Smith160

Accelerated linear and skeletal growth with prenatal onset, poor weight gain, dolichocephaly, prominent eyes, anteverted nose, broad proximal and middle phalanges, narrow distal phalanges, respiratory problems often lethal, absent corpus callosum, pachygyria inferior vermis hypoplasia, pachygyria

Unknown (602535)

McPherson-Clemens: cleft lip/palate-heart161

Lethal, nuchal cysts, short neck, flat face, hypertelorism, upslanting palpebrae, cleft lip/ palate, bilobed tongue, complex hypoplastic heart defects, abnormal lung segmentation, wide spaced nipples, small penis, short hands and feet, deep set nails, organomegaly, crowded cerebral gyri, abnormal hypocampi; subependymal, cerebellar cortical, and leptomeningeal glial heterotopias

AR (601165)

Meckel-Gruber162

Meningoencephalocele; renal cystic dysplasia; congenital hepatic fibrosis; postaxial polydactyly; eye, heart, genital, and other CNS anomalies, including polymicrogyria, heterotopias, and neuroepithelial rosettes

AR (249000) 8q24 11q13 17q22-q23

Megalencephaly-mega corpus callosum163

Mental retardation, no motor development, prominent forehead, low nasal bridge, large eyes; MRI evidence of megalencephaly, a broad corpus callosum, ‘‘enlarged’’ white matter, focal increased thickness of thick gray matter, pachygyric appearance, wide sylvian fissures

Unknown

Microcephaly-intracranial calcification164

IUGR, postnatal growth failure, hepatomegaly, corneal opacities, bile duct hypoplasia, disorganized cortex, small calcified basal ganglia, pachygyria, polymicrogyria; may be allelic with Aicardi-Goutieres and Cree encephalitis

AR (251290)

Mohr-Majewski: oro-facialdigital type IV165

Severe abnormalities of epiglottis, tongue, and larynx; cystic kidneys, gut malrotations, hepatic fibrosis, arhinencephaly, neuronal migrational defects in patient within gamut of OFD II and short rib-polydactyly II

AR (258860)

Muenke: craniosynostosis297

Coronal synostosis, variable radiographic changes include thimble-like middle phalanges, coned epiphyses, carpal and tarsal fusions, brachydactyly, sensorineural deafness

AD (602849) FGFR3, 4p16

Multiple peroxisomal oxidative deficiency166

Clinical presentation like Zellweger cerebro-hepato-renal syndrome (pseudo-Zellweger), but abundant peroxisomes, normal DHAP-AT, high pipecolic acid, and very long chain fatty acids. Gliosis most marked in cerebellum, which contained heterotopias; heterogeneity, peroxisomal b-ketothiolase or bifunctional enzyme defect

AR (261510) 3p22-p23

Nephrotic syndromeinfantile spasms167

Developmental delay, early nephrotic signs due to focal glomerulosclerosis that may show IgM, IgG, and/or C3 deposits, floppy ears, hiatal hernia, flexion contractures; areas of polymicrogyria, agyria, and pachygyria

AR (251300)

Hypomelanosis of Ito

152

(continued)

562

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Non-ketotic hyperglycinemia168

Acute metabolic disease presentation; abnormal mitochondrial glycine cleavage; hypotonia, lethargy, abnormal cry, jaundice, coma, elevated urine and plasma glycine; CNS includes absent corpus callosum, pachygyria

AR (605899) GSCP, 3p21.2-p21.1 GSCT, 9p22 GSCH, 16q24

Occidental congenital muscular dystrophy169

Congenital severe hypotonia muscle weakness with elevated CPK, intelligence normal or with mild delay, variation in fiber size, leukodystrophy that may show postnatal onset, polymicrogyria in some cases who may show seizures, merosin deficiency in some patients

AR (156225) 6q22-q23

Orofacial-digital type I170

Variable mental retardation, sparse and dry hair, excess oral frenula, oral hamartomas, clefting, absent lateral incisors, brachydactyly, polysyndactyly, polycystic kidneys; CNS variable, absent corpus callosum, Dandy-Walker, pachygyria

XLD, male lethal (311200) CXORF5, Xp22.3-p22.2

Pachygyria-hypogenitalism171

Microcephaly, developmental and growth delay, sloping forehead, undescended testis, pachygyria. Hypogenitalism is a non-specific finding with many severe brain anomalies).

AR/XLR?

Pachygyria-agenesis corpus callosum-X-linked172

Microcephaly, lethal in males, severe developmental delay, early onset seizures, agenesis of the corpus callosum, microphallus, neuronal migration defect; less severely retarded male did not have neuroimaging; band heterotopia a possibility

XLD (600102)

PAX6-related eye-brain anomalies173

Microcephaly, anophthalmia, small nares, large pinnae, absent corpus callosum, focal polymicrogyria; compound heterozygote for PAX6 mutations; unilateral polymicrogyria and absent pineal in heterozygotes

AR (106210) PAX6, 11p13

Periventricular nodular heterotopia-autosomal recessive174

Typical periventricular nodular heterotopia, seizures, developmental delay, consanguinity and family history compatible with autosomal recessive inheritance, exclusion of linkage to FLNA and FLNB

AR (608097) ARFGEF2, 20q11.21-q13.2

Periventricular nodular heterotopia-ectodermal dysplasia175

Two cases, one with normal intelligence and bilateral, diffuse periventricular heterotopias, and ectodermal changes limited to hair; second with developmental delay, joint laxity, ataxia, single nodular heterotopia, dental and hair changes, face dysmorphia

Unknown

Periventricular nodular heterotopia-frontonasal176

Mild mental retardation, frontal bossing, low-set ears, prominent glabella, broad nasal root, hypertelorism, epicanthus, high palate þ/ cleft, variable hypoplastic genitalia, bilateral periventricular nodular heterotopia, cortical dysplasia, ventriculomegaly, cerebellar vermis hypoplasia

Unknown, XLR?

Periventricular nodular heterotopia-multiple pterygium177

Microcephaly, mental retardation, seizures, micro-retrognathia, downslanting palpebrae, cleft palate, poor tongue movement, inwardly rotated thumbs, multiple joint pterygia diagnosed at 4.5 years. Single case.

Unknown

Periventricular nodular heterotopia-rhizomelia178

Short stature, short humeri, dysplastic mitral valve, abnormal pinnae, sparse temporal hair, deep paranasal creases, short nose, long philtrum, thin upper lip, brachydactyly, penoscrotal hypospadias, delayed ossification centers

Unknown

Periventricular nodular heterotopia-syndactylycerebellar hypoplasia179

Severe mental retardation, seizures, syndactyly; variable cataracts, hypospadias, areas of cortical dysplasia

XLR

Periventricular nodular heterotopia-unusual appearance180

Three sisters with developmental delay, resistant seizures, upslanting palpebrae, low nasal bridge, long feet with sandal-gap, low T4, urinary tract anomalies, intestinal polyps

AR? (mother unaffected)

Peters anomalymicrocephaly-intestinal atresia181

Developmental delay, Peters anomaly, multiple intestinal atresias in distribution of superior mesenteric artery, extensive migrational defects, parasylvian clefts not reaching the ventricles

Unknown, possible vascular basis

Polyasplenia-caudal deficiency-absent corpus callosum182

Laterality associated defects, imperforate anus, renal anomalies, lumbosacral agenesis, lower limb anomalies; cases reported with meningocele, hydrocephalus; one case with absent corpus callosum and white matter neuronal heterotopias and abnormal cortical architecture

AR?

Polymicrogyria-bilateral frontal183

Polymicrogyria from frontal poles to precentral gyrus and inferiorly to frontal operculum, mild to moderate mental retardation, motor and language delay, spastic quadriparesis or double hemiparesis; consanguinity in 2 of 13 cases

Unknown

Polymicrogyria-bilateral frontoparietal184

Frontoparietal region most involved with PMG, moderate to greater developmental delay, seizures, dysconjugate eye movement, pyramidal and cerebellar signs, ventriculomegaly, white matter changes

AR (606854) 16q12-q21 (continued)

563

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Polymicrogyria-bilateral perisylvian185

Mild to moderate mental retardation, seizures are often difficult to control, pseudobulbar palsy, variable diplegia of the facial, pharyngeal, tongue and masticatory muscles; slight dysarthria to lack of speech; in some families females are significantly affected

Variable, many sporadic (300388) Xq28

Polymicrogyria-sagittalparieto-occipital186

Usually diagnosed in older individuals after onset of seizures; motor signs are absent; cognitive involvement absent or mild

Unknown

Polymicrogyriadermatomyositisinclusions187

Developmental delay, spasticity, cerebellar dysfunction, dermatomyositis, polymicrogyria, paracrystalline inclusions in muscle

AR

Polymicrogyriahydrocephaluscraniosynostosis188

Craniosynostosis, scaphocephaly, severe mental retardation, early lethal, low-set ears, eyebrow hypoplasia, short nose, long philtrum, small mouth, small genitalia. Single case.

Unknown

Polymicrogyriaturribrachycephaly189

Microbrachycephaly, turricephaly, blepharophimosis, midface hypoplasia, prognathism, cryptorchidism, camptodactyly, adducted thumbs

AR?

Potter190

In utero renal insufficiency (agenesis/dysplasia), leading to oligohydramnios, lung, hypoplasia, facial and appendicular deformations. Frontal/occipital vertical neuronal columns, abnormal gyri, cerebellar heterotopias.

Heterogeneous

Prenatal methylmercury191

Minimata disease; severe neurologic impairment with hypertonicity; combination of broad, flat, and simple gyri, and narrow gyri with shallow sulci; heterotopias in white matter, cerebellum; marginal glio-neuronal heterotopias; neuronal anomalies

In utero exposure

Progressive hemifacial atrophy192

Onset in childhood/adolescence of unilateral facial pigmentation, bone and soft tissue atrophy, midline facial groove, trigeminal neuralgia, contralateral Jacksonian seizures; possibly a subset of patients with cortical dysgenesis

Unknown (141310)

Proteus193

Marked and asymmetric overgrowth can lead to a range of complications; skin includes shagreen patches, linear verrucous epidermal nevi, intradermal nevi, lipomas, hemangiomas, patchy dermal hypoplasia, hyperplastic and pebbly plantar overgrowth; frequent ocular problems; CNS abnormalities uncommon, partial absent corpus callosum, lissencephaly, hydrocephalus

Uncertain (176920) Some PTEN, 1q11-q25, mutations claimed but cases questioned296

Sakoda: anophthalmiacortical dysgenesis194

Anophthalmia, cleft lip/palate, short stature, hemivertebrae, basal encephalocele, absent corpus callosum, cerebral dysgenesis. Single case.

Unknown

Samsom: mitochondrial encephalopathy195

Prenatal microcephaly, calcification of frontal lateral ventricles and cerebral hemispheres, partial callosal dysgenesis, polymicrogyria, neuronal heterotopia, severe neonatal metabolic acidosis, abnormalities of complex I and IV, deficient pyruvate dehydrogenase complex in muscle and liver

Unknown

Severe periventricular hyperplasia196

Severe microcephaly, early seizures, lethal; one of the three cases had sloped forehead, hypotelorism, microphthalmia, absent thumbs, micropenis; extremely disorganized neuronal migration causing obliteration of the ventricles; basal ganglia a central mass of nodules

Unknown

Shanske: Seckel-like197

IUGR; severe mental retardation, microcephaly, and short stature; receding forehead, downslanting palpebrae, large beaked nose, retrognathia, dislocated radial head; one family with three children with agenesis of the corpus callosum, cortical dysgenesis, dorsal cerebral cyst, pachygyria

AR (210600)

Smith-Lemli-Opitz198

IUGR, microcephaly, postnatal growth failure, bifrontal narrowness, epicanthus, anteverted nares, prominent alveolar ridges, abnormal genitalia, dermatoglyphic whorls, polydactyly, frontal lobes particularly affected by pachygyria

AR (270400) DHCR7, 11q12-q13

Spinal muscular atrophypachygyria199

Clinical presentation as Werdnig-Hoffmann disease, seizures, variable arthrogryposis; pathology of anterior horn cell disease and pachygyria

Unknown

Spondylocostal dysostosispolymicrogyria200

Severe spondylocostal dysostosis, sacral agenesis, anal atresia, cystic kidneys, variable preaxial polydactyly and cartilage containing skin tags; fetus reported with bicornuate uterus and polymicrogyria

Unknown

Tectocerebellar dysraphiaoccipital encephalocele201

VSD, small mandible, cleft palate, CNS anomalies include posterior encephalocele, absent corpus callosum, hydrocephaly, cerebellar vermis agenesis, heterotopias

Unknown

Thanatophoric-dysplasia202

Neonatal lethal (occasional longer survival), short ribbed, micromelic dwarfism, excess skin folds, achondroplasia-like face, undermineralized spine with ‘‘H’’ or ‘‘U’’-shaped vertebrae on AP, curved femur, metaphyseal changes; polymicrogyria, leptomeningeal, and periventricular neuronal heterotopias

AD (187600) FGFR3, 4p16

(continued)

564

Brain

565

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Tuberous sclerosis

Depigmented macules and hair patches, shagreen patches, fibroangiomas in butterfly distribution, periungual fibromas, phakomas of retina, heterotopias, multiple focal cerebral tubers with absent laminar and columnar organization, and abnormal cellular orientation

AD (191100) TSC1, hamartin, 9q34 TSC2, tuberin, 16p13.3 12q14

Typus Edinburgensis204

Macrocephaly, hirsute, frontal bossing, nasal obstruction, ‘‘small eyes,’’ carp mouth, postnatal growth failure, profound mental retardation, lethal, polymicrogyria, ectopias

t(1;2)(q42.3;q37.1)

Velo-cardio-facial205

Long narrow face, retrognathia, prominent nose with hypoplastic tip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay, congenital heart; especially conotruncal defects; several reports with pachygyria and/or polygyria

AD (192430) del 22q11 del 10p

Weaver206

Prenatal onset of accelerated linear and skeletal growth, delay, hoarse voice, flat occiput, hypertelorism, large ears, long philtrum, camptodactyly, large joint limitation, loose skin, cerebral atrophy with occasional abnormal vessels, pachygyria (one case)

XLR or AR? (277590)

Wiedemann: microcephalyshort thumbs207

Microcephaly, mental retardation, short stature, large anterior fontanel, craniosynostosis, low-set ears, small and fleshy hands and feet, stubby and broad thumbs and halluces, hyperconvex and hypoplastic finger- and toenails, ventriculoseptal defect, frontal brain atrophy, dilatation of basal cisternae, pachy/agyria

XLD/AD?

WiedemannRautenstrauch208

IUGR, postnatal growth failure, prominent head-to-face ratio, progeroid appearance, sparse hair, prominent veins, lipoatrophy, natal teeth, caudal fat pad, initial skeletal signs clear, cerebral sudanophilic demyelinization, polymicrogyria

AR (264090)

Winter: pachygyria-joint contractures-unusual face209

Brachycephaly, large fontanel, small and cystic ear pinnae, flat face and nose, slender nares, hypertelorism, camptodactyly, talipes equinovarus, anomalous superior vena cava, hypoplastic lungs, small kidneys, hypogenitalism; simple and broad cerebral convolutions, pachygyria, polymicrogyria

Uncertain

Winter-Wigglesworth210

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, poorly formed hemispheres; microscopic renal changes

Unknown

XLR-corpus callosum dysgenesis211

Microcephaly, wide anterior fontanel, frontal bossing, telecanthus, broad nasal root, downturned mouth, short broad hands, brachydactyly; absent corpus callosum, interhemispheric cyst, cortical gyral dysplasia

XLR (304100)

Yokochi: athetosis-deafnesspachygyria212

Microcephaly, short stature, mental retardation athetosis, sensorineural deafness, areas of frontal, temporal, and parietal pachygyria. Case report.

Unknown

Zellweger: cerebro-hepatorenal213,214

Hypotonia, postnatal growth failure, large fontanels, high forehead, flat face, excess nuchal skin, hepatic and renal dysgenesis, contractures, hypomyelination, pachygyria (especially inferior olive), polymicrogyria, heterotopias merge with layers V and VI and affect mostly late migrating cells, germinolytic cysts

AR (214100) PEX1, 7q21-q22 PEX2, 8q21.1 PEX3, 6q23-q24 PEX5, 12p13.3 PEX6, 6p Others: 1p22-p21, 1q22, 2p15

Zollino: hypogenitalismpolymicrogyria215

Severe hypotonia, metopic ridge, upslanting palpebrae, megalocornea, epicanthus, smooth philtrum, macrostomia, club feet, agenesis of the corpus callosum, polymicrogyria; female less severely affected than three males

Unbalanced chromosomal translocation

203

Two basic types have been described: a classic four-layered form and one with absence of lamination, which is considered to have an earlier origin.1 In four-layered PMG, the outer marginal cell layer is sharply demarcated from the outer, laminar, cellular layer, which is the equivalent of the fusion of layers II, III, and IV in the normal cortex.2,87 Next to this layer is a cell-sparse layer that represents the equivalent of normal layer V, followed by an inner cellular layer. The subcortical white matter is reduced in thickness. True polymicrogyria thus occurs at a time when neuronal migration is virtually complete. Ferrer and Catala218 used Golgi staining to demonstrate that neurons that had migrated had reached their proper destination. In four cases with associated nodular neuronal heterotopias, the heterotopias and layers II and III of the cortex contained small- to-medium sized nonpyramidal neurons and multipolar neurons with axon plexi,

typical of later migrating cells of the outer cortical layers. Variant forms of polymicrogyria with somewhat atypical histopathology can occur after migration is complete.219 Diagnosis

PMG is a condition whose clinical importance, spectrum of signs, and diagnosis has markedly increased with the advent of MRI techniques (Fig. 15-31). It has been noted that fusion of the molecular layer over the shallow sulci can give a misleading impression of pachygyria. Techniques such as curvilinear reconstruction,89 and other methods that allow for partition size as low as 1.5 mm and the reconstruction of images along chosen planes,183 will allow detection of the increased number and deceased sized gyri. Typically there is a mild diminution of white matter myelination and increased subarachnoid space. CT scans are compromised by the

566

Neuromuscular Systems

Fig. 15-29. Gross brain specimen showing localized area of polymicrogyria. (Courtesy of the Department of Laboratory Medicine and Pathology, Children’s Hospital of Eastern Ontario.)

adjacent skull bones,87 and there are several reports in which it has failed to diagnose PMG accurately.183,220 The presenting clinical signs are highly dependent upon the area and the location affected by the PMG, as well as the presence or absence of associated intracranial malformations. PMG often accompanies schizencephalic clefts and porencephaly, most typically in the distribution of the middle cerebral artery, although the anterior and posterior distributions may be involved.221 Even when the porencephaly is unilateral, involvement with PMG is usually bilateral.1 It has become apparent over the past several years that bilateral PMG occurs in several well-defined patterns, not necessarily related to vascular watersheds, and that these patterns define clinical, and in some cases genetic, entities. These bilateral distributions include parasagittal parieto-occipital,186 perisylvian,185 sylvian and parieto-occipital,222 frontal,183 and fronto-parietal.184

Fig. 15-30. Lateral view of the brain from a term newborn infant showing polymicrogyria, Arnold-Chiari malformation. Dissection revealed internal hydrocephalus and agenesis of the inferior olivary nuclei. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Fig. 15-31. FLAIR (fluid-attenuated inversion recovery) MRI axial sequence, supraventricular region, with abnormal upward extension of the sylvian fissures, both broadly open rather than closed. Note the increased thickness of the perisylvian cortex with multiple small sulci, as well as nodular irregularity of the underlying gray-white junction. (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario.)

Defined by Kuzniesky et al.185 in a group of 31 patients, congenital bilateral perisylvian PMG (CBPP) is the most distinctive PMG syndrome. When involved with PMG, the sylvian fissure appears more vertical and extends more posteriorly.183 The initial cohort was characterized by mild-to-moderate mental retardation, seizures, pseudobulbar palsy, feeding difficulties, and by varying severity of diplegia of the facial, pharyngeal, tongue, and masticatory muscles. Expressive language difficulties ranged from slight dysarthria to lack of speech. Seizures occurred in 25 of the patients and covered a range of types, although partial were infrequent, and were often difficult to control. The adult syndrome of pseudobulbar palsy, facio-pharyngeal-glossal-masticatory diplegia, is the Foix-Chavany-Marie complex and reflects bilateral anterior operculum damage or maldevelopment. It is thought that the pediatric equivalent described by Worster-Drought likely had an equivalent cortical malformation.89 As more cases of CBPP have been reported, the overall prevalence of reported neurologic signs has fallen and additional anomalies have been noted.223,224 The most typical neurologic sign appears to be difficulty with protrusion and lateral movement of the tongue and/or dysarthria.89,223 Arthrogryposis, micrognathia, pectus excavatum, and esophageal atresia have been noted.224 Miller et al.225 reported three patients with CBPP who presented with unilateral hemiplegia, although in one case the diagnosis of CBPP was not certain. Bingham et al.226 used a quantitative MRI approach to assess

Brain

the size of the sylvian fissure and found it to be enlarged in a group of children with diverse etiologies for their developmental delay, seizures, and marked feeding problems. Noting the similarity of the clinical presentation to that in children with CBPP, they questioned whether underdevelopment of the operculum they had shown might share a common pathogenesis with CBPP. Although the presentation of several other PMG topographies may be characteristic, they are not specific and overlap with the signs and symptoms of other CNS pathology. The patients with bilateral frontal PMG reported by Guerrini et al.183 ranged in age from 10 months to 32 years and presented with mostly mild, but in some cases moderate, mental retardation, delayed motor and language milestones, and either spastic quadriparesis or double hemiparesis. Seizures were seen in less than half the patients, but many were young at the time of assessment. Chromosome 16q12q21-linked frontoparietal PMG is typified by moderate or greater mental retardation, epilepsy, dysconjugate gaze, and pyramidal and cerebellar signs.184 Parieto-occipital PMG is usually diagnosed in older patients during evaluation onset of seizures. Motor signs are absent, and any cognitive involvement is likely to be mild.186 In addition to these relatively circumscribed bilateral presentations, PMG may be more generalized and accompany other CNS anomalies, thus presenting with severe to profound mental retardation, additional severe CNS deficits, and seizures. In contrast, localized expression of PMG has been noted in otherwise normal individuals with specific learning deficits such as dyslexia and dysphasia, 227,228 and in benign epilepsy with centrotemporal spikes.229 An excess of small gyri is frequently described in ArnoldChiari type II and has been quantified by McLendon et al.230 However, although true four-layered polymicrogyria has been demonstrated in a significant portion of cases, in others the underlying neurohistology has been entirely normal, and the term polygyria has been suggested for this condition.230 Distribution and Etiology

Major areas of polymicrogyria are probably uncommon, although no systematic prevalence data are available. It is possible that small, localized areas of PMG may be more prevalent among patients with more minor types of cerebral dysfunction, but this will remain a question until systematic and sensitive MRI studies have been carried out on well-defined cohorts of patients. The frequent occurrence of PMG at the edge of what are considered clastic lesions, and its association with infections such as cytomegalovirus (CMV) and toxoplasmosis, suggest a disruptive basis for PMG. That a common denominator could be hypoperfusion is supported by the watershed distribution of many cases. Evrard et al.231 have summarized causes of hypoxia and/or perfusion failure, and they have included fetal and maternal origin. The brain is considered susceptible to insults causing PMG throughout virtually the entire period of cell migration, and perhaps beyond.1,183 Typical polymicrogyria has been well documented prior to 20 weeks gestation.1 Unlayered PMG is considered to reflect an earlier insult than the classic four-layered type but both may be seen in contiguous areas of the same brain.95 The concurrence could reflect a sustained or recurrent insult or perhaps a gamut of severity from a single event. Cases with associated subependymal or subcortical heterotopias clearly predate completion of cell migration. The gross polygyric appearance is considered to arise from an exaggeration of the normal differential rate of growth between the inner and outer cortical layers.2 Susuki and Choi232 were able to produce pathology very similar to human four-layered PMG with

567

cryogenic injury to the neonatal rat cortex. Recovery of pial-glial integrity was found to be critical in determining whether migrating neurons were likely to reach their normal positions. Montenegro et al.96 compared the rates of positive family history and prenatal events in three groups of patients with malformations of cortical development (MCD) with each other and with controls: 1) focal cortical dysplasia, 2) heterotopia/pachygyria/agyria, and 3) PMG/schizencephaly. Prenatal events were reported in 37% of patients with MCD and 5% of controls. Family history and prenatal events were not increased in group 1. A positive family history of neurologic impairment was noted in 32% of patients in group 2 and 39% of those in group 3. Five of the 14 positive family histories in the PMG/schizencephaly group were of a first-degree relative with CBPP. Prenatal events were reported in 42% of groups 2 and 3, and six of 15 such events in the PMG/schizencephaly group were failed attempted abortions. In a similar vein, Toti et al.233 compared cortical architecture in 32 fetuses suffering spontaneous abortion due to ascending chorioamnionitis with eight induced abortions as controls. They found that 25 (78%) cases, but none of the controls, showed one or more of three types of cortical pathology. In 19 of the cases, although the glia-limitans was intact, the molecular layer was broken by granular cell neurons, resulting in an undulating cortex with many small and irregular gyri projecting in various directions. The inner cell layers were less involved. Eight of the cases (8/18 < 20 weeks gestation) showed premature folding of the brain surface, fusion of the molecular layer, and the presence of small blood vessels. The granular cell layers appeared normal. Finally, in eight cases there was loss of granular cells, a thin cortex or laminar cell depletion, and/or necrosis that often just involved the middle cell layers. In two cases there were visible cortical microhemorrhages; generally the meninges were hypervascular. In all cases the gross morphology was normal, and they hypothesized that these changes could evolve into PMG in surviving infants. Among infectious causes CMV has been particularly associated with PMG, and Norman et al.1 have emphasized the importance of considering the temporal relationship of the detection of CMV infection and its attribution as a cause for PMG. Their studies of fetal brains infected with CMV from 17 to 40 weeks gestation showed marked variation in pathology dependent upon the timing and duration of the infection. Two hydropic fetuses had cerebral infarcts with PMG located around the infarct margins. Based on evidence from their cases, the authors concluded that CMV mediated migrational defects could arise from one or more of the following: direct viral-induced neuronal or glial cell death, loss of cells in the VZ, loss of glial-pial border integrity, and vascular insults due to either local vasculitis or systemic hypotension. The overwhelming majority of cases of PMG are sporadic, and this includes forms that do sometimes show clear evidence of a single gene cause. Only two of the 31 patients with CBPP reported by Kuzniesky et al.185 had a positive family history. One family had an affected set of male monozygotic twins; the finding in the other family was compatible with X-linked inheritance. A multicenter study of familial CBPP found that 10 families fit with X-linked inheritance, one family fit best with autosomal dominant with reduced penetrance, and one family was likely autosomal recessive with pseudodominance related to consanguinity. Among X-linked families there was marked intra- and interfamilial variability. In some families, only males were symptomatic, while in other families females showed variable manifestation of CBPP. Villard et al.234 have shown linkage to Xq28.

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Neuromuscular Systems

As discussed, autosomal recessive bilateral frontoparietal polymicrogyria has been linked to 16q12-q21. Although the parents of 2 of the 13 patients with bilateral frontal PMG were cousins, there were no instances of recurrent PMG in those families. There are other reports of recurrent PMG in siblings, some in concert with pachygyria (see Section 15.5.2). Also, PMG has been reported in a number of known and unknown genesis syndromes summarized in Table 15-6. However, at this time virtually nothing is known beyond the specific Xq28 and 16q12-q21 linkages about the genes involved in PMG. A small minority of cases of schizencephaly-associated PMG is caused by mutations in the EMX2 homeotic gene on 10q26.4 No EMX2 mutations have been found in patients with CBPP or parieto-occipital PMG (discussed in ref 183). Unilateral PMG was found in 1 of 24 patients with known mutations in PAX6.173 The patient was one of three who had Cterminal extending mutations, and the mother who carried the same mutation was thought to also have an area of PMG. There is evidence that a gross appearance of polymicrogyria, in the absence of a typical four-layered cortex, can occur with insults at or around 24 weeks gestation. Such cases may show a greater macrophage and glial response than found in cases arising earlier in gestation. An often quoted example is that of the mother poisoned by carbon monoxide at 24 weeks gestation.95 Ferrer216 reported detailed anatomic and Golgi studies of a case of unlayered PMG associated with bilateral porencephaly. The thickness of the cortex varied, as did the histopathology, which did not show abrupt transformation to the normal zones. Partially preserved gyri were separated by narrow sulci, and there was a gradient of severity away from the porencephalies. Although the neurons were randomly orientated the general distribution of types approached normal in the better preserved areas. Transformed RGC and some heterotopias were noted; the Golgi studies resembled those produced by freezing the cortex surface of rats at a time when neuronal migration is about complete.3,216 Ferrer216 pointed out that the blood supply to the cortex during months 5 and 6 is via the right-angled penetration of spiral artery branches of superficial cortical vessels, which have poor anastomotic connections as compared with the superficial meningeal network. Infarction would lead to variable damage in those arterial territories. Subsequent cortical growth toward the damaged areas would result in fusion of the molecular layer with central glial-mesodermic scarring. Neuronal organization at the borders of scarred areas would be impaired due to the prior vascular compromise. Prognosis, Treatment, and Prevention

It is evident from the previous discussion that the prognosis for patients with PMG is highly dependent on the presence or absence of accompanying anomalies such as porencephaly, and on the extent and specific topography of the lesion. Generalized PMG is usually accompanied by other CNS malformations. There will continue to be a bias toward the assessment with suitable MRI of patients with significant mental retardation and/or neurologic signs. Therefore, it is important to keep in mind that later onset seizures may be the presenting sign of patients with parietooccipital PMG,186 and that developmental delays can be mild in CBPP and in bilateral frontal PMG, in which motor signs may predominate.183 Kuker et al.224 have suggested that the association of CBPP and esophageal atresia may predict a poor developmental outcome. Of the 36 patients in the PMG/schizencephaly group studied by Montenegro et al.,96 32 were listed as having normal intelligence. All four stated to have some degree of retardation had associated schizencephaly. The prognosis for patients whose

polymicrogyria is limited to small areas can be quite favorable, and the condition is less likely to be diagnosed. For example, polymicrogyria localized to the left posterior superior temporal gyrus has been reported in some patients with dyslexia.227 Treatment would appear to be limited to providing control of seizures and developmental support for learning and motor difficulties that may arise. Surgical options are limited to perhaps cases of associated heterotopia that can be clearly shown to be the focus for refractory seizures. Options for prevention appear limited to the recognition of syndromes with known recurrence risks. In some syndromes associated malformations might be detectable by ultrasound, or a genetic or biochemical test can be applied (Table 15-6). In suitable families with either CBPP or bilateral frontoparietal PMG, there may be the option of applying linkage studies to Xq28 or 16q12q21. Methods to reduce maternal complications during pregnancy, including CMV and toxoplasmosis, may also reduce the population prevalence of PMG. Changes that proved to be polymicrogyria have been detected by 24 weeks gestation using fetal MRI.299 15.5.4 Heterotopias Definition

Heterotopias are collections of neurons that have arrested at an abnormal position along or beyond their normal path of neuronal migration (Fig. 15-32). Heterotopias can be further subcategorized according to whether they are generalized or focal, and as to their location as subependymal, subcortical, or beyond the cortical plate and into the molecular and leptomeningeal space.10 The latter are also referred to as ectopias and leptomeningeal heterotopias, but the term most often used today is marginal glioneuronal heterotopia. Subcortical band heterotopia has been discussed under lissencephaly. Norman et al.1 stress that numbers of single heterotopic (ectopic) neurons can be found scattered in the subcortical white matter of most brains, regardless of maturity, and that extensive experience is required to judge whether their numbers are excessive. There is some consensus that a cluster of
12 neurons describes a microscopic heterotopia.235 Fig. 15-32. Axial cross section of brain showing periventricular nodular heterotopias (arrows). (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

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Diagnosis

With development of modern neuroimaging techniques, most notably MRI, the diagnosis of heterotopia is no longer a primarily post mortem diagnosis, and its clinical importance as a cause of seizures and/or developmental delay has become apparent. Lesions range from 0.5 to 3 cm.220 The predominant location may correlate with a specific syndrome. For example, in some situations the arrest is predominantly between the ventricular zone and the external sagittal stratum (ESS); whereas in classic lissencephaly and WalkerWarburg syndrome, the halt is between the ESS and the cortical plate in the corona radiata.3 Use of narrow MRI slices (< 3 mm) with appropriate weighting to distinguish gray from white matter is important,87 and separation of the gray matter heterotopia from surrounding white matter is facilitated as CNS myelination progresses and matures. Barkovich 236 has described the MRI morphology of subcortical heterotopias, which may present as multiple nodules, curvilinear bands of cortex always extending into the white matter in at least two points, or a combination of the two with the nodules lying deep to the more peripheral curvilinear areas. The curvilinear bands may contain apparent blood vessels and/or CSF-containing spaces. Heterotopias are the most prevalent of the cerebral dysplasias.237 Seizures, which are often refractory, are the more common presentation in all types of heterotopia and may be accompanied by developmental delay. Clearly there is a bias toward ascertainment of symptomatic cases, and heterotopias can be an incidental finding at autopsy.1 Furthermore, heterotopias can be associated with other cortical anomalies, which may account for some of the symptomatology.88,238 Of five patients studied by Spalice et al.,239 the two who were not developmentally delayed were the same two who lacked associated cortical anomalies. Associated cortical anomalies may be subtle and not apparent on MRI. Borgatti et al.240 described a 17-year-old boy with a single periventricular nodular heterotopia near the right ventricular occipital horn and seizures, in whom neuropsychological testing showed abnormalities of frontal associative function. The EEG showed bilateral slow waves, and a single photon PET scan increased tracer uptake over the frontal area, providing evidence of a cortical disturbance beyond that suggested by the heterotopia. That neuronal heterotopias are highly associated with seizures, and the fact that neurons that do not make interconnections

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are subject to apoptosis, suggest that interneuronal connections must occur and that they likely extend beyond the individual heterotopia. In one study, the typical periventricular heterotopias contained both neuronal and glial cells.88 There were small and medium pyramidal cells, polymorphic neurons, small stellate neurons, and rare neurons with opposed double dendrite arbors. The neurons showed a random orientation and a reduced number of dendritic spines. The changes were similar to those reported with radiation damage by x-ray, Zellweger syndrome, and neurons transplanted into young rat brains.88 Extrinsic axons were noted. Hannan et al.240 examined nodular heterotopias from four patients with diverse clinical presentations and differing associated CNS anomalies. With a combination of standard histology and carbocyanide dye tracing, they observed that few of the surrounding fibers penetrated the nodules and that projections from the nodules were uncommon. In one case they were able to show a connection between adjacent nodules. They were able to show numerous cells expressing calretinin and neuropeptide Y, an expression pattern typical of GABAergic interneurons. However, the intranodular neurons were less complex than normal cortical neurons. Importantly, the overlying cortex showed evidence of a generalized migrational defect in the form of clusters of calretinin-positive cells. In an immunohistochemical study of neurosurgically removed heterotopias, decreased expression of the a-subunit of Ca2/ calmodulin dependent kinase II and its active phosphorylation form was observed.237 In severe cases with associated anomalies of cortical lamination, there were also reduced N-methyl-d-aspartate receptor units. The authors hypothesized that these changes might play a role in increased excitability and the seizures associated with heterotopia. Nodular heterotopias appear to be the most commonly diagnosed form of heterotopia, and their most frequent location is along the subependymal region of the posterior lateral ventricles. They may occur singly or as multiples, at times creating a diffuse row extending around the ventricular surface. They may also occur lateral to the basal ganglia and thalamus.1 X-linked dominant bilateral periventricular nodular heterotopia (BPNH) (Fig. 15-33) is of particular note because of its genetic implications, and because filamin 1 (FLN1) has been identified as the gene affected (vide infra).242 The X-linked nature of the condition was identified because of an excess of females

Fig. 15-33. T1-weighted MRI, coronal sequence, parieto-occipital region. The two panels are adjacent MRI sections. Note the extensive nodules of gray matter in the walls of both lateral ventricles. The apparent intraventricular mass in the left ventricle of the left panel is the posterior termination of the thalamic pulvinar nucleus, the plane of section being slightly offcenter (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario.)

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with BPNH, the occurrence of families with female-to-female transmission, and an increase of male pregnancy wastage in those families. Affected women are generally of normal to borderline low intelligence and present with seizures of multiple types. Variability is considered in part due to random X-inactivation, with lethality in the hemizygous male. In one family a liveborn male, who carried the affected haplotype, died of severe systemic bleeding at day 3.242 The bone marrow showed an arrest of myeloid and erythroid differentiation, suggesting that coagulation abnormalities may account for the loss of affected males. The MRI is characterized by bilateral, rounded, homogeneous, periventricular masses with a signal intensity characteristic of gray matter.243 There may be mild hypoplasia of the corpus callosum and cerebellar vermis, the latter resulting in an enlarged cisterna magna. The nodular pathology varies from groups of neurons with apparently random size and orientation, to an organization reminiscent of cortical lamination.244 In an autopsied case reported by Kakita et al.,245 which had a proven FLN1 mutation, the authors were able to show bundles of neuronal fibers extending into the neighboring white matter, between adjacent heterotopias, and into the cerebral cortex. The cortical cytoarchitecture was abnormal, with the normally columnar neuronal pattern distorted around abnormal blood vessels that ran closely packed and parallel across the cortical layers. Women with XL-BPNH, and an affected male with an Xq28 duplication, appear to have an excess of non-CNS anomalies, which include premature stroke, patent ductus arteriosis, minor finger anomalies, and perhaps disturbance of gut motility.242 Further genotype-phenotype correlations will be of interest. For the most part, marginal glioneuronal heterotopias (MGNH) have remained a pathologic diagnosis (Fig. 15-34), although large or extensive lesions may possibly be visible with careful MRI examination of the superficial cortex. They are commonly associated with other major malformations and often go unreported. They are more commonly found in infra- than supratentorial locations and appear of major importance in the fetal alcohol syndrome.3,231 Infratentorial

Fig. 15-34. Leptomeningeal neuroglial heterotopia. The leptomeningeal space is completely obliterated by a dense fibrillary tissue containing astrocytic and neuronal cells of various sizes. The superficial cortex underneath shows reactive gliosis and aberrant neurons in the molecular layer. The pia mater is absent. (Courtesy of Dr. Jean Michaud, Department of Laboratory Medicine and Pathology, Children’s Hospital of Eastern Ontario.)

MGNH usually do not contain neurons and are usually located beside the brain stem.1 MGNH of the cerebral cortex frequently do contain neurons, and their extent is extremely variable, ranging from a single chance lesion to a sheet covering the cortex as in cobblestone lissencephaly. Where present, the MGNH often give the sulcus a shallow appearance. And when an individual lesion can be identified, it has a visible stalk-like connection to the molecular layer.246 Two unusual types of neuronal heterotopia are mentioned here, although they do not meet the strict definition of a heterotopia. There have been a number of reports of apparent heterotopic neuronal tissue on the scalp with no detectable connection to the intracranial cavity. Neuronal and glial elements have been shown clearly in at least one instance.247 Similar situations may arise intracranially.248 The origin is unclear but could represent pinched off neuroectoderm that continued to develop, or a cephalocele in which the original connection was lost. The second type is an unusual situation, termed by some accessory brain, wherein there is an intracranial mass or partially organized brain with neurons, astrocytes, ependyma, and choroid plexus.249 One proposed origin is as an extra telencephalic vesicle developing at the time of cerebral cleavage. Distribution and Etiology

The population prevalence of heterotopias is unknown, although they are considered the most common type of cerebral dysgenesis. Small lesions are very likely to be overlooked or not recorded at autopsy, and ascertainment during life is highly dependent on their being symptomatic and the appropriate neuroimaging studies being performed. These anomalies are not infrequent in brains that have other structural anomalies such as Arnold-Chiari malformation or porencephaly. In one series, subependymal heterotopias were detected by MRI in 3 of 6 patients undergoing surgery for encephalocele and in 4 of 8 with encephalocele who came to autopsy.250 Soto Ares et al.238 found 10 cases of subependymal and 11 cases of focal or diffuse subcortical heterotopias among 22 patients selected because of seizures and

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developmental delay. In two of the patients with focal subcortical heterotopia, they were unable to determine any clinical-radiologic correalation. In a series of 133 consecutive surgical specimens from patients with extra temporal lobe epilepsy, Frater et al.251 identified 59 (44%) with neuronal heterotopia. This is similar to the study by Hardiman et al.,252 who found heterotopias in 42% and neuronal clustering in 28% of resected brain specimens from patients with focal epilepsy and whose EEG demonstrated the focal origin. Leventer et al.253 reviewed their series of 109 patients in whom a malformation of cortical development (MCD) had been identified, and heterotopic gray matter (19%) was the most common lesion, followed by cortical tubers (17%). They noted that pediatric patients with MCD had a significant rate of associated non-CNS anomalies (19%), and heterotopias are listed as accompanying a number of syndromes in Table 15-6. Lower rates of neuronal heterotopias (3.3%) were found in a study of institutionalized mentally retarded patients,93 perhaps reflecting a milder clinical impact in most cases of heterotopia. The most important development in understanding the etiology of neuronal heterotopias has been the discovery, through classic linkage, the study of a male with a duplication Xq28,254 and the candidate gene approach, that mutations in filamin 1 (FLN1) were responsible for XL-BPNH. Filamin 1 is expressed at high levels in the developing brain, and it is a member of a family of actinbinding proteins that reorganize actin in response to cell-cell signaling.243 As such, it is thought to play a role in cell motility. Its additional involvement in blood vessel formation and coagulation might further explain some of the non–CNS malformations that have been observed in the syndrome, and perhaps also the male lethality through defective coagulation.243 Sheen et al.,255 using SSCP, found FLN1 mutations in five of six families with a pedigree characteristic of XL-BPNH, and in 6 of 31 females with sporadic subependymal neuronal heterotopia (SNH). All six of the positive sporadic cases had an MRI characteristic of XL-BPNH, whereas no mutations were found among the six women whose MRI was atypical. They also found mutations in 2 of 24 males with sporadic SNH. Mutations in FLN1 that cause BPNH are all loss of function; and in all the familial and four of the female sporadic cases, the changes were either nonsense mutations near the N-terminus or splice site mutations that predict an unstable mRNA and truncated protein. The mutations in two of the sporadic female cases and the two male patients were predicted to produce less detrimental changes in gene function. One of the males had a typical MRI, while the second had only a few nodules; both were clinically mildly affected. Thus, FLN1 plays an important role in SNH, particularly in those patients with a positive family history and/or a typical MRI. Although somatic mosaicism has not been demonstrated for this gene, it remains possible that relatively local somatic changes in FLN1, DCX, or any of the other genes involved in migration could give rise to some paucinodular cases of neuronal heterotopia. There is some evidence that a subset of cases of BPNH may be due to autosomal recessive inheritance (Table 15-6).174 Battaglia et al.256 noted that their patients with BPNH tended to have a positive family history of seizures, were more likely to be female, to have structural anomalies in the posterior fossa, and to have multiple seizure types (FLN1 studies were not available) than patients with unilateral SNH. The later tended to have drugresistant focal seizures that had a visual or auditory onset. Of interest was that the unilateral heterotopias were paratrigonal in location, a watershed area, suggesting the possibility of vascular compromise as an etiology.

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It is to be expected that the study of single gene human syndromes may reveal relatively specific findings. For example, in Zellweger syndrome the parasylvian gyri are smaller, and the upper central gyri are larger, than normal. While the six-layered cortex is maintained, heterotopias including all neuronal classes are found throughout the cortex and subcortical white matter. The horizontal lamination becomes partly inverted, and the layers are uneven due to different levels of migration along adjacent radial glial fascicles. The observations suggest disordered migration over a prolonged period of time and are consistent with the metabolic basis for this condition.3,231 The etiology of MGNH appears to be nonspecific and related to compromise of the integrity of the glia-limitans. The glia-limitans is formed by gestational age 6 to 7 weeks by the apposition of the ends of the RGC to the basal lamina of the pial surface. Below is the molecular layer, whose maturation may be an important boundary to cell migration.257 In areas of superficial scarring, the neurons appear freed from their usual constraints and continue their migration into the molecular and pial layers. The underlying cortex may show abnormalities not seen in adjacent cortex that lacks heterotopia. Such findings are typical of the rat cortex–freezing experiments, as well as of alcohol embryopathy.3 Astrocyte transformation of the RGC as a response to injury may be the pathway that frees the neurons from normal constraints. MGNH are common in the Dreher-Shaker short tail mouse, in which disproportion in growth between CNS and skull entraps the growing brain, resulting in a variety of lesions, including damage to the superficial cortex, with scarring.3 Ligon et al.258 observed MGHN, equivalent to those seen in humans, in Emx2 / mice. The heterotopias were detected as early as day 13.5, which is during early neuronal migration and preplate formation. They also provided evidence of over expression of Wnt1 in the roof-plate organizer region and dorsal telencephalon, and that Emx2 acts normally as a Wnt1 repressor. Prognosis, Treatment, and Prevention

It seems likely that heterotopias per se, even when quite extensive, are unlikely to be associated with developmental delay or neurologic deficits. However, heterotopias are commonly associated with other CNS lesions, including developmental anomalies of the overlying cortex that can be invisible to MRI, which can be responsible for significant clinical signs. The two patients with periventricular heterotopias reported by Spalice et al.239 who were of normal intelligence had no associated CNS or non-CNS lesions. The remaining three patients were developmentally delayed and had other CNS lesions such as areas of pachygyria and/or extracranial anomalies that included bifid thumbs, cardiomyopathy, and metatarsal agenesis. Heterotopias are associated with seizures, which may be resistant to medical treatment, thus leading to consideration of surgery. Jan259 reported a pair of female monozygotic twins who presented because of megalencephaly and were found to have BPNH. At age 6 years, they were seizure free and showed normal development. Andermann89 has stressed the point that the epileptogenic abnormalities may be distant from the heterotopia and that it may remain unclear as to whether the seizures result from the heterotopia or overlying cortical dysplasia. Invasive cortical recording may be required to determine the site of the epileptogenic focus. Failure to do so may result in surgery that is ineffectual. Hardiman et al.252 showed a significant excess of heterotopias and abnormal neuronal clustering in patients selected for surgical treatment of intractable temporal lobe epilepsy of demonstrable focal origin. The presence of severe heterotopias and/or clustering in the surgical specimen was significantly correlated with a

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favorable response to operative management. This provides strong evidence in support of a causative role for the heterotopias in the etiology of the seizures. Steams et al.260 reported a favorable response to callosectomy in a patient with intractable atonic seizures associated with diffuse bilateral heterotopias. Prevention of heterotopias is limited to recognition of families with XL-BPNH and other metabolic or syndromic conditions. The offer of genetic counseling, and where appropriate, prenatal diagnosis should be made. Onyeje et al.261 reported prenatal ultrasound detection of a subcortical heterotopia at 23 weeks gestation. However, the situation was unusual in that the heterotopia had caused a midline shift with compression of the cerebral ventricle, hydrocephalus, and hydrops fetalis. Importantly, there was no evidence of invasion of the surrounding tissue. Postnatal MRI and autopsy confirmed the diagnosis. Bargallo et al.262 made the diagnosis of BPNH at 29 weeks gestation through a combination of ultrasound and fetal MRI. They emphasize the difficulty posed to ultrasound diagnosis by the normally large germinal matrix. An enlarged cisterna magna may draw attention to the presence of underlying CNS pathology. MRI of the mother revealed typical BPNH, which emphasizes the importance of studying the mother, who may be completely asymptomatic, in order to detect XL-BPNH. 15.5.5 Focal Cortical Dysplasia Definition

Focal cortical dysplasia is a localized malformation of cortical development that is intracortical. Gross malformations of cortical development including agyria/pachygyria, polymicrogyria, and macroscopic heterotopias are excluded. Focal cortical dysplasias (FCD) can be further subdivided according to their specific histology, but to date there is no classification that has had extensive use of a significant period of time to establish its clinical validity and relevance. This section follows the suggested classification of Palmini and Luders, which derived from a workshop on the terminology and classification of cortical dysplasias.235 A slight modification is that a group of very mild cortical dysplasias is referred to herein as type 0 simply to give them a place in the nomenclature. The subtypes are defined by the presence of architectural abnormalities (dyslamination) and the presence or absence of one or more of immature and/or giant cells or dysmorphic neurons with or without balloon cells. Immature neurons are homogeneous, round or oval cells with a large nucleus and sparse cytoplasm. Giant neurons may be found throughout layers II to VI and have a normal pyramidal shape, but are larger than normal neurons of layer V. Dysmorphic neurons can be increased in size and have an abnormal shape, orientation, and cytoskeleton. There is clumping of Nissl substance, and special immunostaining shows an excess of cytoplasmic neurofilaments.235 Balloon cells can be multinucleated; the nuclei are eccentric, the cytoplasm eosinophilic, and the cell membrane thin. They are usually large and can be massive. Vimentin staining is relatively specific for these cells.263 Taylor type FCD is sometimes used to describe FCD with balloon cells, but the initial patients reported by Taylor et al.264 included patients with dysmorphic neurons both with and without balloon cells. The suggested classification of FCD is outlined in Figure 15-35. Diagnosis

Most diagnoses of FCD are made in the context of medically refractory seizures, and these lesions clearly have a high epileptogenic

Type 0—Mildest forms of malformations of cortical development 0A: Abnormality confined or adjacent to cortical layer I i) neurons present in the molecular layer ii) persistent subpial granular layer iii) small area(s) of marginal glioneuronal heterotopia 0B: Malformation outside of layer I i) small clusters (
12) of heterotopic white matter neurons ii) dysgenesis of hippocampal formation Type I—Architectural dyslamination with no abnormal cellular elements IA: Architectural dyslamintion alone IB: As per IA with immature and/or giant neurons Type II—Architectural dyslamination with abnormal neurons IIA: Architectural dyslamination plus dysmorphic neurons þ/ immature neurons or giant cells IIB: As per IIA plus balloon cells (most severe form of FCD)

Fig. 15-35. Classification and definition of focal cortical dysplasias.235

potential. Typically they present as partial seizures, often accompanied by motor and secondary generalized seizures. Status epilepticus is common in the history. The EEG shows a high frequency of continuous spiking or other types of highly epileptogenic patterns.265 Electrocorticography can be used to better define the bounds of the lesion and tends to show generous amounts of interictal, semi-rhythmic epileptogenic activity over the FCD. Especially in the more severe type II dysplasias, this activity can be virtually continuous.266 The EEG/electrocortical pattern differs from that seen in cerebral tumors, which are in the differential diagnosis for the clinical presentation. The epileptoform activity is intrinsic to the FCD and does not arise from the surrounding normal tissue, as is the case for tumors.267 Dysplasia may be accompanied by gray matter thickening and a homogeneous hyperintensive signal in the subcortical white matter that extends in a tapering pattern to the lateral ventricles; frontal lobe is more likely to be a dysplasia and temporal lobe a neoplasm.268 Factors that influence the clinical presentation of FCD include the subtype of pathology, the location, and the extent of the lesion. Type 0 lesions are very unlikely to be detected by neuroimaging, and thus far there appear to be few data as to whether they can be suspected with diagnostic techniques such as singlephoton emission computed tomography (SPECT) or PET. Very often they are discovered after the fact in a patient with a neurologic or behavioral complaint, and the causative role remains unproven. However, a positive role has been suggested for some cases of epilepsy, developmental delay, autism, and schizophrenia.235 Type I FCD has been found as the only pathology in patients who have had successful surgical treatment for their epilepsy, and clearly it is clinically important in some patients.269 What is not known is the frequency of asymptomatic type I and type II FCD, although type II is pathologically more abnormal and is more likely to be detected on neuroimaging. The extent of FCD can range from a few Type 0 heterotopic neurons in the mesiotemporal area that are of questionable significance, to type II FCD of an entire hemicortex (Fig. 15-36). The whole cortex can be involved without causing enlargement,89 but usually there is an associated hemimegalencephaly with macrogyria, enlarged lateral ventricles, poor gray–white demarcation, a dyslaminated architecture, usually with a wide distribution of dysmorphic neurons, heterotopic subcortical groups of neurons,

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Fig. 15-36. T1-weighted MRI, coronal sequence, fronto-central region, from a young boy with congenital left spastic hemiparesis and epilepsy. The left hemisphere is normal in appearance, whereas the right shows an abnormal gyral pattern in the entire convexity area, including an abnormally configured sylvian fissure. The right lateral ventricle is enlarged. (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario.)

and often multinucleated giant cells in the molecular layer.270 Of interest is an association of FCD with dysplastic tumors including gangliogliomas, dysembryoplastic neuroepithelial tumors, and xanthoastrocytomas.271 Surrounding the tumors an area of dyslamination with dysmorphic neurons and associated subcortical heterotopias may be seen. Patients usually present under the age of 20 years with refractory seizures, and the MRI is characterized by poorly defined borders to the mass, lack of edema, and absence of a mass effect.89 Similar findings, together with calcification, which is unusual in FCD, have been reported in association with a hamartoma.272 FCD may be accompanied by skin changes that are usually ipsilateral and confined to the head and neck; most commonly multiple hemangiomas or linear nevus, and are associated with several syndromes including neurofibromatosis, hypomelanosis of Ito, and tuberous sclerosis (Table 15-6). The later is of particular note because its pathology is highly associated with balloon cells and the MRI findings of transmantle dysplasia (TD) (vide infra). Of importance and interest has been the relative sensitivity of neuroimaging techniques in detecting the presence of FCD. MRI may give a normal result in the presence of FCD, and detection rates are higher for type II lesions.273 Signs suggestive of FCD can include focal cortical thickening, abnormal gyral and sulcal contours, a blurred cortical–subcortical transition with abnormal signal intensity in subcortical white matter, and an increased signal intensity in T2-weighted, proton density, or fluid-attenuated inversion recovery (FLAIR) studies.273,274,275 Bronen et al.276 noted a prominent CSF space overlying an area of loss of cortical volume (dimple) in 29 of 71 (41%) of cases of FCD. In about half of patients this sign was more apparent than other MRI signs, and it

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was particularly prominent (22/25) in lesions with a primarily architectural pathology. The MRI can show TD, which was first described by Barkovich et al.,277 in a group of 18 patients who presented with seizures or a neurologic deficit under the age of 20 years. The findings consist of an abnormal signal extending radially and inward from the cortex to the superiolateral wall of the lateral ventricle. The associated pathology is that of type IIB FCD with astrogliosis, and the lesion is associated with, but is not unique to, tuberous sclerosis.278 Barkovich and Peacock279 described a type of sublobar dysplasia, which they considered to be a distinct cortical malformation. The report concerned five patients who were of normal intelligence and had no focal neurologic deficit in whom a local area of cortical dysplasia, not specific to any lobe, was separated from the cortex by a deep infolding of the cortex. In all patients, the dysplastic cortex was thickened with an abnormal sulcal depth and pattern, and the ipsilateral lateral ventricle was abnormal. Thinning to absence of the corpus callosum and hypoplastic cerebellar vermis were common associated findings. One patient who was ascertained because of a calvarial defect was seizure free at 13 years. The other four presented with seizures, but only two had evidence of persistent partial epilepsy. Chan et al.274 performed high-resolution T2-weighted fast multiplanar inversion-recovery MR (FMPIR) on 42 patients with suspected neocortical seizures, and in 10 they predicted the presence of FCD. In three cases the only MRI finding was localized blurring of the gray–white border, and in two patients this was only detectable with FMPIR. The diagnosis of FCD was confirmed in all seven patients in whom surgery was performed. Although adequate cerebral tissue was available for study, the study does not inform with respect to the negative predictive value of FMPIR. Scalp EEG was able to localize the lesion in five of the eight surgically treated patients, and PET was correct in three of three patients in whom it was applied. Kim et al.273 reported a blinded, retrospective comparison of the detection of FCD by MRI versus [18F] fluorodeoyglucose PET (FDGPET) in a consecutive series of 19 patients with surgically proven FCD. The MRI studies included a series of T1- and T2weighted studies in the axial, sagittal, and coronal planes, as well as 3D-spoiled gradient studies with 1.6-mm sections. The surgical specimens were subdivided into grade I (4), grade II (4), which would seem to fall into type I, and grade III (11), which appears to correspond with type II FCD. MRI detected 10 of 19 (53%) of FCD lesions, of which 9 were grade III. The anomalies noted were broad gyri (6), thick cortex (6), abnormal sulcal contour (6), indistinct gray–white junction (8) and increased white matter signal (9). PET was positive in 15/17 (83%) cases in which it was performed, including seven of the eight grade I and II, and nine of the ten grade III FCD. The size of the lesion as estimated by PET did not correlate with the grade; in 65% of cases detected by both methods, the malformation was judged by PET to cover a wider area. The authors noted that their detection rate by MRI was lower than for some prior reports. This could relate to case selection. Surface coil MRI with 3D acquisition may be more sensitive,280 especially with the addition of curvilinear reformatting.281 More comparative studies using a standardized classification system are required. Study of the uptake of specific ligands may add to the information provided by PET. There remains much to learn about the cell types and their behavior in FCD, and the reasons behind the high epileptogenicity of these developmental malformations. There is evidence of an increase in excitatory neurotransmitters in FCD, and a decrease in intra- and perilesional inhibition.89 An increase in excitatory and

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decrease in GABAergic neurons have been noted.282 When compared with normal cortex, type I and II FCD cortex both show an increased cellularity in lamina I, but only in type I was the population of Cajal-Retzius cells (CR) significantly increased.283 Jansky et al.284 performed functional MRI (fMRI) on a cross section of MCD and noted activity in response to simple tasks in all polymicrogyria, schizencephaly or mild FCD. However, activity was detected in less than half of heterotopias or type II FCD. Focal EEG slowing and focal neurologic signs correlated with lack of fMRI response. In vitro electrophysiologic patch-clamp studies also appear to confirm that there is some validity in separating the different histopathologic types of FCD. Cepeda et al.285 showed that immature pyramidal and dysmorphic pyramidal neurons did not show significant abnormality compared with normal; whereas what were likely balloon cells showed evidence that they did not receive synaptic inputs. What appeared to be giant cells produced abnormal currents and influxes under testing conditions. Distribution and Etiology

There are no data as to what proportion of the different types of FCD are symptomatic and, combined with the fact that FCD will not be noted during most post-mortem studies, this means that there is no meaningful estimate of their prevalence in the general population. FCD has been reported in between 6% to 23% of most surgical epilepsy series.273,290 Prayson and Eastes271 found 52 cases among 360 (14%) lobectomy specimens from patients with epilepsy. The patients ranged in age from 3 months to 47 years, and there was no significant sex difference. The temporal lobe was most commonly affected (34), followed by the frontal (18), with a few patients each having occipital, parietal, or multiple lobe involvement. Of note, 13 (25%) of their patients had an associated tumor (ganglioglioma, 8; dysembryoblastic neuroepithelial, 3; low-grade astrocytoma, 2), and 4 (13%) had tuberous sclerosis. These data do not show whether the lobar distribution, and rates of associated tumors and other syndromes, are representative of FCD in general or, more likely, are biased toward cases most likely to be symptomatic. At this time, very little is known about the pathogenesis of FCD. Inherited and perinatal factors appear unlikely to play a significant role.96 Whatever the mechanism, it is clear that the population of cells involved can be very small and lead to circumscribed involvement, or large, as in cases of hemimegalencephaly. There is some evidence that the subtypes of FCD vary in their cell types and gene expression. As mentioned there is an excess of CR cells in FCD IA that is not seen in type IIB.283 Cotter et al.286 looked at a number of proteins in the Notch/Wnt signaling pathway and found differences in the expression of several between FCD balloon cells and FCD giant neurons. For example, balloon cells had absent Notch-1 and elevated APC, whereas giant neurons had elevated Notch-1 and normal APC. This pathway is important in neuronal and glial determination, and one could speculate as to whether perturbations in the likes of the APC gene might play a role in the association with dysplastic tumors. Barkovich et al.277 speculate that transmantle dysplasia (TD) is due to a primary stem cell defect and include the lesion in their classification (I-B-3-iv) as a ‘‘malformation due to abnormal neuronal and glial proliferation.’’10 The association of TD and balloon cells with tuberous sclerosis led Becker et al.287 to compare the rates of sequence changes in certain exons of the TSC1 and TSC2 genes in 48 cases of type II FCD and 200 control samples. They found amino acid altering sequence changes in 2.3% of exons 5 and 35% of exons 17 in the type IIB FCD compared with 0% and 1%, respectively, in

the controls. The comparable figures for silent base-pair changes in exons 14 and 22 were 37.8% and 45% for the FCD and 15% and 23.8% for controls. Loss of heterozygosity for TSC1 was noted in 11 FCD samples. In contrast, TSC2 exhibited only silent base-pair substitutions at the same frequency as controls. Therefore, TSC1 may have a role in the pathogenesis of type IIB FCD. Using trinucleotide repeat number (TNR) variations at the X-linked androgen receptor locus, Hua and Crino288 showed random X-inactivation in both heterotopic neurons and balloon cells. In contrast, closely apposed normal neurons showed 70– 80% homology for TNR, which led the authors to conclude that the FCD cells arose in post-mitotic neurons, or from a population of progenitor cells. Growing interest in the nature and origin of FCD will undoubtedly lead to significant changes in understanding over the next several years. Prognosis, Treatment, and Prevention

The clinical presentation of FCD is predominantly that of epilepsy, which is often medically refractory. Prognosis is therefore primarily a question of severity, frequency, and the successful management of seizures. FCD may also be more frequent in patients with posttraumatic seizures, suggesting that these developmental lesions provide a focus of susceptibility to further damage. Mental retardation is uncommon, affecting only 1 of 21 patients with FCD discussed by Montenegro et al.96; but, focal neurologic signs may occur in extensive and diffuse lesions, and mild developmental problems may be more common. Klein et al. compared verbal and performance IQ between a group of 15 children with developmental mass lesions (glial-neuronal hamartomas, 8; dysembryoplastic neuroepithelial tumor, 4; ganglioneuroma, 4) and 39 children with FCD that was divided into mild, moderate, and severe.289 Performance IQ scores in those with mass lesions were in the low–normal range and were significantly higher than for children with FCD, whose mean scores tended to fall in the borderline range. Likewise, those in the former group who had right-sided lesions had clearly normal mean verbal scores, whereas those with right-sided FCD were significantly lower and in the low–normal range. Interestingly, there was no significant difference in verbal scores for left-sided lesions, with scores tending to be at the borderline level; and there was no correlation with IQ and the histologic scoring of the FCD pathology. Subsample sizes were small and the assessments were not all standardized, but the work points out the need for more study of development in individuals with FCD. The primary approach to intractable seizures associated with FCD is operative and, therefore, most information related to outcome derives from surgical series. Factors that might be expected to influence outcome include the location, extent, and histology of the lesion. It does appear that type I has a less severe presentation of seizures than does type II FCD.235,290 Although most clinically recognized FCD is extratemporal, type I may be more likely temporal.290 However, the impact of type on surgical outcome remains unclear, perhaps confounded by other variables such as actual location, variations in histopathologic classification, and chance due to small subtype numbers in the different series. Palmini and Luders235 state that when found retrospectively at surgery, type I FCD has a better prognosis, whereas Kloss et al.291 found no correlation between type and outcome, and Tassi et al.290 obtained better outcomes in patients with type IIB FCD. Partial surgical lobectomy has proved to benefit a significant proportion of patients. In one series of 68 cases, 60% were judged to have good results, with 50% seizure free at 2 years and 7%

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unchanged.291 Age at surgery had no impact and the outcomes were similar in patients followed to 3 years. Tassi et al.290 provided outcomes for seizure control for 40 of 52 patients 1 year post surgery. Forty two percent of patients with type I, two of four with type IIA, and 9 of 12 with type IIB FCD were seizure free at 1 year. The seemingly better outcomes for patients with type IIB lesions is not necessarily attributable to the histopathologic differences and might reflect the small sample numbers, or perhaps the location and size of the lesions. For example, 66% of the type I were temporal as compared with 13% of the type IIB FCD. Vigliano et al.278 reported successful suppression of seizures in three of four patients with tuberous sclerosis associated transmantle dysplasia. The authors cautioned that seizures might be anticipated to return because of other associated tuberous sclerosis pathology. Factors to be considered in surgical outcome include location in the perirolandic cortex235 and the fact that the FCD may extend beyond the borders of the lesion as visualized by neuroimaging. Seizures may continue to originate from surrounding FCD following removal of a dysplastic tumor. Studies such as PET, electrocorticography, and deep cortical recording may serve to better define the extent of the lesion. Raymond et al.292 reported that FCD was seen in 15% of their series of patients with hippocampal sclerosis. Ho et al.293 carried out comparative volumetric studies of the amygdala (AM) and hippocampal formation (HF) in a series of 30 patients with type IIB FCD of the temporal lobe. They noted decreased AM volume in 18 and HF volume in 26 of the patients. In contrast with patients who had isolated hippocampal sclerosis (i.e., not associated with FCD), there was a very high rate of bilateral involvement. The authors favor secondary damage from recurrent FCD-driven seizures as a cause for the AM and HF atrophy because the temporal lobe cortex, AM, and HF derive from different germinal matrices. They cautioned that these atrophic areas could become independent epileptogenic foci and compromise results of FCD surgery. Further cautions arise from the fMRI studies that have been discussed, which show activity in type I lesions and a significant minority of type II FCD.284 Preul et al.294 carried out extensive neuroimaging, electrophysiologic and functional studies on a 16-year-old boy with a large fronto-parietal nodular heterotopia that had overlying areas of cortical dysplasia. They were able to show compensatory cortical reorganization, and that the heterotopia and dysplastic cortex retained some motor and sensory function. Therefore, there is concern that removal of such areas at surgery could lead to functional loss. To date there does not appear to be any approach to the primary prevention of FCD. References (Malformations of Cortical Development) 1. Norman M, McGillivray BC, Kalousek DK, et al.: Neuronal migration disorders and cortical dysplasias. In: Congenital Malformations of the Brain. Pathological, Embryological, Clinical, Radiological and Genetic Aspects. Norman MG, McGillvray BL, Kalousek DK, et al., eds. Oxford University Press, New York, 1995, p 223. 2. Volpe JJ: Normal and abnormal human brain development. Clin Perinatol 4:3, 1977. 3. Caviness VS, Mission I-P Jr, Gadisseux I-F: Abnormal neuronal patterns and disorders of neocortical development. In: From Neuron to Reading: Toward a Neurobiology of Dyslexia. AM Galaburda, ed. MIT Press, Cambridge, MA, 1990, p 406. 4. Ross ME, Walsh CA: Human brain malformations and their lessons from neuronal migration. Ann Rev Neurosci 24:1041, 2001. 5. Mallamaci A, Mercurio S, Muzio L, et al.: The lack of Emx2 causes impairment of Reelin signaling and defects of neuronal migration in the developing cerebral cortex. J Neurosci 20:1109, 2000.

575 6. Gupta A, Tsai L-H, Wynshaw-Boris A: Life is a journey: a genetic look at neocortical development. Nature Rev Genet 3:342, 2002. 7. Meyer G, Wahle P: The paleocortical ventricle is the origin of reelinexpressing neurons in the marginal zone of the foetal human cortex. Eur J Neurosci 11:3937, 1999. 8. Sarnat HB, Flores-Sarnat L: Role of Cajal-Retzius and subplate neurons in cerebral cortical development. Semin Pediatr Neurol 9:302, 2002. 9. Uher BF, Golden JA: Neuronal migration defects of the cerebral cortex: a destination debacle. Clin Genet 58:16, 2000. 10. Barkovich AJ, Kuzniecky RI, Dobyns WB, et al.: A classification scheme for malformations of cortical development. Neuropediatrics 27:59, 1996. 11. Dobyns WB, Gilbert EF, Opitz JM: Letter to the editor: further comments on lissencephaly syndromes. Am J Med Genet 22:197, 1985. 12. Kato M, Dobyns WB: Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 12:R89, 2003. 13. Ross ME, Swanson K, Dobyns WB: Lissencephaly with cerebellar hypoplasia (LCH): a heterogeneous group of cortical malformations. Neuropediatrics 32:256, 2001. 14. Allanson JE, Ledbetter DH, Dobyns WB: Classical lissencephaly syndromes: does the face reflect the brain. J Med Genet 35:920, 1998. 15. Landrieu P, Husson B, Pariente D, et al.: MRI-neuropathological correlations in type 1 lissencephaly. Neuroradiology 40:173, 1998. 16. Friede RL: Developmental Neuropathology. Springer-Verlag, Wien, 1975, p 298. 17. Dobyns WB, Kirkpatrick JB, Hittner HM, et al.: Syndromes with lissencephaly. II: Walker-Warburg and cerebro-oculo-muscular syndromes and a new syndrome with type II lissencephaly. Am J Med Genet 22:157, 1985. 18. Ostrovskaya TI, Lazjuk GI: Cerebral abnormalities in the Neu-Laxova syndrome. Am J Med Genet 30:747, 1988. 19. Gardner RJ, Savarirayan R, Dunne KB, et al.: Microlissencephaly with cardiac, spinal and urogenital defects. Clin Dysmorphol 10:203, 2001. 20. Rodriguez Criado G, Rufo M, Gomez de Terreros I: A second family with Micro syndrome. Clin Dysmorphol 8:241, 1999. 21. Barth PG, Mullaart R, Stam FC, et al.: Familial lissencephaly with extreme neopallial hypoplasia. Brain Dev 4:145, 1982. 22. Toyo-oka K, Shionoya A, Gambello MJ, et al.: 14-3-3 epsilon is important for neuronal migration by binding to Nudel: a molecular explanation for Miller-Dieker syndrome. Nat Genet 34:274, 2003. 23. Dobyns WB, Pagon RA, Curry CR, et al.: Clinical and molecular studies in 62 patients with type I lissencephaly. Proc Greenwood Genet Center 10:64, 1991. 24. Sergi C, Zoubaa S, Schiesser M: Norman-Roberts syndrome: prenatal diagnosis and autopsy findings. Prenat Diagn 20:505, 2000. 25. Ledbetter SA, Kuwano A, Dobyns WB, et al.: Microdeletions of chromosome 17p13.3 as a cause of isolated lissencephaly. Am J Hum Genet 50:182, 1992. 26. Pilz DT, Macha ME, Precht KS, et al.: Fluorescence in situ hybridization analysis with LIS1 specific probes reveals a high deletion mutation rate in isolated lissencephaly sequence. Genet Med 1:1, 1998. 27. des Portes V, Francis F, Pinard J-M, et al.: doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). Hum Mol Genet 7:1063, 1998. 28. Hong SE, Shugart YY, Huang DT, et al.: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26:93, 2000. 29. Nissenkorn A, Weintraub S, Sadeh M, et al.: Lissencephaly associated with congenital hypomyelinating and axonal neuropathy. Pediatr Neurol 19:313, 1998. 30. Kitamura K, Yanazawa M, Sugiyama N, et al.: Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 32:359, 2002. 31. Dobyns WB, Patton MA, Stratton RF, et al.: Cobblestone lissencephaly with normal eyes and muscle. Neuropediatrics 27:70, 1996. 32. Clark BJ, Lee WR, Doyle D, et al.: A novel pattern of oculocerebral malformation. Br J Ophthalmol 81:470, 1997.

576

Neuromuscular Systems

33. Dobyns WB, Pagon RA, Curry CJR, et al.: Clinical and molecular status in 62 patients with type I lissencephaly. Proc Greenwood Genet Ctr 10:64, 1991. 34. Fukuyama Y, Ohsawa M, Suzuki H: Congenital progressive muscular dystrophy of the Fukuyama type-clinical, genetic and pathologic considerations. Brain Dev 3:1, 1981. 35. Kimura S, Sasaki Y, Kobayashi T, et al.: Fukuyama-type congenital muscular dystrophy and the Walker-Warburg syndrome. Brain Dev 15:182, 1993. 36. Cormand B, Avela K, Pihko H, et al.: Assignment of the muscle-eyebrain disease gene to 1p32-p34 by linkage analysis and homozygotes mapping. Am J Hum Genet 64:126, 1999. 37. Seidahmed MZ, Sunada Y, Ozo CO: Lethal congenital muscular dystrophy in two sibs with arthrogryposis multiplex: new entity or variant of cobblestone lissencephaly syndrome. Neuropediatrics 27:305, 1996. 38. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al.: Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 71:1033, 2002. 39. Plauchu H, Encha-Razavi F, Hermier M, et al.: Lissencephaly type III, stippled epiphyses and loose, thick skin: a new recessively inherited syndrome. Am J Med Genet 99:14, 2001. 40. Chitayat D, Meagher-Villemure K, Mamer OA, et al.: Brain dysgenesis and congenital intracerebral calcification associated with 3-hydroxyisobutyric aciduria. J Pediatr 121:86, 1992. 41. Krawinkel MB, Emst M, Fellar A, et al.: Lissencephaly, abnormal lymph nodes, and T -cell deficiency in one patient. Am J Med Genet 33:436, 1989. 42. Choi BH, Matthias SC: Cortical dysplasia associated with massive ectopia of neurons and glial cells within the subarachnoid space. Acta Neuropathol 73:105, 1987. 43. Hughes HE, Harwood-Nash DC, Becker LE: Craniotelencephalic dysplasia in sisters: further delineation of a possible syndrome. Am J Med Genet 14:557, 1983. 44. Krawinkel M, Steen H-J, Terwey B: Magnetic resonance imaging in lissencephaly. Eur J Pediatr 146:205, 1987. 45. Fontaine G, Farriaux JP, Blanckaert D, et al.: Un nouveau syndrome polymalformatif complexe. J Ge´ne´t Hum 25:109, 1977. 46. Aleksic S, Budzilovich G, Graco MA, et al.: Intracranial lipomas, hydrocephalus and other CNS anomalies in oculoauricular-vertebral dysplasia (Goldenhar-Gorlin syndrome). Child Brain 11:285, 1984. 47. Kozlowski K, Tsuruta T: Dysplastic cortical hyperostosis: a new form of lethal neonatal dwarfism. Br J Radiol 62:376, 1989. 48. Kerner B, Graham Jr JJ, Golden JA, et al.: Familial lissencephaly with cleft palate and severe cerebellar hypoplasia. Am J Med Genet 87:440, 1999. 49. Majoor-Krakauer DF, Wladimiroff JW, Stewart PA, et al.: Microcephaly micrognathia and bird headed dwarfism: prenatal diagnosis of a Seckel-like syndrome. Am J Med Genet 27:183, 1987. 50. Warburg M, Sjo O, Fledelius HC, et al.: Autosomal recessive microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and hypogenitalism. Micro syndrome. Am J Dis Child 147:1309, 1993. 51. Buyse M, Bull MJ: A syndrome of osteogenesis imperfecta, microcephaly, and cataracts. Birth Defects Orig Artic Ser XIV(6B):95, 1978. 52. Trounce JQ, Fagan DQ, Young ID, et al.: Disorders of neuronal migration: sonographic features. Dev Med Child Neurol 28:467, 1986. 53. Massa G, Casaer P, Ceulemans B, et al.: Arthrogryposis multiplex congenita associated with lissencephaly: a case report. Neuropediatrics 19:24, 1988. 54. Jones KL, Smith DW: The fetal alcohol syndrome. Teratology 12:1, 1975. 55. De Wals P: Surveillance of retinoic acid embryopathy. Teratology 40:274, 1989. 56. Bermejo E, Garcia-Alix A, Martinez S, et al.: Brain anomalies in infants exposed to valproic acid (VPA) monotherapy during the first trimester of gestation, Proc Greenwood Genet Center 10:115, 1991. 57. Peeden JN Jr, Rimoin DL, Lachman RS, et al.: Spondylometaphyseal dysplasia, Sedaghatian type. Am J Med Genet 44:651, 1992.

58. Sidman RL, Rakic P: Development of the human nervous system. In: Histology and Histopathology of the Nervous System. W Haymaker, RD Adams, eds. Charles C Thomas, Springfield, IL, 1982, p 3. 59. Hatten ME: Central nervous system neuronal migration. Ann Rev Neurosci 22:511, 1999. 60. Reiner O, Carrozzo R, Shen Y, et al.: Isolation of a Miller-Dieker lissencephaly gene containing G protein b-subunit-like repeats. Nature 364:717, 1993. 61. Mizuguchi M, Takashima S, Kakita A, et al.: Lissencephaly gene product. Localization in the central nervous system and loss of immunoreactivity in Miller-Dieker syndrome. Am J Pathol 147:1142, 1995. 62. Leventer RJ, Cardoso C, Ledbetter DH, et al.: LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ. Neurology 57:416, 2001. 63. Hirotsune S, Fleck MW, Gambello MJ, et al.: Graded reduction of PAFAH1B1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat Genet 19:333, 1998. 64. Hoffmann B, Zuo W, Liu A, et al.: The LIS1-related protein NudF of Aspergilus nidulans and its interaction partner NudE bind directly to specific subunits of dynein and dynectin and to a- and g-tubulin. J Biol Chem 276:38877, 2001. 65. Efimov VP, Morris NR: The LIS1-related protein NudF of Aspergilus nidulans interacts with the coiled-coil domain of the NUDE/RO11 protein. J Cell Biol 150:681, 2000. 66. Faulker NE, Dujardin DL, Tai CY, et al.: A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nature Cell Biol 2:784, 2000. 67. Cordoso C, Leventer RJ, Ward HL, et al.: Refinement of a 400 kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 72:918, 2003. 68. Sossey-Alaoui K, Hartung AJ, Guerrini R, et al.: Human doublecortin (DCX) and homologous gene in mouse encode a putative Ca2þ-dependent signaling protein which is mutated in human Xlinked neuronal migration defects. Hum Mol Genet 7:1327, 1998. 69. des Portes V, Abaoub L, Joannard A, et al.: So-called cryptogenic partial seizures resulting from a subtle cortical dysgenesis due to a doublecortin gene mutation. Seizure 11:273, 2002. 70. Pilz DT, Kuc J, Matsumoto N, et al.: Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1. Hum Mol Genet 8:1757, 1999. 71. Howell BW, Horrick TM, Hildebrand JD, et al.: Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development. Curr Biol 10:877, 2000. 72. Reiner O: Pathways of neuronal migration. Nat Genet 32:341, 2002. 73. Ross ME: Full circle to cobbled brain. Nature 418:376, 2002. 74. Michele DE, Barresi R, Kanagawa M, et al.: Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418:417, 2002. 75. Moore SA, Saito F, Chen J, et al.: Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418: 422, 2002. 76. Yoshida A, Kobayashi K, Manya H, et al.: Muscular dystrophy and neuronal migration disorder caused by mutations in glycosyltransferase, POMGnT1. Dev Cell 1:717, 2001. 77. Kobayashi K, Nakahori Y, Miyake M, et al.: An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394:388, 1998. 78. Hartmann D, De Strooper B, Saftig P: Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly. Curr Biol 9:719, 1999. 79. Dobyns WB: The neurogenetics of lissencephaly. Neurol Clin 7:89, 1989. 80. Sergi C, Zoubaa S, Schiesser M: Norman-Roberts syndrome: prenatal diagnosis and autopsy findings. Prenat Diagn 20:505, 2000. 81. Greco P, Resta M, Vimercati A, et al.: Antenatal diagnosis of isolated lissencephaly by ultrasound and magnetic resonance imaging. Ultrasound Obstet Gynecol 12:276, 1998.

Brain 82. Abe S, Takagi K, Yamamoto T, et al.: Assessment of cortical gyrus and sulus formation using MR images in normal fetuses. Prenat Diagn 23: 225, 2003. 83. Crowe C, Jarsani M, Dickerman L: The prenatal diagnosis of WalkerWarburg syndrome. Prenat Diagn 6:177, 1986. 84. Farrell SA, Toi A, Leadman MI, et al.: Prenatal diagnosis of retinal detachment in Walker-Warburg syndrome. Am J Med Genet 28:619, 1987. 85. van Tunen P, Dobyns WB, Rich DC, et al.: Molecular detection of microscopic and submicroscopic deletions associated with MillerDieker syndrome. Am J Hum Genet 43:587, 1988. 86. Haan EA, Fumess ME, Knowles S, et al.: Osteodysplastic primordial dwarfism: report of a further case with manifestations similar to those of types I and III. Am J Med Genet 33:224, 1989. 87. Barkovich AJ, Chuang SH, Norman D: MR of neuronal migration anomalies. AJR Am J Roentgenol 150:179, 1988. 88. Fabregues I, Ferrer I, Cusi MV, et al.: Fine structure based on the Golgi method of abnormal cortex and heterotopic nodule in pachygyria. Brain Dev 6:317, 1984. 89. Anderman F: Cortical dysplasias and epilepsy: a review of architectonic, clinical, and seizure patterns. Adv Neurol 84:479, 2000. 90. Bartolomei F, Gavaret M, Dravet C, et al.: Familial epilepsy with unilateral and bilateral malformations of cortical development. Epilepsia 40:47, 1999. 91. Caraballo RH, Cersosimo RO, Espeche A, et al.: Bilateral posterior agyria-pachygyria and epilepsy. Brain Dev 25:122, 2003. 92. Liang JS, Lee WT, Young C, et al.: Agyria-pachygyria: clinical, neuroimaging, and neurophysiological correlations. Pediatr Neurol 27: 171, 2002. 93. Shaw C-M: Correlates of mental retardation and structural changes of the brain. Brain Dev 9:1, 1987. 94. Jellinger K: Neuropathological aspects of infantile spasms. Brain Dev 9:349, 1987. 95. McBride MC, Kemper TL: Pathogenesis of the four layered microgyric cortex in man. Acta Neuropathol 57:93, 1982. 96. Montenegro MA, Guerreiro MM, Lopes-Cendes I, et al.: Interrelationship of genetic and prenatal injury in the genesis of malformations of cortical development. Arch Neurol 59:1147, 2002. 97. Goldstein DJ, Mirkin LD: Nager acrofacial dysostosis: evidence for apparent heterogeneity. Am J Med Genet 30:741, 1988. 98. Savarirayan R, Thompson EM, Abbott KJ, et al.: Cerebral cortical dysplasia and digital constriction rings in Adams-Oliver syndrome. Am J Med Genet 86:15, 1999. 99. Amor DJ, Leventer RJ, Hayllar S, et al.: Polymicrogyria associated with scalp and limb defects: variant of Adams-Oliver syndrome. Am J Med Genet 93:328, 2000. 100. Ades LC, Clapton WK, Morphett A, et al.: Polydactyly, campomelia, ambiguous genitalia, cystic dysplastic kidneys, and cerebral malformation in a fetus of consanguineous parents: a new multiple malformation syndrome, or a severe form of oral-facial-digital syndrome Type IV? Am J Med Genet 49:211, 1994. 101. Sybert V, Pagon RA, Ramsdell L, et al.: True agonadism: report of a case analyzed with Y-specific DNA probes. Am J Med Genet 55:113, 1995. 102. Sztriha L, al-Gazali L, Dawodu A, et al.: Agyria-pachygyria and agenesis of the corpus callosum: autosomal recessive inheritance with neonatal death. Neurology 50:1466, 1998. 103. Ferrer I, Cusi MV, Liarte A, et al.: A Golgi study of the polymicrogyric cortex in Aicardi syndrome. Brain Dev 8:518, 1986. 104. Glaser T, Jepeal L, Edwards JG, et al.: PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 7:463, 1994. 105. Angle B, Hersh JH: Anophthalmia, intracerebral cysts, and cleft lip/ palate: expansion of the phenotype in oculocerebrocutaneous syndrome? Am J Med Genet 68:39, 1997. 106. Cohen MM Jr, Kreiborg S: The central nervous system in the Apert syndrome. Am J Med Genet 35:36, 1990. 107. Arena JF, Schwartz C, Stevenson R, et al.: Spastic paraplegia with iron deposits in the basal ganglia: a new X-linked mental retardation syndrome. Am J Med Genet 43:479, 1992.

577 108. Persutte WH, Kurczynski TW, Chaudhuri K, et al.: Prenatal diagnosis of autosomal dominant microcephaly and postnatal evaluation with magnetic resonance imaging. Prenatal Diagn 10:631, 1990. 109. Nwokoro NA, Jaffe R, Barmada M: Baller-Gerold syndrome: a postmortem examination. Am J Med Genet 47:1233, 1993. 110. Ramer JC, Mascari MJ, Manders E, et al.: Syndrome identification #149: trigonocephaly, pachygyria, retinal coloboma, and cardiac defect: a distinct syndrome. Dysmorph Clin Genet 6:15, 1992. 111. Greenhalgh KL, Newbury-Ecob RA, Lunt PW, et al.: Siblings with Bohring-Opitz syndrome. Clin Dysmorphol 12:15, 2003. 112. Lower KM, Turner G, Kerr BA, et al.: Mutations in PHF6 are associated with Bo¨rjeson-Forssman-Lehmann syndrome. Nat Genet 32:661, 2002. 113. North KN, Hoppel CL, De Girolami U, et al.: Lethal neonatal deficiency of carnitine palmitoyltransferase II associated with dysgenesis of the brain and kidneys. J Pediatr 127:414, 1995. 114. Carpenter BF, Hunter AGW: Micromelia, polysyndactyly, multiple malformations, and fragile bones in a stillborn child. J Med Genet 19:311, 1982. 115. Shotelersuk V, Desudchit T, Suwanwela N: Postnatal growth failure, microcephaly, mental retardation, cataracts, large joint contractures, osteoporosis, cortical dysplasia, and cerebellar atrophy. Am J Med Genet 116A:164, 2003. 116. Hong SE, Shugart YY, Shahwan S, et al.: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26:93, 2000. 117. Sabatino G, Domizio S, Verrotti A, et al.: Fetal encephalopathy with cerebral calcifications: a case report. Child Nerv Syst 10:195, 1994. 118. Milunsky JM, Capin DM: Cerebro-oculo-facial-lymphatic syndrome. Clin Genet 63:291, 2003. 119. Matsuzaka T, Sakuragawa N, Nakayama H, et al.: Cerebro-oculohepato-renal syndrome (Arima’s syndrome): a distinct clinicopathological entity. J Child Neurol l:338, 1986. 120. POSSUM1, Version 5.6. The Murdoch Institute Royal Children’s Hospital, Melbourne, Australia. 121. Coad JE, Angel C, Pierpont MEM, et al.: Microcephaly with agenesis of corticospinal tracts and arthrogryposis, hypospadias, single umbilical artery, hypertelorism, and renal and adrenal hypoplasia-previously undescribed syndrome. Am J Med Genet 71:458, 1997. 122. Wessel HB, Barmada MA, Hashida Y: Congenital alopecia, seizures, and psychomotor retardation in three siblings. Pediatr Neurol 3:101, 1987. 123. Flaherty MP, Grattan-Smith P, Steinberg A, et al.: Congenital fibrosis of the extraocular muscles associated with cortical dysplasia and maldevelopment of the basal ganglia. Ophthalmology 108:1313, 2001. 124. Hageman G, Hoogenraad TU, Prevo RL: The association of cortical dysplasia and anterior horn arthrogryposis: a case report. Brain Dev 16:463, 1994. 125. Serner RN: Whistling face syndrome: MR imaging findings in the brain. Eur Radiol 6:102, 1996. 126. Gardner RJ, Morrison PS, Faigan LA, et al.: Syndrome of a craniofacial dysostosis, limb malformation, and omphalocele. Am J Med Genet 36:133, 1990. 127. Cohen MM Jr: Craniosynostosis: Diagnosis, Evaluation, and Management. New York, Raven Press, 1986 128. Striano S, Ruosi P, Guzzetta F, et al.: Cutis verticis gyrata—mental deficiency syndrome: a patient with drug-resistant epilepsy and polymicrogyria. Epilepsia 37:284, 1996. 129. Boesch CH, Issakainen J, Kewitz G, et al.: Magnetic resonance imaging of the brain in congenital cytomegalovirus infection. Pediatr Radiol 19:91, 1989. 130. Anderson HC, Kratz L, Kelley R: Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay. Am J Med Genet 113:315, 2002. 131. Kuzniecky R: Familial diffuse cortical dysplasia. Arch Neurol 51:307, 1994. 132. Kato M, Takizawa N, Yamada S, et al.: Diffuse pachygyria with cerebellar hypoplasia: a milder form of microlissencephaly or a new genetic syndrome? Ann Neurol 46:660, 1999.

578

Neuromuscular Systems

133. Stanek J, de Courten-Myers G, Spaulding AG, et al.: Case of complex craniofacial anomalies, bilateral nasal proboscides, palatal pituitary, upper limbs reduction, and amnion rupture sequence: disorganization phenotype? Pediatr Dev Pathol 4:192, 2001. 134. Jagadha V, Becker LE: Brain morphology in Duchenne muscular dystrophy: a Golgi study. Pediatr Neurol 4:87, 1988. 135. Echaniz-Laguna A, De Saint-Martin A, Lafontaine AL, et al.: Bilateral focal polymicrogyria in Ehlers-Danlos syndrome. Arch Neurol 57:123, 2000. 136. Ellis IH, Yale C, Thomas R, et al.: Three sibs with microcephaly, congenital heart disease, lung segmentation defects and unilateral absent kidney: a new recessive multiple congenital anomaly (MCA) syndrome? Clin Dysmorphol 5:129, 1996. 137. Froster-Iskenius UG, Meinecke P: Encephalocele, radial defects, cardiac, gastrointestinal, anal, and renal anomaly (MCA) syndrome? Clin Dysmorphol 1:37, 1992. 138. Choi BH, Ruess WR, Kim RC: Disturbances in neuronal migration and laminar cortical organization associated with multicystic encephalopathy in the Pena-Shokeir syndrome. Acta Neuropathol 69:177, 1986. 139. Opitz JM, Kaveggia EG, Adkins WN Jr, et al.: Studies of malformation syndromes of humans XXXIIIC: the FG syndrome-further studies on three affected individuals from the FG family. Am J Med Genet 12:147, 1982. 140. Ferrie CD, Jackson GD, Giannakodimos S, et al.: Posterior agyriapachygyria with polymicrogyria: evidence for an inherited neuronal migration disorder. Neurology 45:150, 1995. 141. Straussberg R, Gross S, Amir J, et al.: A new autosomal recessive syndrome of pachygyria. Clin Genet 50:498, 1996. 142. Van Hove JL, Spiridigliozzi GA, Heinz R, et al.: Fryns syndrome survivors and neurologic outcome. Am J Med Genet 59:334, 1995. 143. Aynaci FM, Aynaci O, Ahmetoglu A, et al.: Fuhrmann syndrome associated with cortical dysplasia. Genet Couns 12:49, 2001. 144. Bartley AJ, Jones DW, Weinberger DR: Genetic variability of human brain size and cortical gyral patterns. Brain 120:257, 1997. 145. Cooperstone BG, Friedman A, Kaplan BS: Galloway-Mowat syndrome of abnormal gyral patterns and glomerulopathy. Am J Med Genet 47:250, 1993. 146. Armstrong L, Clarke JTR: Report of a new case of ‘‘genitopatellar’’ syndrome which challenges the importance of absent patella as a defining feature. J Med Genet 39:933, 2002. 147. Colombo I, Finocchiaro G, Garavaglia B, et al.: Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaric acidemia type II. Hum Mol Genet 3:429, 1994. 148. Silengo M, Ferrero GB, Tornetta L: Pachygyria and cerebellar hypoplasia in Goldberg-Shprintzen syndrome. Am J Med Genet 118A:388, 2003. 149. Hayashi M, Kurati K, Suzuki K, et al.: Megalencephaly, hydrocephalus and cortical dysplasia in severe dwarfism mimicking leprechaunism. Acta Neuropathol (Berl) 95:431, 1998. 150. To¨llner U, Horst J, Manzke E, et al.: Heptocarpo-octatarso-dactylycombined with multiple malformations. Eur J Pediatr 136:207, 1981. 151. Holmes LB, Schoene WC, Benacerraf BR: New syndrome: brain malformation, growth retardation, hypokinesia and polyhydramnios in two brothers. Clin Dysmorphol 6:13, 1997. 152. Ono J, Harada K, Kodaka R, et al.: Regional cortical dysplasia associated with suspected hypomelanosis of Ito. Pediatr Neurol 17:252, 1997. 153. Levin ML, Lupski JR, Carpenter RJ Jr, et al.: An additional case of pachygyria, joint contractures and facial abnormalities. Clin Dysmorphol 2:365, 1993. 154. Verloes A, Narcy F, Fallet-Bianco C: Syndromal hypothalamic hamartoblastoma with holoprosencephaly sequence, microphthalmia, pulmonary malformations, radial hypoplasia and mu¨llerian regression: further delineation of a new syndrome? Clin Dysmorphol 4:33, 1995. 155. Di Gennaro G, Condoluci C, Casali C, et al.: Epilepsy and polymicrogyria in Kabuki make-up (Niikawa-Kuroki) syndrome. Pediatr Neurol 21:566, 1999. 156. Yamaguchi K, Ogawa Y, Handa T: Brain dysplasia associated with Larsen-like syndrome. Pediatr Neurol 14:75, 1996.

157. Lurie IW, Lazjuk GI, Korotkova IA, et al.: The cerebro-reno-digital syndromes: a new community. Clin Genet 39:104, 1991. 158. Sarwar M, Schafer ME: Brain malformations in linear nevus sebaceous syndrome: an MR study. J Comput Assist Tomogr 12:338, 1988. 159. Prudlo J, Stoltenburg-Didinger G, Jimenez E, et al.: Central nervous system alterations in a case of short-rib polydactyly syndrome, Majewski type. Dev Med Child Neurol 35:158, 1993. 160. Summers DA, Cooper HA, Butler MG: Marshall-Smith syndrome: case report of a newborn male and review of the literature. Clin Dysmorphol 8:207, 1999. 161. McPherson E, Clemens M: Cleft lip and palate, characteristic facial appearance, malrotation of the intestine, and lethal congenital heart disease in two sibs: a new autosomal recessive condition? Am J Med Genet 62:58, 1996. 162. Paetau A, Solonen R, Haltia M: Brain pathology in the Meckel syndrome: a study of 59 cases. Clin Neuropathol 4:56, 1985. 163. Go¨hlich-Ratmann G, Baethmann M, Lorenz P, et al.: Megalencephaly, mega corpus callosum, and complete lack of motor development: a previously undescribed syndrome. Am J Med Genet 79:161, 1998. 164. Burn J, Wickramasinghe HT, Harding B, et al.: A syndrome with intracranial calcification and microcephaly in two sibs, resembling intrauterine infection. Clin Genet 30:112, 1986. 165. Ades LC, Clapton WK, Morphett A, et al.: Polydactyly, campomelia, ambiguous genitalia, cystic dysplastic kidneys, and cerebral malformation in a fetus of consanguineous parents: a new multiple malformation syndrome, or a severe form of oral-facial-digital syndrome type IV? Am J Med Genet 49:211, 1994. 166. Wanders RJA, Van Roermund CWT, Schelen A, et al.: A bifunctional protein with deficient enzymic activity: identification of a new peroxisomal disorder using novel methods to measure the peroxisomal beta-oxidation enzyme activities. J Inherit Metab Dis 13:375, 1990. 167. Garty BZ, Eisenstein B, Sandbank J, et al.: Microcephaly and congenital nephrotic syndrome owing to diffuse mesangial sclerosis: an autosomal recessive syndrome. J Med Genet 31:121, 1994. 168. Fletcher JM, Bye AME, Nayanar V, et al.: Non-ketotic hyperglycinaemia presenting as pachygyria. J Inherit Metab Dis 18:665, 1995. 169. Pini A, Merlini L, Tome FMS, et al.: Merosin-negative congenital muscular dystrophy, occipital epilepsy with periodic spasms and focal cortical dysplasia. Report of three Italian cases in two families. Brain Dev 18:316, 1996. 170. Leao MJ, Ribeiro-Silva ML: Orofaciodigital syndrome type I in a patient with severe CNS defects. Pediatr Neurol 13:247, 1995. 171. Pradhan M, Phadke SR, Jain S, et al.: Pachygyria/hypogenitalism: A monogenic syndrome. Am J Med Genet 87:254, 1999. 172. Berry-Kravis E, Israel J: X-linked pachygyria and agenesis of the corpus callosum: evidence for an X chromosome lissencephaly locus. Ann Neurol 36:229, 1994. 173. Mitchel TN, Free SL, Williamson KA, et al.: Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol 53:658, 2003. 174. Sheen VL, Ganesh VS, Topcu M, et al.: Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cortex. Nat Genet 36:69, 2003. 175. Zannolli R, Conversano E, Serracca L, et al.: Cortical periventricular heterotopia with ectodermal dysplasia. Am J Med Genet 113:385, 2002. 176. Guerrini R, Dobyns WB: Bilateral periventricular nodular heterotopia with mental retardation and frontonasal malformation. Neurology 51: 499, 1998. 177. Holtmann M, Woermann FG, Boenigk HE: Multiple pterygium syndrome, bilateral periventricular nodular heterotopia and epileptic seizures—a syndrome? Neuropediatrics 32:264, 2001. 178. Slaney SF, Chong WK, Winter RM: A new syndrome of short stature, distinctive facial features and periventricular grey matter heterotopia. Clin Dysmorphol 8:5, 1999. 179. Dobyns WB, Guerrini R, Czapansky-Beilman DK, et al.: Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: a new X-linked mental reatrdation syndrome. Neurology 49:1042, 1997.

Brain 180. Musumeci SA, Ferri R, Elia M, et al.: A new family with periventricular nodular heterotopia and peculiar dysmorphic features. Arch Neurol 54:61, 1997. 181. Shanske AL, Gurland JE, Mbekeani JN, et al.: Possible new syndrome of microcephaly with cortical migration defects, Peters anomaly and multiple intestinal atresias: a multiple vascular disruption syndrome. Clin Dysmorphol 11:67, 2002. 182. Rodriguez JI, Palacios J, Omenaca F, et al.: Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am J Med Genet. 38:99, 1991. 183. Guerrini R, Barkocich AJ, Sztriha L, et al.: Bilateral frontal polymicrogyria. A newly recognized brain malformation syndrome. Neurology 54:909, 2000. 184. Chang BS, Piao X, Bodell A, et al.: Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 53:596, 2003. 185. Kuzniecky R, Andermann F, Guerrini R, et al.: Congenital bilateral perisylvian syndrome: study of 31 patients. Lancet 341:608, 1993. 186. Guerrini R, Dubeau F, Dulac O, et al.: Bilateral parasagittal parietooccipital polymicrogyria and epilepsy. Ann Neurol 41:65, 1997. 187. De Bleecker J, De Reuck J, Martin JJ, et al.: Autosomal recessive inheritance of polymicrogyria and dermatomyositis with paracrystalline inclusions. Clin Neuropathol 9:299, 1990. 188. Pavone L, Rizzo R, Pavone P, et al.: Diffuse polymicrogyria associated with congenital hydrocephalus, craniosynostosis, severe mental retardation, and minor facial and genital anomalies. J Child Neurol 15:493, 2000. 189. Cohn RD, Gillessen-Kaesbach G, Dobyns WB, et al.: Diffuse polymicrogyria associated with an unusual pattern of multiple congenital anomalies including turribrachycephaly and hypogenitalism. Am J Med Genet 63:314, 1996. 190. Grunnet ML, Bale JF, Jr: Brain anomalies in infants with Potter syndrome (oligohydramnios tetrad). Neurology 31:1571, 1981. 191. Choi BH, Lapham LW, Amin-Zaki L, et al.: Abnormal neuronal migration, deranged cerebral cortical organization and diffuse white matter astrocytosis of human fetal brain: a major effect of methylmercury poisoning in utero. J Neuropathol Exp Neurol 37:719, 1978. 192. Dupont S, Catala M, Hasboun D, et al.: Progressive facial hemiatrophy and epilepsy: a common underlying dysgenetic mechanism. Neurology 48:1013, 1997. 193. Biesecker LG, Happle R, Mulliken JB, et al.: Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84:389, 1999. 194. Ehara H, Kurimara A, Ohno K, et al.: New syndrome with Sakoda complex, bilateral anophthalmia, and cortical dysgenesis. Pediatr Neurol 18:445, 1998. 195. Samsom JF, Barth PG, de Vries JIP, et al.: Familial mitochondrial encephalopathy with fetal ultrasonographic ventriculomegaly and intracerebral calcifications. Eur J Pediatr 153:510, 1994. 196. Shaw CM, Alvord EC: Global cerebral dysplasia due to dysplasia and hypoplasia of periventricular germinal cells. J Child Neurol 11:313, 1996. 197. Shanske A, Caride DG, Menasse-Palmer L, et al.: Central nervous system anomalies in Seckel syndrome: Report of a new family and review of the literature. Am J Med Genet 70:155, 1997. 198. Marion RW, Alvarez LA, Marans ZS, et al.: Computed tomography of the brain in the Smith-Lemli-Optiz syndrome. J Child Neurol 2:198, 1987. 199. Veggiotti P, Beccaria F, Berardinelli A, et al.: Spinal muscular atrophy and bilateral pachygyria: a case report. Epilepsia 35:13, 1994. 200. Lin AE, Harster GA: Another case of spondylocostal dysplasia and severe anomalies. Am J Med Genet 46:476, 1993. 201. Demaerel P, Kendell BE, Wilms G, et al.: Uncommon posterior cranial fossa anomalies: MRI with clinical correlation. Neuroradiology 37:72, 1995. 202. Yamaguchi K, Honma K: Autopsy case of thanatophoric dysplasia: observations on the serial sections of the brain. Neuropathology 21:222, 2001.

579 203. Ferrer I, Fabregues I, Coil I, et al.: Tuberous sclerosis: a Golgi study of cortical tuber. Clin Neuropathol 3:47, 1984. 204. Laing IA, Lyall EGH, Hendry LM, et al.: ‘‘Typus Edinburgensis’’ explained. Pediatrics 88:151, 1991. 205. Ehara H, Maegaki Y, Takeshita K: Pachygyria and polymicrogyria in 22q11 deletion syndrome. Am J Med Genet 117A:80, 2003. 206. Costa T, Eich G, MacGregor D: Weaver syndrome with lissencephaly. Eastern Canadian-New England Clinical Genetics Conference, May 1990, Ottawa, Canada. 207. Wieczorek D, Gillessen-Kaesbach G, Plewa S, et al.: Microcephaly, seizures, genital hypoplasia, and abnormalities of the hands and feet in a 4-year-old boy with possible Wiedemann syndrome. Clin Genet 49: 98, 1996. 208. Martin JJ, Ceuterick CM, Leroy JG, et al.: The Wiedemann-Rautenstrauch or neonatal progeroid syndrome: neuropathological study of a case. Neuropediatrics 15:43, 1984. 209. Cohn RD, Gillessen-Kaesbach G, Dobyns WB, et al.: Diffuse polymicrogyria associated with an unusual pattern of multiple congenital anomalies including turribrachycephaly and hypogenitalism. Am J Med Genet 63:314, 1996. 210. Winter RM, Wigglesworth JS: Unusual association of cerebral and renal abnormalities. Clin Dysmorphol 2:71, 1993. 211. Kang WM, Huang CC, Lin SJ: X-linked recessive inheritance of dysgenesis of corpus callosum in a Chinese family. Am J Med Genet 44:619, 1992. 212. Yokochi K, Aiba K, Kanayama M: A case with athetosis, mental retardation, deafness, and pachygyria. Brain Dev 13:365, 1991. 213. Giustina ED, Boffinet AM, Landrieu P, et al.: A Golgi study of the brain malformation in Zellweger’s cerebro-hepato-renal disease. Acta Neuropathol 55:23, 1981. 214. Barkovich AJ, Peck WW: MR of Zellweger syndrome. AJNR Am J Neuroradiol 18:1163, 1997. 215. Zollino M, Colosimo C, Zuffardi O, et al.: Cryptic t(1;12)(q44;p13.3) translocation in a previously described syndrome with polymicrogyria, segregating as an apparently X-linked trait. Am J Med Genet 117A:65, 2003. 216. Ferrer I: A Golgi analysis of unlayered polymicrogyria. Acta Neuropathol 65:69,1984. 217. Titlebaum DS, Hayward JC, Zimmerman RA: Pachygyric-like changes: topographic appearance at MR imaging and CT and correlation with neurologic status. Radiology 173:663, 1989. 218. Ferrer I, Catala I: Unlayered polymicrogyria: structural and developmental aspects. Anat Emb 184:517, 1991. 219. Curatolo P, Pruna D, Dusmai R: Polymicrogyria: a case detected by MRI. Brain Dev 11:257, 1989. 220. Byrd SE, Osborn RE, Bohan P, et al.: The CT and MR evaluation of migrational disorders of the brain. Part II. Schizencephaly, heterotopia and polymicrogyria. Pediatr Radiol 19:219, 1989. 221. Barth PG, van der Harten JJ: Parabiotic twin syndrome with topical isocortical disruption and gastroschisis. Acta Neuropathol 67:345, 1985. 222. Pupillo GT, Andermann F, Dubeau F, et al.: Bilateral sylvian parietooccipital polymicrogyria. Neurology 46 (Suppl 2):A303, 1996. 223. Guerreiro MM, Andermann E, Guerrini R, et al.: Familial perisylvian polymicrogyria: a new familial syndrome of cortical maldevelopment. Ann Neurol 48:39, 2000. 224. Kuker W, Friese S, Riethmuller J, et al.: Congenital bilateral perisylvian syndrome (CBPS): do concomitant esophageal malformations indicate a poor prognosis. Neuropediatrics 31:310, 2000. 225. Miller SP, Shevell M, Rosenblatt B, et al.: Congenital bilateral perisylvian polymicrogyria presenting as congenital hemiplegia. Neurology 50:1866, 1998. 226. Bingham PM, Parrish B, Chen SC-Y, et al.: Spectrum of disorders associated with enlarged sylvian fissures in infancy. Neurology 51:1732, 1998. 227. Galaburda AM, Sherman GF, Rosen GD, et al.: Developmental dyslexia: four consecutive patients with cortical anomalies. Ann Neurol 18:222, 1985.

580

Neuromuscular Systems

228. Cohen M, Campbell R, Yaghmai F: Neuropathological abnormalities in developmental dysphasia. Ann Neurol 25:567, 1989. 229. Gelisse P, Corda D, Raybaud C, et al.: Abnormal neuroimaging in patients with benign epilepsy with centrotemporal spikes. Epilepsia 44:372, 2003. 230. McLendon RE, Crain BJ, Oakes WJ, et al.: Cerebral polygyria in the Chiari type II (Arnold-Chiari) malformations. Clin Neuropathol 4:200, 1985. 231. Evrard P, de Saint-Georges P, Kadhim HJ, et al.: Pathology of prenatal encephalopathies. In: Child Neurology and Developmental Disabilities. Paul H Brooks, Baltimore, 1989, p 153. 232. Suzuki M, Choi BH: Repair and reconstruction of the cortical plate following closed cryogenic injury to the neonatal rat cerebrum. Acta Neuropathol (Berl) 82:93, 1991. 233. Toti P, De Felice C, Palmeri ML, et al.: Inflammatory pathogenesis of cortical polymicrogyria: an autopsy study. Pediatr Res 44:291, 1998. 234. Villard L, Nguyen K, Cardoso C, et al.: A locus for perisylvian polymicrogyria maps to Xq28. Am J Hum Genet 70:1003, 2002. 235. Palmini A, Luders HO: Classification issues in malformations caused by abnormalities of cortical development. Neurosurg Clin N Am 13:1, 2002. 236. Barkovich AJ: Morphologic characteristics of subcortical heterotopia: MR imaging study. AJNR Am J Neuroradiol 21:290, 2000. 237. Battaglia G, Pagliardini S, Ferrario A, et al.: AlphaCaMKII and NMDAreceptor subunit expression in epileptogenic cortex from human periventricular nodular heterotopia. Epilepsia 43 (Suppl 5):209, 2002. 238. Soto Ares G, Hamon-Kerautret M, Houlette C, et al.: Unusual MRI findings in grey matter heterotopia. Neuroradiology 40:81, 1998. 239. Spalice A, Taddeucci G, Perla FM, et al.: Periventricular nodular heterotopia: report of a pediatric series. J Child Neurol 17:300, 2002. 240. Borgatti R, Zucca C, Piccinellli P, et al.: Unilateral periventricular nodular heterotopia associated with diffuse areas of cerebral functional abnormalities. J Child Neurol 15:622, 2000. 241. Hannan AJ, Servotte S, Katsnelson A, et al.: Characterization of nodular heterotopia in children. Brain 122:219, 1999. 242. Fox JW, Lamperti ED, Eksioglu YZ, et al.: Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 21:1315, 1999. 243. Leventer RJ, Mills PL, Dobyns WB: X-linked malformations of cortical development. Am J Med Genet 97:213, 2000. 244. Harding BN: Gray matter heterotopia. In: Dysplasia of Cerebral Cortex and Epilepsy. Guerrini R, Andermann F, Canapicchi R, et al., eds. Lippincott-Raven, Philadelphia, 1996, p 81. 245. Kakita A, Hayashi S, Moro F, et al.: Bilateral periventricular nodular heterotopia due to filamin 1 gene mutation: widespread glomeruloid microvascular anomaly and dysplastic cytoarchitecture in the cerebral cortex. Acta Neuropath (Berl) 104:649, 2002. 246. Dambska M, Wisniewski KE, Sher IH: Marginal glioneuronal heterotopias in nine cases with and without cortical abnormalities. J Child Neurol 1:149, 1986. 247. Van Geertruyden JP, Fourez TJ, Hansen P, et al.: Heterotopic brain tissue in the scalp. Br J Plastic Surg 48:352, 1995. 248. Nishio S, Mizuno J, Barrow DL, et al.: Intracranial extracerebral glioneuronal heterotopia. Child Nerv Syst 4:246, 1988. 249. Harris CP, Townsend JJ, Klatt EC: Accessory brains (extracerebral heterotopias): unusual prenatal intracranial mass lesions. J Child Neurol 9:386, 1994. 250. Roelens FA, Barth PG, van der Harten JJ: Subependymal heterotopia in patients with encephalocele. Eur J Neurol 3:59, 1999. 251. Frater JL, Prayson RA, Morris HH III, et al.: Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections. Arch Pathol Lab Med 124:545, 2000. 252. Hardiman O, Burke T, Phillips J, et al.: Microdysgenesis in resected temporal neocortex: incidence and clinical significance in focal epilepsy. Neurology 38:1041, 1988. 253. Leventer RJ, Phelan EM, Coleman LT, et al.: Clinical and imaging features of cortical malformations in childhood. Neurology 53:715, 1999. 254. Fink JM, Dobyns WB, Guerrini R, et al.: Identification of a duplication of Xq28 associated with bilateral periventricular nodular heterotopia. Am J Med Genet 61:379, 1997.

255. Sheen VL, Dixon PH, Fox JW, et al.: Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet 10:1775, 2001. 256. Battaglia G, Granata T, Farina L, et al.: Periventricular nodular heterotopia: epileptogenic findings. Epilepsia 38:1173, 1997. 257. Choi BH: Developmental events during the early stages of cerebral cortical neurogenesis in man: a correlative, light, electronmicroscopic, immunohistochemical and Golgi study. Acta Neuropathol (Berl) 75: 441, 1988. 258. Ligon KL, Echelard Y, Assimacopoulos S, et al.: Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia. Development 130:2275, 2003. 259. Jan MMS: Outcome of bilateral periventricular nodular heterotopia in monozygous twins with megalencephaly. Dev Med Child Neurol 41:486, 1999. 260. Steams M, Wolf AL, Barry E, et al.: Corpus callosectomy for refractory seizures in a patient with cortical heterotopia: case report. Neurosurgery 25:633, 1989. 261. Onyeije CI, Sherer DM, Jarosz CJ, et al.: Prenatal sonographic findings associated with sporadic subcortical nodular heterotopia. Obstet Gynecol 91:799, 1998. 262. Bargallo N, Puerto B, De Juan C, et al.: Hereditary subependymal heterotopia associated with mega cisterna magna: antenatal diagnosis with magnetic resonance imaging. Ultrasound Obstet Gynecol 20:86, 2002. 263. Spreafico R, Pasquier B, Minotti L, et al.: Immumocytochemical investigation of dysplastic human tissue from epileptic patients. Epilepsy Res 32:34, 1998. 264. Taylor DC, Falconer MA, Bruton CJ, et al.: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 34:369, 1979. 265. Gambardella A, Palmini A, Andermann F, et al.: Usefulness of focal rhythmic discharges on scalp EEG of patients with focal cortical dysplasia and intractable epilepsy. Electroencephalogr Clin Neurophysiol 98:243, 1996. 266. Morioka T, Nishio S, Ishibashi H, et al.: Intrinsic epileptogenicity of focal cortical dysplasia as revealed by magnetoencephalography and electroencephalography. Epilepsy Res 33:177, 1999. 267. Palmini A, Gambardella A, Andermann F, et al.: Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 37:476, 1995. 268. Bronen RA, Vives KP, Kim JH, et al.: Focal cortical dysplasia of Taylor, balloon cell subtype: MR differentiation from low-grade tumors. AJNR Am J Neuroradiol 18:1141, 1997. 269. Keene DL, Jimenez CC, Ventureyra E: Cortical microdysplasia and surgical outcome in refractory epilepsy of childhood. Pediatr Neurosurg 29:69, 1998. 270. Adamsbaum C, Robain O, Cohen PA, et al.: Focal cortical dysplasia and hemimegalencephaly: histological and neuroimaging correlations. Pediatr Radiol 28:583, 1998. 271. Prayson RA, Estes ML: Cortical dysplasia: a histopathological study of 52 cases of partial lobectomy in patients with epilepsy. Hum Pathol 26:493, 1995. 272. Maehara T, Arai N, Shimizu H, et al.: Cortical dysplasia with ossification. Epilepsia 41:1489, 2000. 273. Kim SW, Na DG, Byun HS, et al.: Focal cortical dysplasia: comparison of MRI and FDGPET. J Comp Assit Tomog 24:296, 2000. 274. Kirchhof K, Harting I, Bast T, et al.: Focal dysplasias: neurological findings and differential diagnosis. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 175:1056, 2003. 275. Chan S, Chin SS, Nordli DR, et al.: Prospective magnetic resonance imaging identification of focal cortical dysplasia, including the nonballoon cell subtype. Ann Neurol 44:749, 1998. 276. Bronen RA, Spencer DD, Fulbright RK: Cerebrospinal fluid cleft with cortical dimple: MR imaging marker for focal cortical dysgenesis. Radiology 214:657, 2000. 277. Barkovich AJ, Kuzniecky RI, Bollen AW, et al.: Focal transmantle dysplasia: a specific malformation of cortical development. Neurology 49:1148, 1997.

Brain 278. Vigliano P, Canavese C, Bobba B, et al.: Transmantle dysplasia in tuberous sclerosis: clinical features and surgical outcome in four children. J Child Neurol 17:752, 2002. 279. Barkovich AJ, Peacock W: Sublobar dysplasia. A new malformation of cortical development. Neurology 50:1383, 1998. 280. Lee BC, Hatfield G, Park TS, et al.: MR imaging surface display of the cerebral cortex in children. Pediatr Radiol 27:199, 1997. 281. Bastos AC, Comeau RM, Andermann F, et al.: Diagnosis of subtle focal dysplastic lesions: curvilinear reformatting from three dimensional magnetic resonance imaging. Ann Neurol 46:88, 1999. 282. Spreafico R, Battaglia G, Arcelli P, et al.: Cortical dysplasia. An immunological study of three patients. Neurology 50:27, 1998. 283. Garbelli R, Frassoni C, Ferrario A, et al.: Cajal-Retzius cell density as a marker of type of focal cortical dysplasia. Neuroreport 12:2767, 2001. 284. Jansky J, Ebner A, Kruse B, et al.: Functional organization of the brain with malformations of cortical development. Ann Neurol 53:759, 2003. 285. Cepeda C, Hurst RS, Flores-Hernandez J, et al.: Morphological and electrophysiological characterization of abnormal cell types in pediatric cortical dysplasia. J Neurosci Res 72:472, 2003. 286. Cotter D, Honavar M, Lovestone S, et al.: Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex. Acta Neuropathol (Berl) 98:465, 1999. 287. Becker AJ, Urbach H, Scheffler B, et al.: Focal cortical dysplasia of Taylor’s balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. Ann Neurol 52:29, 2002. 288. Hua Y, Crino PB: Single cell lineage analysis in human focal cortical dysplasia. Cereb Cortex 13:693, 2003. 289. Klein B, Levin BE, Duchowny MS, et al.: Cognitive outcome with epilepsy and malformations of cortical development. Neurology 55:230, 2000. 290. Tassi L, Colombo N, Garbelli R, et al.: Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 125:1719, 2002. 291. Kloss S, Pieper T, Pannek H, et al.: Epilepsy in children with focal cortical dysplasia (FCD): results of long-term seizure outcome. Neuropediatr 33:21, 2002. 292. Raymond AA, Fish DR, Stevens JM, et al.: Association of hippocampal sclerosis with cortical dysgenesis in patients with epilepsy. Neurology 44:1841, 1994. 293. Ho SS, Kuzniecky RI, Gilliam F, et al.: Temporal lobe developmental malformations and epilepsy. Neurology 50:748, 1998. 294. Preul MC, Leblanc R, Cendes F, et al.: Function and organization in dysgenic cortex. Case report. J Neurosurg 87:113, 1997. 295. Giuliano F, David A, Edery P, et al.: Macrocephaly-cutis marmorata telangiectasia congenita: seven cases including two with unusual cerebral manifestations. Am J Med Genet 126A:99, 2003. 296. Cohen MM, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003. 297. Grosso S, Farnetani MA, Beradi R, et al.: Medial temporal lobe dysgenesis in Muenke syndrome and hypochondroplasia. Am J Med Genet 120A:88, 2003. 298. Viot G, Sonigo P, Simon I, et al.: Neocortical neuronal arrangement in LIS1 and DCX lissencephaly may be different. Am J Med Genet 126A:123, 2004. 299. Righini A, Zirpoli S, Mrakic F, et al.: Early prenatal MR imaging diagnosis of polymicrogyria. AJNR Am J Neuroradiol 25:343, 2004.

15.6 Agenesis of the Corpus Callosum Definition

Agenesis of the corpus callosum is complete or partial failure of the callosal commissural fibers to cross the midline and form the major neopallial connection (the corpus callosum) between the

581

two cerebral hemispheres (Figs. 15-37, 15-38). In current literature the term callosal dysgenesis is most often used to describe partial callosal agenesis, but hypogenesis may also be found. The definition is restricted to primary developmental failure and excludes secondary atrophy, destruction, and simple hypoplasia.

Fig. 15-37. Sagittal MRI scan showing absence of the corpus callosum and anterior (white area) lipoma. (Courtesy of Dr. S. Grahovac, Ottawa General Hospital.)

Fig. 15-38. Sagittal MRI scan showing partial absence of the corpus callosum, along with aqueductal stenosis and compensated hydrocephalus. (Courtesy of Dr. S. Grahovac, Ottawa General Hospital.)

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Neuromuscular Systems

Diagnosis

There is a remarkable heterogeneity in absent corpus callosum (ACC) in terms of both its broad etiologic origins and in its association with other CNS and non-CNS anomalies. It has only been within the past decade that the importance of separating these broad nosological groups has been emphasized, so to better enable the unraveling of the complex underlying pathogeneses. As recapitulated by Dobyns,1 there are four general types of ACC: two primary and two secondary. In the first primary subgroup, the axons develop and move toward the midline but are unable to cross. This results in pathognomonic, aberrant, longitudinal bundles of Probst that run along the medial ventricular walls and lateral to the fornices. In the second primary subtype of ACC, the commissural axons or their cell bodies fail to form and therefore never approach the midline. This pattern is typical of some forms of lissencephaly (see Section 15-5) and is seen in Walker-Warburg and several other syndromes. Among the secondary forms of ACC are those associated with major malformations of the forebrain, such as frontal encephaloceles or holoprosencephaly (Section 15-4), and cases in which there is a secondary atrophy leading to marked thinning or even absence of areas of the corpus callosum. Often it is not possible to distinguish a corpus callosum that is thin because of a primary hypoplasia where axons did not arrive in sufficient numbers from an instance in which there was excess apoptosis or another secondary cause for axonal loss. This section is limited to the first subgroup of primary ACC. Intracerebral cysts may accompany ACC, and there is consensus that the types of cysts and their associated clinical and pathological findings may reflect differing underlying pathogenesis. The classification of cysts associated with ACC suggested by Barkovich et al.2 has attained general acceptance, with the understanding that some changes are inevitable as knowledge increases. Type 1 cysts are connected to the ventricular system and have three subtypes. In type 1a, communicating hydrocephalus is the only neocortical abnormality accompanying the ACC and interhemispheric cyst. In type 1b, the egress of CSF to the aqueduct of Sylvius is blocked, most often by fusion of the thalami. The authors provide a compelling argument as to why this should not be considered a form fruste of holoprosencephaly. Microcephaly and hypoplasia of a cerebral hemisphere characterize type 1c. Type 2 cysts do not connect with the ventricular system, and in type 2a there are no other associated CNS findings. In type 2b, the falx is absent and there are subependymal heterotopias and polymicrogyria. Type 2c is defined by subcortical heterotopia; and in type 2d the cyst is of the arachnoid type. Recently, Da´vila-Gutie´rrez3 has suggested an all-inclusive classification that first separates isolated ACC (category 1) from that with associated anomalies (category 2). The latter is then subdivided into the following: 2.1, with other brain anomalies; 2.2, with cysts and incorporating the subtypes of Barkovich et al.2; 2.3 with neuropathy; 2.4, associated with inherited metabolic diseases; 2.5, posited to be due to toxins; 2.6, with a callosal lipoma; and 2.7, with less frequent malformations. If this classification is used one needs to be mindful that some of the categories could include both primary and secondary ACC and their different subtypes. There is a consensus that the presenting signs in individuals with ACC are due to concurrent brain abnormalities and that isolated ACC is essentially asymptomatic. This conclusion is supported by the fact that clinically normal persons have been

found to have ACC at routine autopsy. Furthermore, modern imaging has led to the inter vivo diagnosis of increasing numbers of individuals with normal intelligence in whom it is necessary to test for functions and learning that are dependent on specific inter-cerebral callosal connections in order to detect functional deficiencies due to ACC (vide infra). The spectrum of clinical signs observed and the age at diagnosis are correlated with, and highly dependent on, the ascertainment of the population studied and the clinical threshold at which diagnostic procedures are applied. A common, albeit nonspecific, associated facial appearance is hypertelorism with a broad nose and nasal tip. Diagnosis in the neonatal period may derive from the presence of macrocephaly (notably in types 1a, 1b, 2a, and 2b of Barkovich et al.2), seizures, or craniofacial dysmorphism. Microcephaly may also be seen and is typical of type 2c. The diagnosis in infancy usually follows investigation of developmental delay, seizures, macrocephaly, or microcephaly. Other neurologic signs are frequent, and in a follow-up study of 14 prenatally and 61 postnatally diagnosed cases, 40.6% had poor coordination, 36.2% were spastic, 14.5% had quadriparesis, and 11.6% hemiparesis.4 Postnatal growth failure occurred in 15.9%, 2.9% had increased intracranial pressure, and 5.8% were asymptomatic. Older children may present with learning disability. Infantile spasms are well represented among the seizures, accounting for 7 of 40 cases in one series,5 and being characteristic of some syndromes such as Aicardi (Table 15-7). The clinical spectrum of ACC that ranges from an isolated and asymptomatic malformation to one accompanied by severe mental retardation with associated CNS and other malformations presents a special problem when the diagnosis is suspected on the basis of prenatal ultrasound. Given the benign clinical course of many patients with isolated ACC, most neurologic signs that are observed in patients are attributed to associated CNS anomalies. Symptomatic patients who do not have associated visible brain malformations are assumed to have disturbances that remain undetected with current neuroimaging techniques. A diverse array of malformations of the CNS may accompany ACC. Jeret et al.6 summarized 705 reported and personally studied cases and found that 23% had associated hydrocephalus; 15%, microcephaly; 23%, heterotopias/polymicrogyria; 6%, microgyria; 2.4%, pachygyria; 3%, lissencephaly; and 3%, arhinencephaly. Twenty-three percent had associated cysts, either interhemispheric, porencephalic, Dandy-Walker, or arachnoid. Tumors, including lipoma, papilloma, and meningioma, were present in 7% of cases. Arnold-Chiari type II malformation, neural tube defects, and various cerebellar anomalies have also been noted. Structural anomalies of the eye were common and included retinal lacunae (Aicardi syndrome), colobomas, microphthalmia, and cataracts. A wide array of dysmorphic facial features was also reported, with hypertelorism in 20% of patients being the single most common feature. In a recent series, 44% of patients had an accompanying CNS defect, 29.3% had craniofacial and skeletal signs, 13.3% had cardiorespiratory anomalies, 8% had gastrointestinal defects, and 2.7% had renal malformations.4 Franco et al.7 found undescended testes in 23% of 22 boys with ACC and hypothesized hypothalamic insufficiency as a cause. They also noted renal and ureteral anomalies respectively in 18% and 15% of their 33 patients. The comparable rates for the 18 patients who underwent urinary tract imaging were 33% and 27%. Obviously there is a bias toward dysmorphic and/or symptomatic patients in this type of series. Symptomatic patients who do not have associated visible brain malformations are assumed to have

Table 15-7. Syndromes with absent corpus callosum Syndromes

Prominent Features

Causation Gene/Locus

3-hydroxyisobutyric acid26

Poor neonatal behavior, triangular face, short and sloping forehead, narrow bitemporal distance, shallow supraorbital ridges, epicanthus, micrognathia, adducted thumbs, clinodactyly of toes 4 and 5, intracerebral calcification, cerebellar hypoplasia, agenesis of the corpus callosum, lissencephaly, pachygyria

AR (236795)

Acrocallosal27

Broad high forehead, large fontanel, hypoplastic alae, short neck, macrocephaly, pre and/ or postaxial polydactyly of hands and feet of a variable degree, mental retardation

AR (200900) 12p13.3-p11.2

Acrofacial dysostosis-type Rodriguez28

Severe acrofacial dysostosis, congenital heart defects, absent lung lobation, small kidneys; variable limb anomalies include short limbs, absent fibulae, oligodactyly; hypoplastic scapulae; hydrocephalus, agenesis of the corpus callosum

AR (201170)

Acromesomelic frontonasal dysplasia29

Epibulbar dermoid, cleft nose, notched alae, midline cleft lip/palate, renal anomalies, preand post-axial polydactyly, delayed development; CNS includes absent corpus callosum, Dandy-Walker, hydrocephalus, encephalocele

Unknown

Ades: campomeliapolydactyly-dysplastic kidney30

Cleft epiglottis and tongue, dysplastic larynx, coloboma, cystic dysplastic kidneys, periportal hepatic fibrosis, mesomelia, absent corpus callosum, abnormal gyri

Unknown

Agenesis corpus callosumobesity camptodactyly31

Postnatal growth and developmental delay, android truncal obesity, hypertelorism, upslanting palpebrae, long hands with thin fingers, finger 5 camptodactyly, ventricular septal defect, abnormal venous return

Unknown

Agenesis corpus callosumpyloric stenosisHirschsprung32

Hypertelorism, depressed nasal bridge, hypertrophic pyloric stenosis, callosal agenesis; part of the SMADIP1 Hirschsprung-midline spectrum?

Unknown

Agonadism-CNS anomalies33

Agonadism with urogenital sinus and 46,XY karyotype, severe mental retardation, absent corpus callosum, cerebellar agenesis, pachygyria. Single case.

Unknown

Agyria-pachygyria-absent corpus callosum-AR34

Normancephaly, hypertonia, apnea, neonatal death, absent corpus callosum, cortical dysplasia—probably agyria/pachygyria

AR

Aicardi35

Chorioretinal lacunae, infantile spasms, hypsarrhythmia, vertebral segmentation defects, polymicrogyria, periventricular nodules, colpocephaly, hypoplastic cerebellar vermis

XLD, male lethal (304050), Xp22

Alcohol, prenatal36

IUGR, mild microcephaly, short palpebral fissures, malar hypoplasia, short nose, hypoplastic philtrum, thin upper lip, micrognathia, hypoplastic distal phalanges, tremorous movement, developmental delay

In utero exposure

Andermann: neuropathycallosal agenesis37

Psychomotor delay, progressive flaccid quadriparesis, ptosis, strabismus, brachycephaly, hypoplastic maxilla, anterior horn cell disease, neuronal heterotopias

AR (218000) SLC12A6, 15q13-q14

Anophthalmia-cranial cystscleft lip/palate38

Macrocephaly, microphthalmia, bilateral cleft lip/palate, myoclonic seizures, hypotonia, posterior midline cyst, frontal polymicrogyria, absence of the corpus callosum. Single case; could be part of the oculocerebrocutaneous spectrum

Unknown

Anophthalmia-heminasal aplasia-CNS anomalies39

Postnatal growth and developmental delay, prominent forehead, anophthalmia, heminasal hypo/aplasia, preauricular skin tags, abnormal pinnae, atypical clefts

Unknown

Apert40

Severe craniofacial synostosis, marked syndactyly; developmental delay is common; CNS includes corpus callosum (5/113), limbic system, microgyria, polymicrogyria, heterotopia, ventriculomegaly

AD (101200) FGFR2, 10q25.3-q26

Basal cell nevus41

Prominent supraorbital ridges, heavy eyebrows, broad nasal root, hypertelorism, long mandible, pouting lower lip, basal cell carcinomata, jaw cysts, rib anomalies, palmoplantar pits, calcified falx

AD (109400) PTCH, 9q22.3 PTCH2, 1p32

Ben Ari: trigonocephalycallosal agenesis42

Moderate developmental delay, trigonocephaly, upslanting palpebrae, posteriorly rotated ears, high palate, cubitus valgus, anterior placement of anus, double left collecting system

Unknown

Beta-hydroxyisobutyryl Co A deacylase43

Facial dysmorphia, vertebral anomalies, hemangiomas, severe hypotonia, tetralogy of Fallot, agenesis of cingulate gyrus and corpus callosum; increased urinary cysteine and cysteamine, beta-hydroxyisobutyryl CoA deacylase deficiency

AR (250620)

Blepharophimosis-joint contractures-Dandy Walker cyst44

Short stature, low-set ears, preauricular pits, ptosis, blepharophimosis, epicanthus inversus, multiple joint contractures, kyphoscoliosis, CNS includes absence of the corpus callosum, ventriculomegaly, Dandy-Walker cyst

Unknown

Brooks: XLMR-unusual facegrowth failure45

Severe mental retardation, spasticity, triangular face, bifrontal narrowing, low-set and cupped ears, malar flatness, short and downslanting palpebrae, deep-set eyes, bulbous or beaked nose, tented upper lip, mild knee and elbow contractures, ventriculomegaly; partial agenesis of the corpus callosum in one case

XLR

Brumback: microcephaly46

Microcephaly from birth, normal development at 1 year, craniofacial disproportion, sloping forehead, maintained primitive reflexes, delayed dentition

Unknown (continued)

583

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Buntinx: ocular anomaliespolydactyly47

Mental retardation, blepharophimosis, iris coloboma, upslanting palpebrae, short nose, narrow auditory canals, mixed hearing loss, postaxial polydactyly of hands, hydroureter, large fontanel

AR

Cao: Microcephaly48

Microcephaly from birth, infantile spasms, spastic quadriparesis, severe mental retardation, 1 of 3 cases had retinopathy, aqueduct stenosis (McKusick questions if same as Andermann: neuropathy-callosal agenesis.37)

AR

Carpenter: acrocephalopolysyndactyly type IIchromosome49

Established acrocephalopolysyndactyly syndrome; case with de novo reciprocal translocation 46,XX,t(1;18)(p31;q11) with preaxial polysyndactyly, craniosynostosis and partial agenesis of the corpus callosum

Uncertain

Castro-Gago: optic atrophyheterotopias-callosal agenesis50

Severe mental retardation, hypotonia, optic atrophy, dilated unreactive pupils, agenesis of the corpus callosum, gray matter heterotopias, brain atrophy

Unknown

Cerebral lactic acidosis51

Microcephaly, severe developmental delay, postnatal growth failure, initial hypotonia, spasticity, blindness, metabolic disturbance confined to CNS; CNS anomalies include absent pyramids and corpus callosum, heterotopia of the inferior olive, marginal glialneuronal heterotopia. Clinical features include mutations in E1-alpha subunit of the pyruvate dehydrogenase complex.

XLR (312170) PDH, Xp22.1

Cerebro-facio-thoracicdysplasia52

Mental retardation, macro/brachycephaly, hypertelorism synophrys, bifid and synostosed ribs, narrow chest, elevated scapulas, hemivertebrae, short neck

AR (213980)

Cerebro-oculo-facialskeletal53

Microcephaly, cataracts, joint contractures, early death or severe postnatal growth and developmental failure, severely sloped forehead, prominent nose, cataract, microophthalmia, micrognathia; heterogeneity, some in Cockayne spectrum; CNS include mild cortical neural loss, ventriculomegaly, delayed myelination, abnormal myelinization, gliosis, cerebellar degeneration, partial callosal agenesis

AR (214150)

Cerebro-oculo-nasal54

Macrobrachycephaly, craniosynostosis, anophthalmia, nares separated by a midline groove, nasal skin appendages, low-set ears. The other girl had a single maxillary central incisor; case reported with agenesis of the corpus callosum; other CNS not well documented but may include hydrocephalus, frontal encephalocele, holoprosencephaly, Dandy-Walker cyst.

Unknown

Cerebro-oculo-skeletalrenal55

Optic atrophy, absence of retinal vessels, seizures, growth and developmental delay, elongated clavicles, cupped ribs, mild platyspondyly, rhizomelia, schizencephaly, nephritis/nephrosis

Unknown

Cerebro-renal-digital56

Microcephaly, pterygium colli, cystic renal dysplasia, polysplenia, postaxial polydactyly, stillborn (family G)

AR

CHARGE57

Association of coloboma, heart malformation, choanal atresia, growth and/or mental retardation, ear anomalies and/or deafness. Absent corpus callosum (4/47), arrhinecephaly (2/47), septal agenesis (2/47), vermian agenesis (1/47), meningomyelocele (1/47).

AD (214800) CHD7, 8q12.1 small minority del22q11

Chlorpyrifos, prenatal58

Profound mental retardation, growth retardation, defects involving eyes, ears, palate, teeth, heart, genitalia; abnormal choroid plexus, septum pellucidum, and callosal agenesis; similar to findings in animals

In utero exposure

Chondrodysplasia-callosal agenesis-thrombocytopenia59

Rhizomelia, hypertension, thrombocytopenia, flat nasal root, anteverted nasal tip, wide metaphyses, platyspondyly, deficient dorsal ossification centers of vertebrae, agenesis of the corpus callosum, severe hydrocephalus

Unknown (166990)

Chromosomal aberrations 1,60

Agenesis of the corpus callosum has been reported with about 30 different chromosomal aberrations, and findings vary with the specific imbalance. Most common are trisomy 13, 18, 11q, and mosaic problems.

Chromosomal imbalance

Cleft lip/palate-ectrodactyly61

Half sibs through mother: female had clefting, atrial septal defect, oligodactyly of both feet and hands; male had clefting, syndactyly, ectrodactyly, dysplastic ears (Same as EEC syndrome?)

Unknown

Cocaine, prenatal exposure62

Debatable if recognizable facial appearance, limb reduction, genitourinary anomalies; CNS has included porencephaly, septo-optic dysplasia, schizencephaly, midline cysts, and callosal agenesis

In utero exposure

Coffin-Siris63

Postnatal growth failure; lax joints; coarse face; sparse hair; hypoplastic or absent nails; especially 5th digits; hypertrichosis of body; severe mental retardation

Uncertain (135900) (continued)

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Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Coffin-Lowry

Mental retardation, prominent forehead and supraorbital ridges, downslanting palpebrae, hypertelorism, low nasal bridge with thick septum, small and anteverted nares, full and patulous lips, everted lower lip; soft, hyperextensible, and tapering fingers; non-specific radiographic changes, progressive kyphoscoliosis; three cases reported with ACC

XLD (303600) RDS6KA3

Congenital bowingcamptodactyly-callosal agenesis64

IUGR, bowing of long bones, proximal shortness, camptodactyly, talipes equinovarus, neonatal death, wide metaphyses, increased trabeculation and cortical thickness on concave side, mild platyspondyly

Unknown

Corpus callosum agenesis, isolated65

Uncommonly ACC occurs as a familial condition without associated anomalies. Individuals may be asymptomatic or have various neurologic/developmental problems

AR, XLR, AD (217990, 304100)

Crane: skeletal dysostosisclefting66

Facial dysmorphia, cleft lip/palate, abnormal and low-set ears, hypoplastic alae, absent vertebrae C1-C6 and clavicles, soft tissue syndactyly

AR

Craniofacial dyssynostosis67

Variable developmental delay, premature fusion of the lambdoid and posterior sagittal sutures, dolichocephaly, protuberant forehead; one each of seven original patients had congenital heart defect, agenesis of the corpus callosum, and hydrocephalus (same as craniotelencephalic dysplasia?)

AR (218350) heterogeneity?

Craniotelencephalic dysplasia68

Protruding frontal bone with encephalocele, craniosynostosis, small eyes, absent olfactory nerves, grade 2 lissencephaly, cerebellar heterotopias

Probable AR (218670)

Curatolo: white matter hypoplasia-callosal agenesis70

Severe mental retardation, growth failure, downslanting palpebrae, broad nasal root, hypertelorism, synophrys, long eyebrows, micrognathia, severe diffuse cerebral white matter hypoplasia, agenesis/hypoplasia of the corpus callosum, partial agenesis of cerebellar vermis

Uncertain

Curry-Jones: craniosynostosispolysyndactyly71

Craniosynostosis, asymmetric face, low nasal bridge, anteverted nares, hypertelorism, narrow palpebrae, scarring of eyelids, variable preaxial polysyndactyly of hands and feet, linear hypopigmented streaking of the skin, gut obstruction, intestinal myofibromata

Unknown (601707)

DaSilva: mental retardationmicrocephaly72

Severe retardation, postnatal growth failure, preauricular skin tag, nasal skin tag, camptodactyly, club feet, increased tone, pulmonary infections, lethal

AR (217990)

Dwarfism-microcephaly73

Hydrocephalus, sloping forehead, deformity at base of skull, short limbs, postnatal growth failure, short and cupped ribs, lethal

AR

Delleman: oculocerebrocutaneous74

Psychomotor delay, eye anomalies, orbital cysts, skin tags and defects, calvarial defects, vertebral, rib, hand/foot anomalies, porencephalic cysts

Unknown (164180)

Desmosterolosis75

IUGR, downslanting palpebral fissures, low nasal bridge, thick alveolar ridges, gingival nodules, congenital heart defect, ambiguous genitalia, case with macrocephaly and another with microcephaly, ‘‘immature gyral pattern,’’ cholesterol biosynthesis

AR (602398) Sterol-delta 24-reductase, 1p33-p33.1

Diaphragmatic herniahypertelorism-deafness76

High birth weight, large fontanel, marked hypertelorism, myopia, variable coloboma, short nose, posteriorly rotated ears, sensorineural deafness, diaphragmatic hernia, gut malrotation

AR (222448)

Diaphragmatic herniapulmonary hypoplasiahydrocephalus77

Right diaphragmatic defect, pulmonary aplasia or hypoplasia, borderline developmental delay, atrial septal defect, aqueduct stenosis, ventriculomegaly

AR

DK-phocomelia with thrombocytopenia78

Occipital encephalocele, absent corpus callosum, variable upper limb and digital absence anomalies, hypoplastic thumbs, thrombocytopenia/reduced mega-karyocytes, renal agenesis to milder defects, vaginal atresia, other variable brain anomalies

Unknown (223340) Case with del(13q)

Dobyns: facio-oculo-aural79

Microcephaly, mild trigonocephaly, short nose and jaw, flat philtrum, low-set ears with absent crura and antihelix, microcornea, ectopic pupils, choroidal coloboma, finger contractures, absent corpus callosum

Unknown

Ectodermal dysplasiahypothyroidism80

Relative macrocephaly, large fontanel, hypertelorism, downslanting palpebrae, abnormal ear shape, severe mental retardation, ectopic thyroid remnant

Unknown Uncertain (225040)

Ectrodactyly-diaphragmatic hernia-heart defect81

Bilateral split hands and feet, left diaphragmatic hernia, ventricular septal defect, agenesis of the corpus callosum

Unknown

Edwards: microphthalmia82

Microcephaly, Dandy-Walker cyst, cerebellar vermis hypoplasia, choanal atresia, and other defects in a child whose mother and grandmother had Hallerman-Strieff- like face, aniridia cataract (see PAX6)

AD PAX6

Ehlers-Danlos83

Heterogeneous connective tissue disorder with hyperelasticity/friability most apparent in skin and joints; CNS not limited to a specific type and include cortical dysplasia, heterotopias, bilateral perisylvian polymicrogyria

AD heterogeneity several genes known

257

(continued)

585

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Encephalocele-radial anomalies84

Esophageal atresia, abnormal lung lobulation, congenital heart defect, lung anomalies, radial ray defects, anterior anus, hypoplastic spleen, tracheoesophageal fistula, renal agenesis, partial callosal agenesis, hypoplastic cerebellum, encephalocele, ‘‘cortical microgyria’’

Unknown

Endothelial dystrophy-band keratopathy85

Bilateral corneal clouding, thin and degenerate corneal epithelium, spherical aggregates in Bowman’s membrane with target appearance on EM, abnormal collagen in pre-Decemet’s membrane area

Unknown

Femoral deficiency-facial86

Short anteverted nose, long philtrum, thin upper lip, micrognathia, cleft palate, proximal focal femoral deficiency, preaxial toe polydactyly, reported CNS anomalies include agenesis posterior corpus callosum, brain atrophy, absent septum pellucidum, dilatated lateral ventricles, heterotopias

Associated with maternal diabetes

FG87

Mental retardation, hypotonia, constipation, anal anomalies, broad forehead, cowlick, ‘‘hypotonic facies,’’ often postnatal growth failure and death

XLR (305450) Xq12-q21.3 Multiple loci probable

Fine88

Asymmetric skull with lateral bulging, cleft palate, asymmetric eyes, cataract OD, glaucoma OS, small and abnormal ears, small mouth and mandible, small genitalia, aqueduct stenosis. Single case.

Unknown

Focal dermal hypoplasia89

Skin pigment anomalies, telangiectasias, focal skin atrophy with protruding lipomatous nodules, enamel and dental hypoplasia, perianal and perioral angiofibromata, nail dystrophy hand and foot syndactyly, ocular malformations

XLD, male lethal (305600)

Francois: callosal agenesiscoloboma-vermis hypoplasia90

Marked hypertelorism, downslanting palpebrae, complete eye colobomas, bifid uvula, short neck, diastasis recti, small thumbs, hypoplastic genitalia, microgyria, ventriculomegaly, hypoplastic cerebellar vermis

Unknown

Frontonasal dysplasia91

Spectrum of midcraniofacial anomalies, hypertelorism, cranium bifidum, broad nasal root, bifid tip, cleft nose and/or upper lip; mental retardation correlates with severity of extracranial findings; CNS anomalies uncommon

Most sporadic; some AD (136760)

Frontonasal dysplasiaacromelia33

Craniofacial appearance as described for frontonasal dysplasia,91 short neck, short limbs, preaxial- and/or postaxial polydactyly of all limbs, short humerus and ulna, DandyWalker cyst. Single case.

Unknown

Frontonasal dysplasiacoloboma-Temple type93

Moderate developmental delay, hypertelorism, broad nasal root, nose bifid or with median groove, notched alae, cleft lip/palate, eye coloboma, microphthalmia; part of frontonasal spectrum?

Unknown

Frontonasal dysplasiamacrobleparon-retardation94

Developmental delay, coronal synostosis, prominent forehead, hypertelorism, macroblepharon, ectropion, notched eyelids, high-arched eyebrows, broad and bifid nose, clefting, macrostomia, abnormal pinnae, hand anomalies, callosal hypo/agenesis

Unknown

Fryns: acral-diaphragmatic hernia95

Hydramnios, coarse face, facial hirsutism, cloudy corneae, large nose with broad flat bridge, short upper lip, micrognathia, cleft lip/ palate, abnormal pinnae, hypoplastic distal phalanges and nails, diaphragmatic defects, gut anomalies, cardiac defects, bicornuate uterus; CNS anomalies include agenesis of the corpus callosum, arhinencephaly, heterotopias

AR (229850)

Fullana: caudal deficiencyasplenia96

IUGR, marked caudal regression, hypoplastic pelvis, imperforate/stenotic anus, myelomeningocele, laterality anomalies with asplenia, complex cardiac anomalies. Variant of X-linked laterality syndrome?85

AR or XLR

G97

Dysphagia, stridor, hypertelorism, prominent forehead, laryngotracheal cleft, tracheoesophageal fistula, hypospadias developmental delay, more severe in males

AD (145410) 22q11.2 XLR (300000) Xp22

Genitopatellar98

Coarse face, prominent nasal root and bulbous tip, micrognathia, high palate, soft skin, flexion contractures, dislocated/absent patellae, variable skeletal changes. Case with absent corpus callosum and periventricular neuronal heterotopias

AR (606170)

Glass: ear anomalies-limb reduction100

Cleft palate, stenotic auditory meati, preauricular tags, helical folding; one sib with upper limb deficiencies, other with callosal agenesis and porencephaly

AR

Goldberg-Shprintzen99

Microcephaly, short stature, developmental delay, hypertelorism, submucous cleft palate; diminished white matter, hypo/partial absence corpus callosum, pachygyria, cerebellar hypoplasia

AR (235730) SMADIP1, 2q22 (continued)

586

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Goldblatt: genitopatellar

Hypoplastic/absent patella, contractures of major joints, short stature, cupped ears, flat nasal bridge, midface hypoplasia, micrognathia, crossed renal ectopia, scrotal hypoplasia; 4 of 7 cases with absent corpus callosum

Unknown (606170)

Goldenhar104

Variable asymmetric lower face, especially mandible hypoplasia, microtia, preauricular tags and pits, macrostomia, vertebral anomalies, epibulbar dermoids, variety of CNS defects in low frequency

Sporadic; some AD (164210) 14q32

Greig cephalopolysyndactyly101

Variable postaxial hand and preaxial toe polysyndactyly, telecanthus, hypertelorism, low and wide nasal root

AD (175700) GLI3, 7p13

Grubben: short-dentaleczema105

Pre- and postnatal growth and developmental delay, hypotonia; small, widely spaced or missing teeth, eczematous skin rash; small, puffy hands and feet with tapering digits; partial agenesis of the corpus callosum or ventriculomegaly; selective IgG2 subclass deficiency a possible marker

AR (233810)

Halal-Silver: de Lange-like106

Postnatal growth and developmental delay, microcephaly, low anterior hairline, long eye lashes, depressed nasal bridge, long philtrum, thin upper lip, micrognathia, severe metatarsus adductus

AD

Hendricks: deafness-callosal agenesis-arachnoid cyst107

Normal intelligence, sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cysts, hydrocephalus

AR

Hersh: mirror hands and feetbrain anomalies108

Sagittal synostosis, flat nasal bridge, bulbous nasal tip, hypoplastic alae, hamartomatous enlargement of parotid glands, stenotic ear canals, pelvic kidneys, ventricular septal defects, fusion and platyspondyly of cervical vertebrae, hydrocephalus, callosal agenesis

Unknown

Holmes: brain malformationfetal hypokinesia109

Polyhydramnios, fetal hypokinesia, wide cranial sutures, telecanthus, narrow palpebrae, micrognathia. One sib with agenesis of the corpus callosum, slightly broad gyri, focal cerebellar disorganization; other sib had arhinencephaly, hypoplastic gyri, regions of persistent external cerebral granular layer

Uncertain

Hydrolethalus110

Aqueductal stenosis/hydrocephalus, preaxial and/or postaxial polydactyly hands, cleft lip/ palate, anomalies of pulmonary and cardiovascular systems

AD (236680) 11q23-q25

Hypothalamic hamartomagelastic epilepsy-precocious puberty111

Well established association reported in association with Dandy-Walker cyst, heterotopias, and callosal agenesis

Unknown

Hypothalamic hamartomamicrophthalmia-radial ray112

Hypothalamic hamartoma, microphthalmia, ectopic retinal pigment layer, flat nose, absent/hypoplastic thumb, gut malrotation, small stomach, asplenia, abnormal genitalia. Case with agenesis of the corpus callosum, meningeal dysplasia, abnormal gyral pattern

Unknown

Influenza, prenatal113

Possible rare complication of maternal infection; microphthalmia, malformed pinnae, diaphragmatic hernia, costovertebral defects; ependymal damage, aqueduct forking, hydrocephalus, heterotopias; agenesis of the corpus callosum, cerebellum, pontine and inferior olivary neurons, optic and olfactory nerves; immunohistochemical evidence of influenza virus antigens in brain

Unproven association

Iris dysplasiahypertelorism114

Mesodermal dysgenesis of the iris, telecanthus, hypertelorism, hypotonia, lax joints, sensorineural hearing loss, short stature; callosal agenesis unproven

AD (147590)

Ivemark: asplenia/ polysplenia-situs anomalies115

Polysplenia/asplenia, complex cardiac malformations are usually defects of situs, pulmonary or abdominal situs anomalies; CNS uncommon and include agenesis of the corpus callosum and Dandy-Walker cyst

Unknown AD/AR (208530) 12q13, 6q21–q23

Ives: microcephalymicromelia116

IUGR, perinatal death, fused elbows, forearm shortened with single long bone, two to four digits on hands

AR (251230)

Jonas: pontine hypoplasiacallosal agenesis117

Macrocephaly, frontal bossing, deep-set eyes, short palpebrae, Duane retraction anomaly, hydronephrosis, patent ductus arteriosus, agenesis of corpus callosum, hypoplastic pons; mild, focal, subcortical white matter changes; communicating hydrocephalus

AR

Joubert: cerebellar vermis aplasia plus118

Developmental delay, episodic alternating hyperpnoea and apnea, abnormal ocular movements, coloboma, hypo/aplasia of cerebellar vermis; groups have been separated on basis of retinal dystrophy and renal disease; callosal agenesis uncommon

AR (213300) NPHP1, 2q13 AHI1, 6q23.2-q23.3 9q34.3

Kallmann119

Hypogonadotropic hypogonadism, anosmia, some cases with additional somatic findings; KAL1 on Xp is anosmia; KAL2 (AD) on 8p is loss of function of FGFR1

XLSD (308700) KAL1, Xp22.3 AD (147950) FGFR1, 8p11.2-p11.1 AR (244200)

103

(continued)

587

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Kivlin: anterior chambershort stature120

Variable developmental delay, prominent forehead, round face, telecanthus, sclerocornea, short nose, long philtrum, cupid-bow mouth, variable segment limb shortness, variable hyperextensibility, congenital heart and renal abnormalities, hypospadias. Case report with callosal agenesis.

AR (261540)

Kozlowski-Ouvrier: callosal agenesis-osseous changes121

Mental retardation, wormian bones, thin ribs, abnormal clavicles, small iliae, metaphyseal irregularity, hypoplastic distal phalanges, delayed bone age

Unknown

Leigh122

Early onset encephalomyelopathy, gray matter involvement similar to Wernicke, elevated lactate, pyruvate, urine thiamine triphosphate inhibitor; absence of corpus callosum correlates with severe pyruvate decarboxylase deficiency; multiple nuclear and mitochondrial loci in oxidative phosphorylation pathway

AR (256000) 2q33, 5p15, 5q11.1, 9q34, 11q13, 19p13

Leprechaunism123

Flat nasal bridge, flared nostrils, thick lips, large and low-set ears, breast and genital hyperplasia, hirsutism, postnatal growth failure, lack of response to insulin

AR (246200) INSR, 19p13

L’Hermitte: oxycephaly retardation124

Macrocephaly, oxycephaly with open sutures, high palate, flat face, shallow orbits, porencephaly, absent inferior vermis

AR

Lin-Gettig: craniosynostosiscallosal agenesiscamptodactyly125

Severe mental retardation, metopic/sagittal craniosynostosis, small low-set ears, nasal and external ear stenosis, small palpebrae, epicanthus, small nose, genital hypoplasia, camptodactyly

Uncertain (218649)

Linear sebaceous nevus126

Papular/verrucous lesions with atrophic scars over craniofacial area, pigment changes, ipsilateral brain anomalies, hemimegalencephaly, pachygyria heterotopias, porencephalies, mental retardation, seizures

Unknown (163200)

Lissencephaly-cleft palatecerebellar hypoplasia127

IUGR, cleft palate, ventriculomegaly, long thumbs and halluces, absent digital distal creases, variable brain stem involvement, absent corpus callosum, absent cerebellum, thick and disorganized cortex, no cortical lamination, severe cerebellar hypoplasia

Uncertain

Lujan: marfanoid128

Tall stature, long narrow face, high palate, small jaws, double row of teeth, variable mental retardation, hyperextensible joints and pectus, atrial septal defect, macrocephaly

XLR (309520)

Lurie-Kletsky: callosal agenesis-diaphragmatic defect129

Fetal hydrops, microcephaly, scalp defect, short palpebrae, posterior diaphragmatic defect, agenesis of corpus callosum, ventriculomegaly

Unknown

Majewski: short ribpolydactyly130

Lethal short ribbed micromesomelic dwarfism, short tibiae, pre- and postaxial polydactyly, median cleft lip, genital anomalies, hypoplastic epiglottis and larynx, glomerular cysts, tortuous cerebral vessels, cerebellar vermis hypoplasia, posterior fossa arachnoid cysts, agenesis or hypoplasia of the corpus callosum, pachygyria, neuronal heterotopia

AR (263520)

Marshall-Smith131

Increased birth length and bone age, postnatal growth failure, dolichocephaly, prominent forehead and eyes, choanal atresia, epiglottis anomaly, occasional absence of corpus callosum, pachygyria, hypoplasia inferior vermis

Unknown

MASA69,132

Mental retardation, adducted thumbs, shuffling gait with aphasia or speech delay. May have agenesis of corpus callosum, hydrocephalus due to agenesis of aqueduct of Sylvius. Same gene as X-linked hydrocephalus, X-linked paraplegia type I

XLR (309250) L1CAM, Xq28

Meckel-Gruber133

Cystic dysplastic kidneys, postaxial polydactyly, hydrocephalus, occipital encephalocele, microphthalmia, genital anomalies

AR (249000) 11q13, 17q21-q23, 8q

Micro134

Severe mental retardation, microcephaly, prominent ears, beaked nose with a prominent root, microcornea, cataracts, optic nerve atrophy, retinal dystrophy, small pupils, posterior synechiae, hypertrichosis, agenesis of the corpus callosum, one of three patients stated to have lissencephaly

AR (600118) RAB3GAP, 2q21.3

Microgastria-upper limb reduction135

Microgastria, variable upper limb defects, asplenia/splenogonadal fusion; case reports in association with iris coloboma, orbital cyst, fused thalami, arhinencephaly, agenesis of corpus callosum, several internal anomalies, hypothalamic hamartoma; anophthalmia and porencephalic cyst

Unknown (156810)

Microphthalmia-linear skin defects136

Lethal in males; linear, erythematous skin defects; variable microphthalmia, anterior chamber defects, sclerocornea; short stature; congenital heart defects; CNS include hydrocephalus, colpocephaly, cavum septum pellucidum, variable corpus callosum defect

del Xp22.31 (309801) Xp22.31, male lethality due to loss of holocytochrome ctype synthase

Moerman137

Appearance similar to achondrogenesis, cleft palate, dysplastic kidneys, cardiac anomaly, tetramicromelia, spondylocostal dysostosis, Dandy-Walker cyst

Unknown (continued)

588

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Morning gloryanomalysphenoidal encephalocele138

Characteristic optic nerve, hypertelorism, microphthalmia, other eye anomalies, midline cleft, pituitary/hypothalamic dysfunction, hydrocephalus, absent corpus callosum, sphenoidal encephalocele

Unknown

Mowat-Wilson: Hirschsprung-microcephalyretardation139,140

Microcephaly, large nose, prominent ears, deep-set and large eyes, infero-nasal coloboma, short philtrum, developmental delay, CT evidence of defective neuronal migration; several cases with callosal agenesis

AD ZFHX1B, SMADIP1, 22q22

Muller: cerebral malformationhypertrichosis141

Hypertelorism, telecanthus, microphthalmos, small and low-set ears, hypertrichosis, camptodactyly, overlapping fingers, absent swallowing and suck; variable CNS in sibs including macrocephaly, absent corpus callosum, septum pellucidum cyst, cerebellar hypoplasia

AR (213820)

Muscle-eye-brain142

Early onset severe hypotonia, delayed development, frontal pachygyria, occiput less severe, agenesis of the corpus callosum, hypoplasia of the pons and cerebellar vermis, white matter abnormalities patchy or absent, mild hydrocephalus, nystagmus, anterior chamber defects, glaucoma, myopia, preretinal glial membrane, ERG abnormal after age 1 year, cataracts, myopathy with elevated CK levels; common in Finland

AR (253280) POMGnT1, 1p32-p34.1

Mutchinik143

Microcephaly, hydrocephalus, growth and developmental delay, high forehead, ptosis, downslanting palpebrae, prominent nose, high nasal bridge, protruding ears; 1 of 8 cases with ACC

AR

Nasopharyngeal teratoma144

Massive macrocephaly, broad and triangular flat face, hypertelorism, nasopharangeal hairy polyp through cleft palate, diaphragmatic hernia, Dandy-Walker cyst, cavum septum pellucidum and vergi

Unknown

Necrotizing myopathycataract-cardiomyopathy145

Microcephaly, profound developmental delay, axial hypotonia, extensor plantar reflexes, early onset diarrhea and vomiting, cataracts, cardiomyopathy, raised CK, excess muscle glycogen, necrotizing myopathy, absent corpus callosum, few and swollen cortical axons, no pyramidal tracts

AR (225740)

Neonatal progeroid-callosal agenesis146

IUGR, postnatal growth failure, progeroid appearance, wide fontanels, frontal bossing, prominent scalp veins, entropion, beaked nose, small mouth, lipodystrophy, camptodactyly, hypoplasia lower limb muscles

AR

Neu-Laxova147

IUGR, edema, ichthyosis genital hypoplasia, microcephaly, slanted forehead, flat nose, hypoplastic fingers, syndactyly, lissencephaly

AR (256520)

Neuroepithelial cysts-absent corpus callosum148

Interhemispheric cysts of glioependymal type, absent corpus callosum, neocortical microgyria, abnormal foramen magnum, nodular heterotopias, cerebellar hypoplasia

Unknown

Neurofibromatosis149

Cafe´-au-lait spots, neurofibromas, Lisch nodules, occasional plexiform neuromas, diverse complications of tumors

AD (162200) NF1, 17q11.2

Nezelof: arthrogryposis-renal and hepatic disease150

Joint contractures, muscle atrophy, proximal thumbs, obstructive jaundice, variable liver histology, renal tubular degeneration and/or nephrocalcinosis, reported with microcephaly, corpus callosum anomalies

AR (208085)

Nijmegen breakage151

Growth and variable intellectual impairment, sloping forehead, prominent mid-face and long nose, large and abnormal pinnae, upslanting palpebrae, cafe´-au-lait spots, immunodeficiency, chromosome breakage and rearrangements of 7/14

AR (251260) NBS1, 8q21

Non-ketotic hyperglycinaemia152

Acute metabolic disease presentation; abnormal mitochondrial glycine cleavage; hypotonia, lethargy, abnormal cry, jaundice, coma, elevated urine and plasma glycine; CNS include absent corpus callosum, pachygyria

AR (605899) GCSP, 9p22 GCST, 3p21.2-p21.1 GCSH, 16q24

Oberklaid-Danks: Opitz C-like153

IUGR, postnatal growth failure and death, prominent metopic suture, hirsute forehead with forehead/glabellar hemangioma, synophrys, exophthalmos, hypertelorism, cleft lip/ palate, multiple joint contractures, flexion deformity at wrist, camptodactyly, DandyWalker cyst (1 case), agenesis of the corpus callosum

AR

Oculo-auricular-frontalnasal154

IUGR, microtia, preauricular tags, bifid nose, epibulbar dermoids, cleft lip/palate, midface hypoplasia, renal anomalies

Unknown

Oculo-pituitary155

In one of three families with features similar to septo-optic dysplasia, the patient had ACC but cousin with hypopituitarism did not

Unknown

Ohdo156

Retardation, blepharophimosis, mild microphthalmia, ptosis, hypoplastic teeth, variety of congenital heart defects, cryptorchidism, one report of agenesis of the corpus callosum

AR (249620)

Opitz C-trigonocephaly157

Mental retardation, trigonocephaly, wide alveolar ridges, wide oral frenula, short neck, polydactyly, visceral anomalies. Brain defects include absent corpus callosum, cerebellar vermis agenesis, Dandy-Walker

AR (211750)

(continued)

589

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Oral-facial-digital type I

Midline cleft/notched upper lip, multiple oral frenulae, lobulated tongue with hamartomas, asymmetric brachysyndactyly, variety of other anomalies (including CNS)

XLD, male lethal (311200) CXORF5, Xp22.3-p22.2

Oral-facial-digital type II159

Short stature, hypertelorism, low nasal bridge, broad and bifid nasal tip, hypertrophied oral frenula, cleft and lobulate tongue, cleft palate; brachysyndactyly, preaxial and postaxial polydactyly of hands; preaxial foot polydactyly; usually normal intelligence; CNS includes porencephaly, hydrocephaly, callosal agenesis

AR (252100)

Oral-facial-digital-type Chung160

Hypertelorism, flat nasal bridge, lingual nodule, micrognathia, four-limb postaxial hexadactyly, oromotor dysfunction, Dandy-Walker cyst, hypothalamic hamartoma. Single case

Unknown

Orstavik: aplasia cutisretinal-brain161

Aplasia cutis on scalp and abdomen, broad bulbous nose, small chin, long philtrum, hypoplasia to absence of fingers with the nails attached to metacarpals, ventricular dilatation and cerebral atrophy, variable thalamic calcification; male had agenesis of the corpus callosum

AR

Osteodysplastic primordial dwarfism162

Type I and II and Taybi-Lindes are equivalent. Marked IUGR, prominent nose, micrognathia, sloped forehead, alopecia, dry skin, contractures, early death, variety of skeletal changes

AR (210710)

Osteosclerosis-brain anomalies163

Generalized osteosclerosis, wide metaphyses, wide sutures, large anterior fontanel, downslanting palpebrae, depressed nasal bridge, micrognathia, large posterior fossa cyst, cerebellar hypoplasia, agenesis of the corpus callosum, large interhemispheric cyst, hydrocephalus

AR

Pachygyria-agenesis corpus callosum-X-linked164

Microcephaly, lethal in males, severe developmental delay, early-onset seizures, agenesis of the corpus callosum, microphallus, neuronal migration defect; less severely retarded male did not have neuroimaging; band heterotopia a possibility

XLD (600102)

Pai: corpus callosum lipomafacial polyps165

Median cleft upper lip, facial cutaneous polyps, nasal polyps, normal intelligence; all cases male; associated with corpus callosum lipoma

Unknown

Pallister-Hall166

Low ears, broad nasal bridge, buccal frenula, cleft palate, nail dysplasia, postaxial polydactyly, syndactyly, renal anomalies, imperforate anus. CNS includes hypothalamic hamartoblastoma, arhinencephaly, hydrocephaly, absent corpus callosum, encephalocele, Dandy-Walker, polymicrogyria, heterotopia

AD (146510) GLI3, 7p13

Pallister W167

Mental retardation, seizures, mild spasticity, tremors, high forehead, hypertelorism, frontal cowlick, downslanting palpebrae, strabismus, flat and broad nasal bridge with blunt tip, submucous cleft palate, median cleft of upper lip, absent upper central incisors, cubitus valgus, subluxation of proximal radio-ulnar joints, camptodactyly, clinodactyly; females similar face but not retarded

XLR (311450)

PAX6-related eye-brain anomalies168

Microcephaly, anophthalmia, small nares, large pinnae, absent corpus callosum, focal polymicrogyria; compound heterozygote for PAX6 mutations; unilateral polymicrogyria and absent pineal in heterozygotes

AR (106210) 11p13

Perlman: overgrowth169

Macrosomia, low-set ears, deep-set eyes, small nose, full upper and everted lower lip, serrated alveolar margins, nephromegaly, renal hamartoma/dysplasia, Wilms, islet of Langerhan hyperplasia, hypoglycemia, cryptorchidisim

AR (267000)

Peters anomaly-callosal agenesis-brain calcification170

Peters anomaly, frontal bossing, hypertelorism/telecanthus, malar hypoplasia, bulbous nose, long philtrum, conotruncal heart defect, agenesis of the corpus callosum, intracerebral calcification

Unknown

Phylloid hypomelanosis171

Hypopigmentation distributed in round or oval lesions, large and asymmetrical patches like begonia leaves, and pear-shaped or oblong macules; in 5 of 6 cases there was mosaicism or a translocation of chromosome 13

Chromosome imbalance

Polyasplenia-caudal deficiency-absent corpus callosum172

Laterality associated defects, imperforate anus, renal anomalies, lumbosacral agenesis, lower limb anomalies; cases reported with meningocele, hydrocephalus; one case with absent corpus callosum and white matter, neuronal heterotopias, and abnormal cortical architecture

Uncertain

Proteus173

Marked and asymmetric overgrowth can lead to a range of complications; skin includes shagreen patches, linear verrucous epidermal nevi, intradermal nevi, lipomas, hemangiomas, patchy dermal hypoplasia, hyperplastic and pebbly plantar overgrowth; frequent ocular problems; CNS abnormalities uncommon, partial absent corpus callosum, lissencephaly, hydrocephalus

AD?(176920) Some PTEN, 1q11-q25, mutations claimed but cases questioned258

Proud: XLMR-seizurescallosal agenesis174

Microcephaly, severe mental retardation, seizures, spasticity, coarse face, nystagmus, joint contractures, tapering fingers, porencephaly, agenesis of the corpus callosum, conservative substitution in homeodomain

XLD (300004) ARX, Xp22.13

158

(continued)

590

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Pseudo-TORCH

Severe retardation and seizures, extensive and variable deep and superficial supratentorial and basal ganglia calcification, hepatosplenomegaly, petechial rash; similar to, and may be allelic with, Aicardi-Goutieres and Cree encephalitis; Bedouin family reported with callosal agenesis

AR (251290)

Pyruvate dehydrogenase complex deficiency176

IUGR, perinatal presentation of severe lactic acidosis, and/or poor feeding, hypotonia and lethargy, profound mental retardation, seizures, spasticity, microcephaly, narrow forehead, frontal bossing, wide nasal bridge, long philtrum, blindness; CNS can include cerebral atrophy, callosal agenesis, absent medullary pyramids, abnormal/ectopic inferior olives

XLR/AR (208800) PDH E1 subunit, Xp22.1 11p13

Rubinstein-Taybi177

Short stature, mental retardation, downslanting palpebrae, beaked nose with septum below alae, radially deviated broad thumbs, broad toes

AD (268600) CBD, 16p13

Sakoda-anophthalmiacortical dysgenesis178

Anophthalmia, cleft lip/palate, short stature, hemivertebrae, basal encephalocele, absent corpus callosum, cerebral dysgenesis. Single case.

Unknown

Say: cloverleaf skull-skeletal anomalies179

Short wide clavicles, winged scapulas, prominent costochondral junctions, polysyndactyly of hands and feet, abnormal ulna/radius

Unknown

Schinzel-Giedion: hypertrichosis-midface retraction180

Tall and prominent forehead, hirsute, severe temporal narrowness, full cheeks, groove under eyes, choanal atresia, fleshy earlobes, narrow and deep-set nails, variable post-axial polydactyly, hypospadias, hydronephrosis/hydroureter, congenital heart defects, radiographic anomalies, ventriculomegaly, intraventricular bands, subependymal pseudocysts, leukomalacia

AR (269150)

Seckel181

Severe IUGR, proportionate growth failure, severe mental retardation, receding forehead and chin, downslanting palpebrae, prominent curved nose, dislocated radial head

AR (210600) ATR, 3q22.1-q24, SCKL2, 18p11.31-q11.2

Shanske: Seckel-like182

IUGR; severe mental retardation, microcephaly, and short stature; receding forehead, downslanting palpebrae, large beaked nose, retrognathia, dislocated radial head. One family with three children with agenesis of the corpus callosum, cortical dysgenesis, dorsal cerebral cyst, pachygyria

AR (210600)

Shapira: hyperhydrosishypothermia183

Periodic hypothermia, hyperhydrosis. One report of sibs with recurrent apnea, hypertonia, disturbed respiratory rhythm, white matter spongiosis, Purkinje cell loss

Most sporadic; AR (217990)

Siber: microphthalmia184

Microphthalmia, corneal opacities, hypospadias, one sib had more extensive brain anomalies noted at autopsy

XLR (309800)

Skeletal dysplasia-cloverleaf skull185

Lethal chondrodysplasia with short limbs and hands, cloverleaf skull, narrow chest, lowset ears, large anterior fontanel, hypertelorism, microphthalmia, ventricular septal defect, ambiguous genitalia

AR

Slee: hydrocephalus-growth failure-digital186

Lethal, severe polyventricular hydrocephalus, patent aqueduct of Sylvius, cleft palate, overlapping of the fingers; CNS defects variable and include partial/complete callosal agenesis, hypoplastic mid- and hindbrain, cerebellar agenesis

Uncertain

Smith: Hypopituitarism187

Multiple pituitary hormone deficiency, may be accompanied by retardation (Same as oculo-pituitary?50)

Unknown

Smith-Lemli-Opitz188

IUGR; postnatal growth failure; narrow frontal area, microcephaly; anteverted nares; female external genitalia with 46,XY karyotype; cleft palate; anomalies of eye, heart, and lung, pachygyria

AR (268670) DHCR7, 11q12-q13

Sotos like-macular degeneration189

Macrocephaly, developmental delay, tall stature, prominent forehead, downslanting palpebrae, juvenile atrophic macular degeneration with cone dysfunction, abnormal cavity above the 3rd ventricle, very small lateral ventricles, callosal agenesis

Unknown

Sternal clefts-telangiectasiashemangiomas190

Capillary/cavernous hemangiomas of face and upper trunk, patches of atrophic skin, midline abdominal raphe from sternal cleft to umbilicus. Case reported with microcephaly, microphthalmia, ectopia cordis, diffuse hemangiomatosis, callosal agenesis.

Unknown (140850)

Stippled epiphyses-loose skin-lissencephaly type III191

Microcephaly; arthrogryposis; craniofacial edema with onset in utero; stippled cervical vertebrae, feet, and sacrum; short metacarpals and distal phalanges; agenesis of corpus callosum, agyria, hypoplastic brain stem, diffuse severe neuronal loss

AR

Stippled humeral epiphysesiris colobomata192

Developmental delay, brachycephaly, small nose and anteverted nares, low-set ears, midface hypoplasia, iris coloboma, stippled proximal humeral epiphyses, dysplastic distal phalanges, hepatic fibrosis, deep palmar creases, toenail hypoplasia, partial absence of the corpus callosum, small cerebellar vermis

AR (215105)

Stoll: cerebellar hypoplasiaspastic paraplegia193

Mental retardation, spastic paraplegia, hypoplasia of the cerebellar hemispheres, partial agenesis of cerebellar vermis, agenesis of the corpus callosum

AR (220200)

175

(continued)

591

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Tectocerebellar dysraphiaoccipital encephalocele194

VSD, small mandible, cleft palate; CNS anomalies include posterior encephalocele, absent corpus callosum, hydrocephaly, cerebellar vermis agenesis, heterotopias

Unknown

Temtamy: callosal agenesiscolobomas-retardation195

Macrodolichocephaly, low-set and simple ears, narrow face, hypertelorism, complete colobomas, beaked nose, micrognathia, dental anomalies, dilated aorta, mild brachydactyly of digits 2-5 of hands and feet

AR

Thakker-Donnai196

IUGR, Klippel-Feil, long and downslanting palpebrae, hypertelorism, short nose with blunt tip, small downturned mouth, vertebral anomalies, short esophagus, diaphragmatic hernia, congenital heart defect. One sib with hydrocephalus, the other with callosal agenesis.

AR (227255)

Thanatophoric dysplasia197

Short ribs, micromelia; usually lethal during neonatal period, few with longer survival; achondroplasia-like face, extra skin folds on limbs, ‘‘U’’- or ‘‘H’’-shaped flat vertebrae, ‘‘telephone receiver’’-shaped femora, metaphyseal flare of long bones, short and broad tubular bones

AD (187600) FGFR3, 4p16.3

Thrombocytopenia-Robin sequence198

Mental retardation, pre- and postnatal growth failure, Robin sequence, telecanthus, downslanting palpebrae, short and broad tipped nose, enamel hypoplasia, camptodactyly, cerebellar vermis hypoplasia

Unknown

Toriello-Carey199

Short palpebral fissures, telecanthus, Robin sequence, small nose, abnormal auricles, excess nuchal skin, larynx anomaly, hypospadias, brachydactyly, microcephaly, mental retardation

AR (217980)

Trigonocephalypolysyndactyly-callosal agenesis200

Trigonocephaly, four-limb preaxial polysyndactyly, partial agenesis of corpus callosum. Single case.

Unknown

Tuberous sclerosis201

Depigmented macules and hair patches, shagreen patches, fibroangiomas in butterfly distribution, periungual fibromas, phakomas of retina, heterotopias, multiple focal cerebral tubers with absent laminar and columnar organization, and abnormal cellular orientation

AD (191100) TSC1, hamartin, 9q34 TSC2, tuberin, 16p13.3, 12q14

Van Biervliet: thoracic dystrophy202

IUGR, multiple joint contractures, narrow thorax, small mouth and mandible, appear older than age, developmental delay

AR

Van Maldergem: blepharonaso-facial203

Moderate to severe mental retardation, small and malformed ears, telecanthus, epicanthus, broad and flat nose, wide mouth, camptodactyly, clinodactyly , mild skin syndactyly. Case with ataxia, hypotonia enlarged lateral ventricles, reduced white matter, absence of callosal rostrum.

Unknown

Velocardiofacial204

Long narrow face, retrognathia, prominent nose with hypoplastic tip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay; congenital heart, especially conotruncal defects; several reports with pachygyria and/or polygyria

AD (192430) del 22q11 del 10p

Vici: Immunodeficiencycataracts 205

Hair and skin hypopigmentation, combined immunodeficiency, cleft lip/palate, hypertelorism, hypospadias, cerebellar hypoplasia; may be type I Griscelli syndrome due to MYOVA gene256

AR (242840)

Vles: callosal agenesis-spastic quadriplegia206

Severe mental retardation, spasticity, irregular outline to the lateral ventricles

Uncertain

Walker-Warburg207

Cobblestone lissencephaly, retinal dysplasia, microphthalmia, other eye anomalies, Dandy-Walker cyst, progressive hydrocephalus, myopathy, postnatal growth failure, early death

AR (236670) POMT1, 9q34.1

Warfarin, prenatal208

Significant developmental delay, small and grooved nose with depressed bridge, stippled epiphyses, mild nasal hypoplasia, short fingers, other CNS includes microcephaly, Dandy-Walker cyst, cerebral atrophy

In utero exposure ARSE inhibition

Wells: Apert plus209

Facial features of Apert syndrome with microcornea and coloboma, 2-4 finger syndactyly, mild 4-5 toe syndactyly, non-fused posterior ribs, hemivertebrae, platyspondyly, partial callosal agenesis

Unknown

Winter: osteodysplastic primordial dwarfism210

IUGR, sloped forehead, prominent occiput, alopecia, low-rotated abnormal ears, large-beaked nose, disproportionate short limbs, redundant skin, joint dislocations and limited extension, platyspondyly, delayed ossification of vertebrae, short long bones, broad metaphyses, hypoplastic vermis, absent corpus callosum, few gyri, loss of cortical layers

Unknown

Winter-Wigglesworth211

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, poorly formed hemispheres, microscopic renal changes

Unknown

(continued)

592

Brain

593

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

X-linked corpus callosum dysgenesis212

Microcephaly, wide anterior fontanel, frontal bossing, telecanthus, broad nasal root, downturned mouth, short broad hands, brachydactyly; absent corpus callosum, interhemispheric cyst, cortical gyral dysplasia

XLR (304100)

X-linked lissencephalyabnormal genitalia (XLAG)40,213

Cortex 5–10 mm, posterior ! anterior gradient, no cell sparse zones in agyric areas, deficient small cortical granular cells, immature white matter, poorly demarcated basal ganglia that may have small cysts, agenesis corpus callosum (includes 50% of females), neonatal onset of seizures, hypothalamic dysfunction, ambiguous male genitalia

XLR (300382, 300215) ARX, Xp22.13

Young: macrocephaly214

Relative macrocephaly, prominent forehead, deep-set eyes, developmental delay and hypotonia, cerebellar hypoplasia

AR

Zellweger215

Hypotonia, postnatal growth failure, large fontanels, high forehead, flat face, excess nuchal skin, hepatic and renal dysgenesis, contractures, hypomyelination, pachygyria (especially inferior olive), polymicrogyria, heterotopias merge with layers V and VI and affect mostly late migrating cells, germinolytic cysts

AR (214100) Peroxin1, 7q21-q22 Peroxin2, 8q21.1 Peroxin3, 6q23-q24 Peroxin5, 12p13.3 Peroxin6, 6p Others, 1p22-p21,1q22, 2p15

Zimmer: tetra-amelia216

Polyhydramnios, amelia, severe facial clefting, no nose, ocular anomalies, hydrocephalus, absent ophthalmic and possibly olfactory nerves

XLR (301090)

Zollino: hypogenitalismmicropolygyria217

Severe hypotonia, metopic ridge, upslanting palpebrae, megalocornea, epicanthus, smooth philtrum, macrostomia, club feet, agenesis of the corpus callosum, micropolygyria; female less severely affected than three males

Unbalanced translocation

disturbances that remain undetected with current neuroimaging techniques. There has been a growing interest in the status of the corpus callosum in several less traditional areas. Although hypoplasia of the corpus callosum (HCC) is not the subject of this section, it is of interest that alterations in the shape, angles, and/or thickness of the corpus callosum were seen in 30 of 61 patients with a broad range of genetic syndromes,8 and that similar findings have been noted in a series of 31 treatment naı¨ve schizophrenics.9 Among another series of 140 schizophrenics, two were found to have partial ACC.10 EEGs of patients with ACC may be normal or may show a dysrhythmia, including asynchronous alpha activity.6 This activity reflects the underlying neurologic disturbances and is nonspecific. Central conduction delay on brain stem audiology evoked response and prolonged visual responses may be common in ACC.5 Before the advent of the pneumoencephalogram (PEG), none of the 83 reported cases of ACC had been diagnosed in a living patient The PEG allowed in vivo diagnosis but was an invasive procedure with attendant morbidity and was thus reserved for patients with significant clinical signs. Modern neuroimaging, both prenatally and postnatally, has allowed more liberal investigation, has led to earlier and more frequent diagnosis, and has changed the clinical profile of reported patients. The diagnosis of ACC is based both on the direct demonstration of the absence of this midline structure and on recognition of the characteristic distortion of cerebral architecture. It can be demonstrated by appropriate use of any of the standard neuroimaging procedures (Fig. 15-37). The specific findings are essentially the same regardless of the procedure, although MRI has advantages in distinguishing partial agenesis (Fig. 15-38)11 and in elucidating the presence and characteristics of any associated CNS anomalies.12 In the coronal view, there is a wide separation of the frontal horns and bodies of the lateral ventricles, both of which have sharp angled lateral peaks, giving a ‘‘double horn’’

appearance (Fig. 15-39). A useful sign in distinguishing type 1, primary, from other types of ACC is that, in the former, the callosal fibers persist as an anterior bundle of fibers (of Probst) that causes a concave medial border of the lateral ventricles. In the axial view the lateral ventricles tend to be parallel and more widely separated (Fig. 15-40). In the absence of hydrocephalus, the frontal horns tend to be narrow, whereas the decreased white matter in the occipital region, and the fact that the occipital axons do not form Probst bundles, result in enlarged occipital horns (colpocephaly) and an overall bull’s horns or teardrop appearance (Fig. 15-41).13 Normally, the corpus callosum forms the roof of the 3rd ventricle and, in its absence, the 3rd ventricle tends to ride high between the lateral ventricles. In the axial plane, the dilated and high 3rd ventricle and the combination of the frontal and posterior horns have been likened to a leaping frog.13 Sagittal views can document absence of the corpus callosum and its extent. The cingulate sulcus, which appears to be induced by the corpus callosum, is also absent, and the cingulate gyrus is inverted and has a radial pattern about the roof of the 3rd ventricle (Fig. 15-42). Doppler studies may show abnormal branching of the anterior cerebral artery14 and non-visualization of the pericallosal artery.15 The anterior commissure runs rostral and the hippocampal commissure (HC) infero-caudal to the corpus callosum, and either or both may be present or absent in ACC. When present in ACC, the HC can be mistaken for callosal fibers.14 When the HC is absent, the hippocampus and fornix are hypoplastic and the inferolateral horns of the temporal horns are dilated.14 The timing of prenatal diagnosis of ACC is closely related to its embryogenesis, which is not completed until 20 weeks gestation. Achison and Achison16 carried out a cross sectional ultrasound study of callosal growth in 270 pregnancies, between 16 to 37 weeks gestation, using transabdominal and transcervical ultrasound, as dictated by fetal position. They were able to measure the length, width, and thickness in 258 cases and showed a linear

594

Neuromuscular Systems

Fig. 15-40. Axial CT scan at the level of the lateral ventricles showing parallel ventricles with somewhat convex medial borders. (Courtesy of Department of Radiology, Children’s Hospital of Eastern Ontario.)

Callosal lipomas are associated with at least partial ACC about half the time, but their presence may obscure the ultrasound confirmation of ACC. Bennett et al.18 reviewed the results of routine 16 to 22 week obstetric ultrasound scans that had been performed in 15 fetuses diagnosed with ACC in the 3rd trimester. Ten of the earlier scans were completely normal; two fetuses had extracranial anomalies; and three had CNS malformations, only two of which were suggestive of ACC. Fig. 15-39. Coronal section at the level of the thalamus showing absent corpus callosum (arrows). (Courtesy of Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

relationship of growth to gestational age with maximal growth at 19 to 21 weeks. The corpus callosum was identified as a hypoechogenic structure demarcated by two echogenic lines; on the mid-sagittal view, bound above by the callosal sulcus and the cingulate gyrus and below by the cavae; on the coronal view, the superior border is the echogenic interhemispheric midline, the lateral the frontal horns, and again the cavae below. Growth of the length and width is comparable in males and females, but the corpus callosum is significantly larger in females throughout gestation,17 an interesting observation in light of a consistent excess of male predominance in ACC. The prenatal ultrasound signs that confirm ACC are the same as those observed in the postnatal period, but the required imaging views may be obscured by fetal position, and there is a consensus that the diagnosis is unreliable before 20 weeks gestation. Clues that lead to a suspicion of ACC include ventriculomegaly, a high position of the 3rd ventricle, and failure to visualize the cavum septum pellucidum.14,18 It is notable that mild ventriculomegaly is more typical of ACC than is severe ventriculomegaly.18 ACC occurs in up to 10% of mild19and 3% of overall prenatal ventriculomegaly.20

Fig. 15-41. Axial CT scan at the level of the anterior ventricles showing their separation by an enlarged and rising third ventricle. (Courtesy of Department of Radiology, Children’s Hospital of Eastern Ontario.)

Brain

595

Fig. 15-42. Brain cut sagittally in the midline showing absence of the corpus callosum (arrows) and radial arrangement of the cingulate gyrus. (Courtesy of Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

Good sagittal views, which are necessary to best directly assess the midline structures, may be difficult to obtain, especially if the fetus is in a cephalic position. Vesentin et al.21 were successful in 89% of 126 pregnancies at 19 to 24 week gestation by using the frontal suture, as opposed to the anterior fontanel, to obtain midline views, and transvaginal sonography can be used to advantage, facilitated by having the patient in the lithotomy position with cephalic presentations.22 Wang et al.23 were able to obtain an adequate sagittal view, between 18 and 32 weeks gestation, in only 3.1% of fetuses in the cephalic position when they used standard 2D-ultrasound. However, they were successful in 25/32 (78%) of cases when they applied 3D-sonography with multiplanar reformatting. Although prenatal MRI is not routinely applied, there is growing evidence that the newer equipment, with scan times of 1 second or less, can effectively confirm or rule out ACC, determine its extent, and often confirm the presence of additional CNS anomalies.24,25 Optimal neuroimaging should allow distinction between primary and secondary ACC, as well as their subtypes. ACC is a common component of a number of multiple malformation syndromes and is an occasional finding in a number of others that are summarized in Table 15-7. The rate of chromosomal and non-chromosomal syndromic causes of ACC is highly dependent on ascertainment and what authors include as a syndrome diagnosis. For example, one series included cerebral palsy, dyslexia, and Asperger as syndrome diagnoses. Overall in the series reviewed, it appeared that up to 15% of ACC is associated with a chromosome imbalance, and that about 12% of patients have had a specific syndrome diagnosis. Some series have claimed a known etiology in almost half of cases, but this is not the general experience to date. Single case reports of ACC in common syndromes or diseases such as G6PD deficiency, sickle cell anemia, cystic fibrosis, Noonan syndrome, and arthrogryposis may be coincidental.

malformation, are generally confined to symptomatic individuals. A significant proportion of isolated, and indeed complex, cases will be missed on routine prenatal ultrasound, thus eliminating this possible source of an estimate of prevalence. Reports from routine autopsy series are probably the closest estimates of true prevalence, but rates observed in selected populations are of interest, and a representative sample of these rates is summarized in Table 15-8. Table 15-8. Prevalence of ACC with different methods of ascertainment Rate per 10,000 Source of Ascertainment

0.5

Reference

Routine autopsy series

218

Unselected hospitalized population

219

36

Stillbirths and neonatal autopsies

220

36

Referral to pediatric neurology service

221

70

10–30

Large series of pneumoencephalograms

222

101

Consecutive MRI series in neurologically abnormal children

223

157

Consecutive MRI series in patients under 17 years

224

230

Series of mentally retarded children

225

300

Cases of prenatally detected ventriculomegaly

300–500

1000

Cases among all CNS anomalies detected by prenatal ultrasound Cases of prenatally detected mild ventriculomegaly

20 226

19

Other Small Series of Specific Conditions

Distribution and Etiology

Determination of the true prevalence of ACC is confounded by the fact that isolated cases may be essentially asymptomatic, and neuroimaging studies, which are required to document the

43

Patients with choanal atresia (23)

142

New cases of schizophrenia (140)

731

Patients with hypoplastic left heart (41)

227 10 228

596

Neuromuscular Systems

Almost all series report an excess of males with ACC, and the male-to-female ratio in the papers reviewed for this section was 1.84:1. As mentioned, the male corpus callosum lags behind that of the female in thickness throughout gestation, and Barkovich et al.2 have suggested that the skewed sex ratio may be specific to certain subtypes of ACC. Interestingly, the BALB/cCF mouse model shows a female excess.229 At 6 to 8 weeks gestation, the dorsal rostral portion of the telencephalon, the lamina terminalis, thickens and becomes densely cellular and is called the lamina reuniens of His (LR). A median groove, the sulcus medianus telencephali medii, is formed when the lamina reuniens folds along its dorsal part during week 8. During week 9, proliferation of the LR cells causes the groove to deepen and brings the edges closer, so that they become separated by a single layer of early meninges.230 By week 10, the sulcus is obliterated by fusion, thus forming the massa commissuralis. The latter grows in a dorsal direction over the ensuing 5 to 7 weeks and is the path through which the commissural fibers pass to form the corpus callosum.231 Contrary to some earlier views, this is not a passive pathway that acts simply as a conduit for axonal migration. The neocortical neurons that will ultimately form the corpus callosum derive mainly from cortical layers 2, 3, and 5. En route they must make several directional changes. First they travel ventrally to the intermediate zone, then medially toward the midline and the cingulate gyrus, again vertically to the corticoseptal boundary, medially across the midline, and finally reversing the process in the contralateral hemisphere.102,232 There are several active processes that must occur in and around the midline to allow and guide the passage of the callosal axons. Apoptosis of a midline glial barrier is required, and in a mouse model where this fails to occur, ACC results.3 A glial sling (GS) is formed in the midline across the massa commissuralis of cells derived from the medial wall of the lateral ventricles. An absence or interruption of the GS results in ACC, and the malformation can be rescued by insertion of a glial-coated membrane. The glial cells of the GS do not show the characteristics of mature glial cells.232 In the BALB/c mouse, the development of the GS and subsequently the corpus callosum is interfered with by the development of a midline, fluid-filled gap. A dorsal midline bulge accompanies this gap where corpus collosal axons have approached the midline. Ventrally there is a narrow midline groove that resembles the human sulcus medianus telencephali medii. The abnormal gap is seen in almost all of the BALB/c mice, but its size and impact are variable, thus accounting for the variable spectrum of callosal defects observed. The development of the midline gap is itself a normal developmental step in the formation of the septal cavity, but it appears after formation of the GS and crossing of the callosal axons. Between the lateral margins of the GS and the medial ventricular walls there develops a glial wedge of cells, ventral to the eventual corpus callosum. Dorsal to the future corpus callosum, glial cells form the indusium grissium, which is a thin structure that derives from the cingulate gyrus and runs the length of the corpus callosum.232 Excising or altering the orientation of the glial wedge or indusium grissium will result in ACC. The midline glial cells produce a number of evolutionarily conserved molecules whose expression affects axonal pathfinding across the midline. In Drosophila, the glial cells were shown to secrete Slit, and axons expressing its receptor (Robo) are guided across the midline, whereas those not expressing Robo turn away and form the perforating pathway.233,234 The growing tip of the axon (growth cone) requires a number of intermediate targets along its course, to which it is either attracted or repelled. The major fascicles of axons are proceeded by a vanguard of pioneering axons that appear to show the way for those

following. Evidence using carbocyanine dyes in mice have shown that during initial migration the pioneering axons are only about 200 microns in advance of the main axonal bundles but that this distance increases to 0.5–2.5 mm as the midline is crossed.235 Ablation of the pioneering axons will also result in ACC. Recently it has been shown that neurons from the cingulate gyrus are the first to cross the midline, and that they provide guidance to the neocortical callosal axons. There is also some evidence that some cingulate axons travel laterally and may provide guidance to the cortical axons as they travel to the midline.232 The caudal callosal axons may use the axons of the hippocampal commissure for guidance across the midline.102 The first fibers to cross the midline are the anterior and hippocampal commissures, which link older parts of the brain. The former can be recognized growing medially as early as 6 weeks and to cross by 54 days gestation.3 The corpus callosum forms in a rostral to caudal sequence, with the earliest fibers or the rostrum crossing at 74 days, followed by the genu and body, with the splenium and adult morphology present by 115 days.3 Richards et al.102 argue that the most caudal, hippocampal dependent, callosal axons may cross at or near the same time as the most rostral components. As the cerebral hemispheres grow in a caudal direction, there is parallel anteroposterior elongation of the corpus callosum, forming the body and splenium. From this point further development of the corpus callosum consists of enlargement, and it reflects the rapidly expanding cerebral hemispheres.231 Disturbances beyond 18–20 weeks would be expected to show hypoplasia or secondary destruction. The latter is distinguishable by absence of the bundle of Probst and is suspected in cases where an anterior or middle component of the corpus callosum is absent in the presence of normal posterior components. Relatively little is known about the pathogenesis of type 1, primary ACC, in humans. Early theories have included vascular and infectious disruption as causes, but Barkovich and Norman236 have questioned the assumption that ACC reflects an insult occurring at the time the corpus callosum is developing. After studying the known embryologic timing of specific cerebral malformations found in association with ACC, they proposed that damage to the sulcus medianus telencephali medii prior to formation of the corpus callosum was more compatible with the timing of the associated malformations. Disruption later in gestation may still account for cases of ACC that do not fit the embryologic timetable, as well as for callosal hypoplasia. Other suggested etiologies have included failure of closure of the anterior neuropore causing absence of the lamina terminalis, and dilatation of the roof of the 3rd ventricle, secondary to hydrocephalus, causing interference with the midline.4 ACC is etiologically heterogeneous. Infectious agents, prenatal alcohol exposure, and maternal diabetes have been implicated in case reports, while a variety of vitamin deficiencies and irradiation have been used to produce ACC in animals.237 Anomalies in the corpus callosum, including absence, have been well documented in fetal alcohol syndrome.36 ACC can occur in association with a number of unrelated inborn errors of metabolism. Dobyns238 reported ACC in 6 of 15 patients with nonketotic hyperglycinemia. Abnormal gyral patterns and cerebellar hypoplasia were also noted. ACC has also been present in cases of unspecified lactic acidosis, pyruvate carboxylase and dehydrogenase deficiencies, Zellweger syndrome, histidinemia, Hurler syndrome, mucolipidoses III and IV, and Lowe syndrome (Table 15-7).6,122 Metabolic causes may account for up to 4% of cases.4 A recent review102 listed 34 mouse genes associated with absent and/or reduced size of the corpus callosum. The nature of

Brain

their activities encompassed guidance molecules, transcription factors, extracellular matrix molecules, intracellular signaling/cytoplasmic molecules, and growth factors. The broad spectrum of syndromes and the Mendelian inheritance of isolated ACC reported in humans suggest that many human genes may have an impact on development of the corpus callosum. However, not all the syndromes in Table 15-7 are known to cause type 1, primary ACC, and in relatively few is ACC a high frequency manifestation of the syndrome. Two important human ACC associated genes have thus far been isolated. Neuronal cell adhesion molecule L1 (L1CAM) is a transmembrane glycoprotein belonging to the I-set of the immunoglobulin super family (IgSF). The first mutations in L1CAM were found in patients with X-linked hydrocephalus due to stenosis of the aqueduct of Sylvius (HSAS), and it has since been associated with a number of X-linked conditions that may express ACC, under the acronym CRASH,69 a term not favored for clinical use (Table 157).69 L1CAM has six immunoglobulin-like and five fibronectin type III–like extracellular domains, a single transmembrane segment, and a short cytoplasmic C-terminus. It is expressed in outgrowing axons and growth cones of post-mitotic cells in the central and peripheral nervous system and plays a role in neuronal-neuronal and neuronalSchwann cell adhesion, myelination, axonal outgrowth and pathfinding, growth cone morphology, and neuronal migration.69 Given its wide range of influences, it is not surprising that L1CAM has many extracellular and intracellular interactions. These include homophilic interaction with other cells, heterophilic involvement with other IgSF proteins, with neurocan and phosphacan, with a number of cis-acting factors such as NCAM, and with a variety of signal transduction pathways.69 Known mutations are spread widely across the gene, and for the most part, the mechanism whereby ACC occurs is not known. The C-terminus of L1CAM is anchored via interaction with ankrin to the actin cytoskeleton, and mutations in mouse ankrinB lead to callosal hypoplasia.232 Missense mutations in the C-terminus of three patients with ACC have been shown to cause diminished L1CAM-ankrin interaction.239 The second important ACC gene to be isolated was SLC12A6 in patients with Andermann syndrome (Table 15-7).240 This autosomal recessive gene shows a founder effect in the Charlevoix and Saguenay-Lac-St-Jean region of Quebec, where the gene has an estimated prevalence of 1 in 23. The primary characteristic of the syndrome is that of an early onset of progressive neuropathy and, contrary to the impression sometimes given in the literature, ACC is not an obligatory feature of the syndrome. In a survey of 64 Quebec patients, 37 (57.8%) had complete ACC, 6 (9.4%) had partial ACC, and in 21 (32.8%) the corpus callosum was intact.241 Indeed, the homozygous mouse knockout model has a neuropathy and behavioral changes but not ACC, thus suggesting a role for other genes and/or environmental factors in modifying the impact of mutations in SLC12A6 on callosal development. SLC12A6 is involved in the KCC3 mediated transport of Kþ and CL. It is as yet unclear how perturbations in ion transport affect axonal migration and result in the type 1, primary ACC, seen in Andermann syndrome. Prognosis, Treatment, and Prevention

The prognosis for patients with ACC is entirely dependent on the presence or absence of accompanying cerebral dysfunction and associated malformations. One might expect that ACC would lead to some failure of normal lateralization of brain function and impairment in tasks that are thought to rely heavily on crossed pathways. However, Ettlinger et al.242 carried out a broad

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battery of tests in patients who had ACC and normal intelligence and concluded that ‘‘the most conspicuous feature of our present results is the lack of impairment found amongst the acallosal patients.’’ In a study specifically directed at language, Jeeves and Temple243 concluded that ‘‘retrieving words in response to rhymes was the only language deficit clearly exhibited by all three acallosals discussed in this paper.’’ As testing becomes more sophisticated and specific, subtle differences in the performance of patients with isolated ACC do become apparent. Evidence from mice suggests the differences may be highly task dependent. Acallosal 129 x BALB/c mice show no deficits in behavior or motor performance on a notched balance, but do have impaired running speed on wheels with differing inter-rung distances.244 Human studies in both acallosal and callosectomy patients have detected deficits in explicit learning of repetitively presented visual sequences that require bimanual, but not those requiring unimanual, keyboard responses245; decreased speed and accuracy of bilateral visual matching246; and ability to localize a moving, binaurally presented sound.247 There is also evidence that acallosal and callosectomy patients may develop compensatory neurologic paths, and that in some cases this is limited to those with ACC. Normal subjects show little difference in reaction time (RT) to crossed and uncrossed visual response tasks (CUD), and little difference when the stimuli are presented unilaterally versus bilaterally. Patients with ACC show significantly larger CUD and improvement with bilateral stimuli, suggesting subcortical neuronal summation.248 This summation is only apparent when the bilateral signals are positive (go/go) and are not seen when one signal is positive (go) and the other negative (no-go) for the set task.249 Acallosal patients may perform better than controls in localizing unilateral auditory stimuli, suggesting a compensation toward the use of unilateral cues.247 The response times of patients with ACC to color and shape discrimination tasks presented in one or other visual field and requiring crossed and uncrossed manual responses were the same as in controls, whereas a callosectomy patient showed increasing errors as the task complexity increased.250 Brown et al.251 studied four patients with ACC, two with partial ACC, and one with a callosectomy. None of the patients showed ipsilateral hemisphere visual evoked responses, thus demonstrating that the posterior corpus callosum is necessary for this interhemispheric transfer. However, acallosal patients, but not the callosectomy patient, were as capable as the controls in comparing bilaterally presented letters, suggesting transfer via the anterior commissure. On the other hand, the patients with complete ACC were unable to perform the matching when presented with complex visual patterns, and those with partial ACC were able to do so. Given that isolated ACC is essentially a benign, asymptomatic malformation, there will be a bias toward ascertainment of patients who have neurologic dysfunction due to an associated malformation. As discussed previously, the presenting signs vary with the age at diagnosis, and one would expect some correlation between the age at which a patient becomes symptomatic and the clinical prognosis. Lacey5 reported that all but 2 of 32 children diagnosed in infancy and who were older than 12 months at follow-up had developmental quotients less than 80. In contrast, of eight children diagnosed at age 4 years or older, three had IQs in the 80s and four others were considered normal. Thus, in contrast to those who develop signs later in life and to those with isolated ACC, neonates and infants who have neurologic signs have a poor prognosis. However, the prognosis is related to the signs and symptoms secondary to the associated malformations and not to the age of the subject per se.4,221

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Earlier studies were based on autopsy diagnoses or the use of relatively invasive diagnostic procedures; the diagnosis was heavily biased toward patients with severe seizure disorders or mental retardation. More recent studies present a more optimistic perspective for patients with ACC. Of 56 patients ascertained through the British Neurological Survey Unit, 3 of 19 pediatric patients were delayed and four had hemiplegia; of the 31 adults, 19 were considered to have some intellectual delay, of which two-thirds were mild.252 Thirty-two of the 56 patients had seizures: 20 generalized, 12 focal, and 4 focal leading to generalized seizures. About one-third of the patients had neuropsychiatric symptoms, but ascertainment was through neuropsychiatric clinics. Shevell221 ascertained 24 cases among 6911 consecutive patients in a neurology clinic. These cases were ascertained prenatally (9), neonatally (6), and later (9), and had high rates of associated complications including microcephaly (8), dysmorphia (12), and seizures (11). Overall, 83% had some developmental delay, and in 71% the delay was moderate to severe. Again, there is the bias of ascertainment through a neurology clinic, and it seems that a prenatally ascertained group, carefully subdivided by the subtype of ACC and carefully followed for associated anomalies and long-term development, will give the best overview of prognosis. In jurisdictions that permit termination of pregnancy beyond 20 weeks gestation, the prediction of neurologic outcome can be the determining factor in the decision whether or not to continue a pregnancy. When termination of the pregnancy is not an option, accurate information concerning prognosis can help parents to prepare for the birth of their child. Current evidence suggests that the timing of the diagnosis of ACC, that is, whether it occurs prenatally, neonatally, or later, is not a determinant of prognosis.4,221 Prognosis is largely dependent on the presence or absence of associated CNS malformation and syndromes. The major difference between prenatal and postnatal diagnosis is the reduced ability to detect the presence of associated anomalies and the inability to carry out functional studies on the fetus. Gupta and Lilford253 reviewed 70 cases of prenatally ascertained ACC reported in the literature prior to 1995. In group 1 were 34 patients considered prenatally to have isolated ACC and followed up after birth. Three cases were found to have additional anomalies postnatally: one with trisomy 8 mosaicism, one who died, and one in whom follow-up was lacking. Of the 31 cases confirmed as isolated, in four the pregnancy was terminated, leaving 27 livebirths, of whom 23 were developmentally normal, two were mildly delayed, and one was severely delayed. The severely delayed patient had fetal alcohol syndrome, and in one patient there was no follow-up. The length of follow-up was from birth to 11 years with a mean of 29 months. In group 2 were patients noted on prenatal ultrasound to have additional anomalies. In 16 of 36 cases the pregnancy was interrupted, and in four there was in utero death. Of the 16 patients who survived, there was no information on five, two were normal, and nine had mental and/or motor delay. There have been a number of follow-up studies on prenatally ascertained cases of ACC. Vergani et al.13 reported a normal outcome in five of seven isolated cases after 6 months to 8 years follow-up, with the two delayed patients having Aicardi syndrome (Table 15-7). Their seven complex cases included lissencephaly (3), trisomy 13, Arnold-Chiari malformation, porencephaly, and pleural effusion in a fetus with a family history of Andermann syndrome (Table 15-7). Of 15 cases reported by Bennett et al.,18 there were three in utero deaths, all with complex associated findings. Six children showed normal development, five had isolated ACC, and one had polydactyly. The two patients with definite

mental retardation had associated anomalies that were detected prenatally (partial trisomy 3, abnormal thalami and Dandy-Walker cyst). In four cases the developmental outcome was not clearly reported. Although an elevated position of the third ventricle and a widened interhemispheric fissure have been estimated to have respective relative risks for a poor outcome of 2.2 (CI 1.4-3) and 2.5 (CI 1.6-3.4),253 the former was seen in all six cases with a normal outcome in this series and is a poor discriminator. The most complete outcome study to date is that of Moutard et al.,254 who have attempted to follow 21 prenatally ascertained patients with apparently isolated ACC. All patients had normal karyotypes and viral studies, and a postnatal examination at 9 to 14 months to rule out any associated anomalies. One patient was lost to follow-up; three (with normal development at 3, 6, and 8 years) were excluded, as the research group did not follow them. Full scale IQ (FSIQ) in those followed to 2 years was 80–89 (3) and 90–109 (13); in those followed to 4 years it was < 80 (1), 80–89 (2), 90–109 (5), and >110 (1); and in those followed to 6 years it was < 80 (1), 80–89 (2), 90–109 (3), and >110 (1). Handedness was the same as in the general population; all but one child had normal manual dexterity; males had equivalent outcomes to females; and the FSIQ at 2 years was not predictive of that at 4 and 6 years. The authors noted that maternal sociocultural factors were a risk factor for lower IQ, that many of the IQs were below 100, and that subtle differences in speech development became apparent with age. Although some have claimed a better prognosis in partial than in complete ACC,4 it was not apparent in this study. Treatment of ACC is essentially that of careful evaluation for associated CNS and other malformations and control of associated signs and symptoms such as hydrocephalus and seizures. Seizure control is not different from that in patients without ACC. Given the importance of associated CNS anomalies in determining the prognosis of ACC, careful consideration should be given to the use of fetal MRI when ACC is suspected on prenatal ultrasound, especially where a decision may be pending about the continuation of the pregnancy. A fetal karyotype should also be considered, especially as not all chromosome abnormalities associated with ACC have a high likelihood of additional malformations that would be noted on ultrasound. A very few cases of ACC may be due to preventable teratogen exposures such as rubella or alcohol. Otherwise, prevention is based on making specific syndrome diagnoses and thus providing appropriate genetic counseling and specific prenatal diagnosis. Although the typical ultrasound signs of ACC are not generally noted until after 20 weeks gestation, the diagnosis is possible between 18 and 20 weeks gestation on a sagittal view. Techniques to obtain these views should be applied in high-risk histories and when other clues, such as ventriculomegaly, are noted. Furthermore, many of the associated CNS malformations that are associated with a poor prognosis may be detected on routine sonography. Indeed, a normal mid-trimester ultrasound is a favorable prognostic indicator in the face of later diagnosed ACC.18 The false-positive diagnosis of ACC has generally been confined to reports prior to 1990, but care must be taken not to misdiagnose fetuses with ACC as having hydrocephalus. Advice on prenatally ascertained cases of ACC should be based on the completeness and sophistication of the imaging studies at hand and the current literature of similar cases. One must be mindful that some of the syndromes most strongly associated with ACC (e.g., Aicardi and Andermann) are not expected to provide specific prenatal clues as to their presence, and that non-CNS malformations can have a significant impact on prognosis.255

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References (Agenesis of the Corpus Callosum) 1. Dobyns WB: Absence makes the search grow longer. Am J Hum Genet 58:7, 1996. 2. Barkovich AJ, Simon EM, Walsh CA: Callosal agenesis with cyst. A better understanding and a new classification. Neurology 56:220, 2001. 3. Da´villa-Gutie´rrez G: Agenesis and dysgenesis of the corpus callosum. Sem Pediatr Neurol 9:292, 2002. 4. Goodyear PWA, Bannister CM, Russel S, et al.: Outcome in prenatally diagnosed fetal agenesis of the corpus callosum. Fetal Diagn Ther 16:139, 2001. 5. Lacey DJ: Agenesis of the corpus callosum: clinical features in 40 children. Am J Dis Child 139:953, 1985. 6. Jeret JS, Serur D, Wisniewski KE, et al: Clinicopathological findings associated with agenesis of the corpus callosum. Brain Dev 9:255, 1987. 7. Franco I, Kogan S, Fisher J, et al.: Genitourinary malformations associated with agenesis of the corpus callosum. J Urol 149:1119, 1993. 8. Gabrielli O, Bruni S, Coppa GV, et al.: White-matter alterations and callosal abnormalities in syndromic patients with mental retardation. J Child Neurol 17:164, 2002. 9. Keshavan MS, Diwadkar VA, Harenski K, et al.: Abnormalities of the corpus callosum in first episode, treatment naı¨ve schizophrenia. J Neurol Neurosurg Psychiatry 72:757, 2002. 10. Swayze VW 2nd, Andreasen NC, Ehrhardt JC, et al.: Developmental abnormalities of the corpus callosum in schizophrenia. Arch Neurol 47:805, 1990. 11. Jinkins JR, Whittemore AR, Bradley WG: MR imaging and corticocallosal dysgenesis. AJNR Am J Neuroradiol 10:339, 1989. 12. Ku¨ker W, Mayrhofer H, Mader I, et al.: Malformations of the midline commissures: MRI findings in different forms of callosal dysgenesis. Eur Radiol 13:598, 2003. 13. Vergani P, Ghidini A, Strobelt N, et al.: Prognostic indicators in the prenatal diagnosis of agenesis of corpus callosum. Am J Obstet Gynecol 170:753, 1994. 14. Pilu G, Sandri F, Perolo A, et al.: Sonography of fetal agenesis of the corpus callosum: a survey of 35 cases. Ultrasound Obstet Gynecol 3:318, 1993. 15. Descamps PH, Lewin F, Body G, et al.: Prise en charge obste´tricale des age´ne´sies du corps calleux. Neurochirurgie 44 (Supp 1):93, 1998. 16. Achiron R, Achiron A: Development of the human fetal corpus callosum: a high-resolution, cross-sectional sonographic study. Ultrasound Obstet Gynecol 18:343, 2001. 17. Achiron R, Lipitz S, Achiron A: Sex-related differences in the development of the human fetal corpus callosum: in utero ultrasonographic study. Prenat Diagn 21:116, 2001. 18. Bennett GL, Bromley B, Benacerraf BR: Agenesis of the corpus callosum: prenatal detection usually is not possible before 22 weeks of gestation. Radiology 199:447, 1996. 19. Goldstein RB, LaPidus AS, Filly RA, et al.: Mild lateral cerebral ventriculomegaly. Clinical course and outcome. Am J Obstet Gynecol 164: 863, 1990. 20. Filly RA, Cardoza JD, Goldstein RB, et al.: Detection of fetal central system anomalies. A practical level of effort for routine sonogram. Radiology 172:403, 1988. 21. Visentin A, Pilu G, Falco P, et al.: The transfrontal view: a new approach to the visualization of the fetal midline cerebral structures. J Ultrasound Med 20:329, 2001. 22. Malinger G, Zakut H: Transvaginal visualization of the corpus callosum. Am J Obstet Gynecol 171:1677, 1994. 23. Wang P-H, Ying T-H, Wang P-C, et al.: Obstetrical three-dimensional ultrasound in the visualization of the intracranial midline and corpus callosum of fetuses with cephalic presentation. Prenat Diagn 20:517, 2000. 24. Rapp B, Perrotin F, Marret H, et al.: Value of fetal cerebral magnetic resonance imaging for the prenatal diagnosis and prognosis of corpus callosum agenesis. J Gynecol Obstet Biol Reprod 31:173, 2002. 25. D’Ercole C, Girard N, Cravello L, et al.: Prenatal diagnosis of fetal corpus callosum agenesis by ultrasonography and magnetic resonance imaging. Prenat Diagn 18:247, 1998.

599 26. Chitayat D, Meagher-Villemure K, Mamer OA, et al.: Brain dysgenesis and congenital intracerebral calcification associated with 3-hydroxyisobutyric aciduria. J Pediatr 121:86, 1992. 27. Schinzel A: The acrocallosal syndrome in first cousins: widening of the spectrum of clinical features and further support for autosomal recessive inheritance. J Med Genet 25:332, 1988. 28. Rodriguez JI, Palacios J, Urioste M: New acrofacial dysostosis syndrome in 3 sibs. Am J Med Genet 35:484, 1990. 29. Verloes A, Gillerot Y, Walczak E, et al.: Acromelic frontonasal ‘‘dysplasia’’: further delineation of a subtype with brain malformation and polydactyly (Toriello syndrome). Am J Med Genet 42:180, 1992. 30. Ades LC, Clapton WK, Morphett A, et al.: Polydactyly, campomelia, ambiguous genitalia, cystic dysplastic kidneys, and cerebral malformation in a fetus of consanguineous parents: a new multiple malformation syndrome, or a severe form of oral-facial-digital syndrome Type IV? Am J Med Genet 49:211, 1994. 31. Verloes A, Lesenfants S: Agenesis of the corpus callosum, camptodactyly and obesity. Clin Dysmorphol 9:107, 2000. 32. Sayed M, al-Alaiyan S: Agenesis of corpus callosum, hypertrophic pyloric stenosis and Hirschsprung disease: coincidence or common etiology? Neuropediatrics 27:204, 1996. 33. Sybert V, Pagon RA, Ramsdell L, et al.: True agonadism: report of a case analysed with Y-specific DNA probes. Am J Med Genet 55:113, 1995. 34. Sztriha L, al-Gazali L, Dawodu A, et al.: Agyria-pachygyria and agenesis of the corpus callosum: autosomal recessive inheritance with neonatal death. Neurology 50:1466, 1998. 35. Rosser TL, Acosta MT, Packer RJ: Aicardi syndrome: spectrum of disease and long-term prognosis in 77 females. Pediatr Neurol 27:343, 2002. 36. Bookstein FL, Sampson PD, Connor PD, et al.: Midline corpus callosum is a neuroanatomical focus of fetal alcohol damage. Anat Rec 269:162, 2002. 37. Dupre N, Howard HC, Mathieu J, et al.: hereditary motor and sensory neuropathy with agenesis of the corpus callosum. Ann Neurol 54:9, 2003. 38. Angle B, Hersh JH: Anophthalmia, intracerebral cysts, and cleft lip/ palate: expansion of the phenotype in oculocerebrocutaneous syndrome? Am J Med Genet 68:39, 1997. 39. Guion-Almeida ML, Richieri-Costa A: New syndrome of growth and mental retardation, structural anomalies of the central nervous system, and first branchial arch, anophthalmia, heminasal a/hypoplasia, and atypical clefting: report on four Brazilian patients. Am J Med Genet 87:237, 1999. 40. Cohen MM Jr, Kreiborg S: The central nervous system malformations in the Apert syndrome. Am J Med Genet 35:36, 1990. 41. Lo Muzio L, Nocini PF, Savoia A, et al.: Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet 55:34, 1999. 42. Ben Ari J, Shuper A, Mimouni M, et al.: Agenesis of corpus callosum associated with double urinary collecting system, trigonocephaly and other minor anomalies: a new association (Letter). Eur J Pediatr 148:787, 1989. 43. Brown GK: Metabolic disorders of embryogenesis. J Inherit Metab Dis 17:448, 1994. 44. Meinecke P, Pfeiffer RA: Blepharophimosis, joint contractures, short stature, severe mental retardation and complex brain malformation. A ‘new’ MCA/MR syndrome? Zaragoza, 1st European Meeting of Dysmorphology, p46, 1990. 45. Brooks SS, Wisniewski K, Brown WT: New X-linked mental retardation (XLMR) syndrome with distinct facial appearance and growth retardation. Am J Med Genet 51:586, 1994. 46. Brumback RA, Prensky AL: Case report 41. Synd Ident IV(I):12, 1976. 47. Buntinx I, Majewski F: Blepharophimosis, iris coloboma, microgenia, hearing loss, postaxial polydactyly, aplasia of corpus callosum, hydroureter, and developmental delay. Am J Med Genet 36:273, 1990.

600

Neuromuscular Systems

48. Cao A, Cianchetti C, Signorini E, et al.: Agenesis of the corpus callosum, infantile spasms, spastic quadriplegia, microcephaly and severe mental retardation in three siblings. Clin Genet 12:290, 1977. 49. Ward J, Vieto E, Lee D, et al.: Acrocephalopolysyndactyly, pentalogy of Fallot, and hypoacusis in a patient with a de novo reciprocal translocation involving the short arm of chromosome 1 and the long arm of chromosome 18. J Med Genet 30:438, 1993. 50. Castro-Gago M, Rodriguez-Nunez A, Eiris J, et al.: Familial agenesis of the corpus callosum: a new form? Arch Fr Pediatr 50:327, 1993. 51. De Meirleir L, Lissens W, Denis R, et al.: Pyruvate dehydrogenase deficiency: clinical and biochemical diagnosis. Pediatr Neurol 9:216, 1993. 52. Guion-Almeida ML, Richieri-Costa A, Saavedra D, et al.: Cerebrofaciothoracic syndrome. Am J Med Genet 61:152, 1996. 53. Sakai T, Kikuchi F, Takashima S, et al.: Neuropathological findings in the cerebro-oculo-facio-skeletal (Pena-Shokeir II) syndrome. Brain Dev 19:58, 1997. 54. Ercal D, Say B: Cerebro-oculo-nasal syndrome: another case and review of the literature. Clin Dysmorphol 7:139, 1998. 55. Silengo MC, Lerone M, Pelizza A, et al.: A new syndrome with cerebrooculo-skeletal-renal involvement. Pediatr Radiol 20:612, 1990. 56. Lurie IW, Lazjuk GI, Korotkova IA, et al.: The cerebro-reno-digital syndromes: a new community. Clin Genet 39:104, 1991. 57. Tellier AL, Cormier-Daire V, Abadie V, et al.: CHARGE syndrome: report of 47 cases and review. Am J Med Genet 76:402, 1998. 58. Sherman JD: Chlorpyrifos (Dursban)-associated birth defects: report of four cases. Arch Environ Health 51:5, 1996. 59. Faye-Petersen OM, Ward K, Carey JC, et al.: New syndrome? Osteochondrodysplasia with rhizomelia, platyspondyly, callosal agenesis, thrombocytopenia, hydrocephalus, and hypertension. Am J Med Genet 40:183, 1991. 60. POSSUM1, Version 5.6. The Murdoch Institute, Royal Children’s Hospital, Melbourne, Australia. 61. Rodini ES, Freitas JA, Richieri-Costa A: Ectrodactyly, cleft lip/palate syndrome. Am J Med Genet 38:539, 1991. 62. Gieron-Korthals MA, Helal A, Martinez CR: Expanding spectrum of cocaine induced central nervous system malformations (Case report). Brain Dev 16:253, 1994. 63. Lucaya J, Garcia-Conesa JA, Bosch-Barryeras JM, et al.: The Coffin-Siris syndrome: a report of four cases and review of the literature. Pediatr Radiol 11:35, 1981. 64. al-Gazali LI, Bakir M, Hamid ZM, et al.: Congenital bowing of the long bones associated with camptodactyly, talipes equinovarus and agenesis of the corpus callosum. Clin Dysmorphol 9:93, 2000. 65. Wilson WG, Kennaugh JM, Kugler JP, et al.: Agenesis of the corpus callosum in two brothers. J Med Genet 20:416, 1983. 66. Crane JP, Heise RL: New syndrome in three affected siblings. Pediatrics 68:235, 1981. 67. Morton JEV: Craniofacial dyssynostosis: A further clinical report. Am J Med Genet 79:8, 1998. 68. Hughes HE, Harwood-Nash DC, Becker LE: Craniotelencephalic dysplasia in sisters: further delineation of a possible syndrome. Am J Med Genet 14:557, 1983. 69. Fransen E, Van Camp G, Vits L, et al.: L1-associated diseases: clinical geneticists divide, molecular geneticists unite. Hum Mol Genet 6:1625, 1997. 70. Curatolo P, Cilio MR, Del Giudice E, et al.: Familial white matter hypoplasia, agenesis of the corpus callosum, mental retardation and growth deficiency: a new distinctive syndrome. Neuropediatrics 24:77, 1993. 71. Temple IK, Eccles DM, Winter RM, et al.: Craniofacial abnormalities, agenesis of the corpus callosum, polysyndactyly and abnormal skin and gut development-the Curry Jones syndrome. Clin Dysmorphol 4:116, 1995. 72. Naritomi K, Tohma T, Goya Y, et al.: Delineation of the da Silva syndrome. Am J Med Genet 49:313, 1994. 73. Juberg RC, Van Ness MB: A new form of hereditary short limbed dwarfism with microcephalus. Clin Genet 7:111, 1975.

74. Moog U, Kruger G, Stengel B, et al.: Oculocerebrocutaneous syndrome: a case report, a follow-up, and differential diagnostic considerations. Genet Couns 7:257, 1996. 75. Anderson HC, Kratz L, Kelley R: Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay. Am J Med Genet 113:315, 2002. 76. Donnai D, Barrow M: Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder? Am J Med Genet 47: 679, 1993. 77. Bieber FR, Dawson AE, Holmes LB: Etiologic complexities of diaphragmatic defects: right diaphragmatic hernia, pulmonary hypoplasia/ agenesis, and hydrocephalus in sibs. Am J Med Genet 41:164, 1991. 78. Cherstvoy E, Laziuk G, Lurie I, et al.: Syndrome of multiple congenital malformations including phocomelia, thrombocytopenia, encephalocele, and urogenital abnormalities. Lancet 2:485, 1980. 79. Dobyns WB, Pagon RA, Curry CJR, et al.: Clinical and molecular status in 62 patients with type I lissencephaly. Proc Greenwood Genet Ctr 10:64, 1991. 80. Silengo M, Silvestro L, Capizzi G, et al.: Ectodermal dysplasia, primary hypothyroidism, and agenesis of the corpus callosum: variable expression of a single syndrome? J Med Genet 35:157, 1998. 81. Saal HM, Bulas DI: Ectrodactyly, diaphragmatic hernia, congenital heart defect, and agenesis of the corpus callosum. Clin Dysmorphol 4:246, 1995. 82. Edwards JG, Lampert RP, Hammer ME, et al.; Ocular defects and dysmorphic features in three generations. J Clin Dysmorphol 2(3):8, 1984. 83. Thomas P, Bossan A, Lacour JP, et al.: Ehlers-Danlos syndrome with subependymal periventricular heterotopias. Neurology 46:1165, 1996. 84. Froster-Iskenius UG, Meinecke P: Encephalocele, radial defects, cardiac, gastrointestinal, anal, and renal anomaly (MCA) syndrome? Clin Dysmorphol 1:37, 1992. 85. Akhtar S, Bron AJ, Meek KM, et al.: Congenital hereditary endothelial dystrophy and band keratopathy in an infant with corpus callosum agenesis. Cornea 20:547, 2001. 86. Leal E, Macias-Gomez N, Rodriguez L, et al.: Femoral-facial syndrome with malformations of the central nervous system. Clin Imaging 27:23, 2003. 87. Graham JM Jr, Superneau D, Rogers RC, et al.: Clinical and behavioural characteristics in FG syndrome. Am J Med Genet 85:470, 1999. 88. Ayme´ S, Philip N: Fine-Lubinsky syndrome: a fourth patient with brachycephaly, deafness, cataract, microstomia and mental retardation. Clin Dysmorphol 5:55, 1996. 89. Baughman FA Jr, Worcester DD: Agenesis of the corpus callosum in a case of focal dermal hypoplasia. Mt Sinai J Med 37:702, 1970. 90. Francois J, Eggermont E, Evens L, et al.: Agenesis of the corpus callosum in the median facial cleft syndrome and associated ocular malformations. Am J Ophthalmol 76:241, 1973. 91. Warkany J, Bofinger MK, Benton C: Median facial cleft syndrome in half sisters: dilemmas in genetic counselling. Teratology 8:273, 1973. 92. Verloes A, Gillerot Y, Walczak E, et al.: Acromelic frontonasal dysplasia: further delineation of a subtype with brain malformation and polydactyly (Toriello syndrome). Am J Med Genet 42:180, 1992. 93. Temple IK, Brunner H, Jones B, et al.: Midline facial defects with ocular colobomata. Am J Med Genet 37:23, 1990. 94. Guion-Almeida ML, Richieri-Costa A: Frontonasal dysplasia, macroblepharon, eyelid colobomas, ear anomalies, macrostomia, mental retardation, and CNS structural anomalies. A new syndrome? Clin Dysmorphol 8:1, 1999. 95. Van Hove JLK, Spiridigliozzi GA, Heinz R, et al.: Fryns syndrome survivors and neurologic outcome. Am J Med Genet 59:334, 1995. 96. Rodriguez JI, Palacios J, Omenaca F, et al.: Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am J Med Genet 38:99, 1991. 97. Guion-Almeida ML, Richieri-Costa A: CNS midline anomalies in the Opitz G/BBB syndrome: report on 12 Brazilian patients. Am J Med Genet 43:918, 1992. 98. Armstrong L, Clarke JTR: Report of a new case of ‘‘genitopatellar’’ syndrome which challenges the importance of absent patella as a defining feature. J Med Genet 39:933, 2002.

Brain 99. Silengo M, Ferrero GB, Tornetta L: Pachygyria and cerebellar hypoplasia in Goldberg-Shprintzen syndrome. Am J Med Genet 118A: 388, 2003. 100. Glass IA, Walford-Moore J, Chapman S, et al.: Ear anomalies, clefting and limb reduction defects: a new autosomal recessive condition? Clin Dysmorphol 3:150, 1994. 101. Marafie MJ, Temtamy SA, Rajaram U, et al.: Greig cephalopolysyndactyly syndrome with dysgenesis of the corpus callosum in a Bedouin family. Am J Med Genet 66:261, 1996. 102. Richards LJ, Plachez C, Ren T: Mechanisms regulating the development of the corpus callosum and its agenesis in mouse and human. Clin Genet 66:276, 2004. 103. Cormier-Daire V, Chauvet ML, Lyonnet S, et al.: Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation. J Med Genet 37:520, 2000. 104. Aleksic S, Budzilovich G, Greco MA, et al.: Intracranial lipomas, hydrocephalus and other CNS anomalies in oculoauriculo-vertebral dysplasia (Goldenhar-Gorlin syndrome). Childs Brain 11:285, 1984. 105. Ainsworth SB, Baraitser M, Mueller RF, et al.: Selective IgG2 subclass deficiency—a marker for the syndrome of pre/postnatal growth retardation, developmental delay, hypotrophy of distal extremities, dental anomalies and eczema. Clin Dysmorphol 6:139, 1997. 106. Halal F, Silver K: Syndrome of microcephaly, Brachmann-de Lange-like facial changes, severe metatarsus adductus, and developmental delay: mild Brachmann-de Lange syndrome? Am J Med Genet 42:381, 1992. 107. Hendriks YMC, Laan LAEM, Vielvoye GJ, et al.: Bilateral sensorineural deafness, partial agenesis of the corpus callosum, and arachnoid cysts in two sisters. Am J Med Genet 86:183, 1999. 108. Hersh JH, Dela Cruz TV, Pietrantoni M, et al.: Mirror image duplication of the hands and feet. Am J Med Genet 59:341, 1995. 109. Holmes LB, Schoene WC, Benacerraf BR: New syndrome: brain malformation, growth retardation, hypokinesia and polyhydramnios in two brothers. Clin Dysmorphol 6:13, 1997. 110. Anyane-Yeboa K, Collins M, Kupsky W, et al.: Hydrolethalus (Salomen-Horva-Norio) syndrome: further clinicopathological delineation. Am J Med Genet 26:899, 1987. 111. Gulati S, Gera S, Menon PS, et al.: Hypothalamic hamartoma, gelastic epilepsy, precocious puberty—a diffuse cerebral dysgenesis. Brain Dev 24:784, 2002. 112. Levin ML, Lupski JR, Carpenter RJ Jr, et al.: An additional case of pachygyria, joint contractures and facial abnormalities. Clin Dysmorphol 2:365, 1993. 113. Conover PT, Roessmann U: Malformational complex in an infant with intrauterine influenza viral infection. Arch Path Lab Med 114:535, 1990. 114. de Hauwere RC, Leroy JG, Adriaenssens K: Iris dysplasia, orbital hypertelorism, and psychomotor retardation: a dominantly inherited developmental syndrome. J Pediatr 82:679, 1973. 115. Noack F, Sayk F, Ressel A, et al.: Ivemark syndrome with agenesis of the corpus callosum: a case report with a review of the literature. Prenat Diagn 22:1011, 2002. 116. Ives EJ, Houston CS: Autosomal recessive microcephaly and micromelia in Cree Indians. Am J Med Genet 7:351, 1980. 117. Jonas REJ, Kimonis VE, Morales A: Possible new autosomal recessive syndrome of partial agenesis of the corpus callosum, pontine hypoplasia, focal white matter changes, hypotonia, mental retardation, and minor anomalies. Am J Med Genet 73:184, 1997. 118. Zamponi N, Rossi B, Messori A, et al.: Joubert syndrome with associated corpus callosum agenesis. Eur J Neurol 6:63, 2002. 119. Parr JH: Midline cerebral defects and Kallmann’s syndrome. J R Soc Med 81:355, 1988. 120. Camera G, Centa A, Pozzolo S, et al.: Peters-Plus syndrome with agenesis of the corpus callosum: report of a case and confirmation of autosomal recessive inheritance. Clin Dysmorphol 2:317, 1993. 121. Kozlowski K, Ouvrier RA: New syndrome. Agenesis of the corpus callosum with mental retardation and osseous lesions. Am J Med Genet 48:6, 1993.

601 122. Bamforth F, Bamforth S, Poskitt K, et al.: Abnormalities of the corpus callosum in patients with inherited metabolic diseases. Lancet 2:451, 1988. 123. Summitt RL, Favara BE: Leprechaunism (Donahue’s syndrome): a case report. J Pediatr 74:601, 1969. 124. L ‘Hermitte MMJ, Ajuriaguerra J de, Trotot RP: Oxycephalie avec age´ne´sie de la commissure calleuse et du vermis inferieur. Rev Neurol 76:146, 1944. 125. Hedera P, Innis JW: Possible third case of Lin-Gettig syndrome. Am J Med Genet 110:380, 2002. 126. Dodge NN, Dobyns WB: Agenesis of the corpus callosum and DandyWalker malformation associated with hemimegalencephaly in the sebaceous nevus syndrome. Am J Med Genet 56:147, 1995. 127. Kerner B, Graham JJ Jr, Golden JA, et al.: Familial lissencephaly with cleft palate and severe cerebellar hypoplasia. Am J Med Genet 87:440, 1999. 128. Lacombe D, Bonneau D, Verloes A, et al.: Lujan-Fryns syndrome (Xlinked mental retardation with marfanoid habitus): report of three cases and review. Genet Couns 4:193, 1993. 129. Lurie IW, Kletsky SK: Syndrome identification case report #145: agenesis of the corpus callosum, hydrocephaly, diaphragmatic hernia, and hydrops fetalis. Dysmorphol Clin Genet 4:63, 1990. 130. Prudlo J, Stoltenburg-Didinger G, Jimenez E, et al.: Central nervous system alterations in a case of short-rib polydactyly syndrome, Majewski type. Dev Med Child Neurol 35:158, 1993. 131. Summers DA, Cooper HA, Butler MG: Marshall-Smith syndrome: case report of a newborn male and review of the literature. Clin Dysmorphol 8:207, 1999. 132. Boyd E, Schwartz CE, Schroer RJ, et al.: Agenesis of the corpus callosum associated with MASA syndrome. Clin Dysmorphol 2:332, 1993. 133. Fried K, Liban E, Lurie M, et al.: Polycystic kidneys associated with malformations of the brain, polydactyly and other birth defects in newborn sibs. J Med Genet 8:285, 1971. 134. Rodriguez Criado G, Rufo M, Gomez de Terreros I: A second family with Micro syndrome. Clin Dysmorphol 8:241, 1999. 135. Meinecke P, Bonnemann CG, Laas R: Microgastria-hypoplastic upper limb association: a severe expression including microphthalmia, single nostril and arhinencephaly. Clin Dysmorphol 1:43, 1992. 136. Paulger BR, Kraus EW, Pulitzer DR, et al.: Xp microdeletion syndrome characterized by pathognomonic linear skin defects on the head and neck. Pediatr Dermatol 14:26, 1997. 137. Moerman PH, Vandenberghe K, Fryns JP, et al.: A new lethal chondrodysplasia with spondylocostal dysostosis, multiple internal anomalies and Dandy-Walker cyst. Clin Genet 27:160, 1985. 138. Lees MM, Hodgkins P, Reardon W, et al.: Frontonasal dysplasia with optic disc anomalies and other midline craniofacial defects: a report of six cases. Clin Dysmorphol 7:157, 1998. 139. Mowat DR, Wilson MJ, Goossens M: Mowat-Wilson syndrome. J Med Genet 40:305, 2003. 140. Amiel J, Espinosa-Parrilla Y, Steffann J, et al.: Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures. Am J Hum Genet 69:1370, 2001. 141. Muller F-M, Barth GM, Menger H, et al.: Cerebral malformation, seizures, hypertrichosis, distinct face, claw hands, and overlapping fingers in sibs of both sexes. Am J Med Genet 47:698, 1993. 142. Cormand B, Avela K, Pihko H, et al.: Assignment of the muscle-eyebrain disease gene to 1p32-p34 by linkage analysis and homozygotes mapping. Am J Hum Genet 64:126, 1999. 143. Doerfler W, Wieczorek D, Gillessen-Kaesbach G, et al.: Three brothers with mental and physical retardation, hydrocephalus, microcephaly, internal malformations, speech disorder, and facial anomalies: Mutchinick syndrome. Am J Med Genet 73:210, 1997. 144. Aughton DJ, Sloan CT, Milad MP, et al.: Nasopharyngeal teratoma (‘hairy polyp’), Dandy-Walker malformation, diaphragmatic hernia, and other anomalies in a female infant. J Med Genet 27:788, 1990. 145. Lyon G, Arita F, Le Galloudec E, et al.: A disorder of axonal development, necrotizing myopathy, cardiomyopathy and cataracts: a new familial disease. Ann Neurol 27:193, 1990.

602

Neuromuscular Systems

146. Abdel-Salam GM, Czeizel AE: A new case of neonatal progeroid syndrome with agenesis of corpus callosum. Genet Couns 10:377, 1999. 147. Encha-Razavi F, Larroche JC, Roume J, et al.: Lethal familial fetal akinesia sequence (FAS) with distinct neuropathological pattern: type III lissencephaly syndrome. Am J Med Genet 62:16, 1996. 148. Barth PG, Uylings HBM, Stam FC: Interhemispheral neuroepithelial (glioependymal) cysts, associated with agenesis of the corpus callosum and neocortical maldevelopment. Child Brain 11:312, 1984. 149. Atlas SW, Zimmerman RA, Bruce D, et al.: Neurofibromatosis and agenesis of the corpus callosum in identical twins: MR diagnosis. AJNR Am J Neuroradiol 9:598, 1988. 150. Coleman RA, Van Hove JLK, Morris CR, et al.: Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: additional findings or a new syndrome (ARCC-NDI). Am J Med Genet 72:335, 1997. 151. Bekiesinska-Figatowska M, Chrzanowska KH, Sikorska J, et al.: Cranial MRI in the Nijmegen breakage syndrome. Neuroradiology 42:43, 2000. 152. Fletcher JM, Bye AME, Nayanar V, et al.: Non-ketotic hyperglycinaemia presenting as pachygyria. J Inherit Metab Dis 18:665, 1995. 153. Bohring A, Silengo M, Lerone M, et al.: Severe end of Opitz trigonocephaly (C) syndrome or new syndrome? Am J Med Genet 85:438, 1999. 154. Ishmael HA, Begleiter ML, Regier EJ, et al.: Oculoauriculofrontonasal syndrome (OAFNS) in a nine-month-old male. Am J Med Genet 107: 169, 2002. 155. Weill J, Boudailliez B, Piussan C, et al.: Malformations ce´re´brales et oculaires avec insuffisance ante´hypophysaire de caractere familial. J Ge´ne´t Hum 33:31, 1985. 156. Sonoda T, Ohdo S, Ohba K, et al.: Association of congenital heart disease, blepharoptosis, and short stature. Jpn J Hum Genet 34:291, 1989. 157. Zampino G, DiRocco C, Butera G, et al.: Opitz C trigonocephaly syndrome and midline brain anomalies. Am J Med Genet 73:484, 1997. 158. Anneren G, Arvidson B, Gustavos KH, et al.: Oro-facial-digital syndromes I and II: radiological methods for diagnosis and the clinical variations. Clin Genet 26:178, 1984. 159. Balci S, Guler G, Kale G, et al.: Mohr syndrome in two sisters: prenatal diagnosis in a 22-week-old fetus with post-mortem findings in both. Prenat Diagn 19:827, 1999. 160. Chung WY, Chung LP: A case of oral-facial-digital syndrome with overlapping manifestations of type V and type VI: a possible new OFD syndrome. Pediatr Radiol 29:268, 1999. 161. Orstavik KH, Stromme P, Spetalen S, et al.: Aplasia cutis congenita associated with limb, eye, and brain anomalies in sibs: a variant of the Adams-Oliver syndrome?. Am J Med Genet 59:92, 1995. 162. Sigaudy S, Toulain A, Monda A, et al.: Microcephalic osteodysplastic primordial dwarfism Taybi-Linder type: report of four cases and review of the literature. Am J Med Genet 80:16, 1998. 163. al-Gazali LI, Bakalinova D, Bakir M: Central nervous system malformations, dense bones and facial dysmorphism: a new autosomal recessive syndrome. Clin Dysmorphol 7:123, 1998. 164. Berry-Kravis E, Israel J: X-linked pachygyria and agenesis of the corpus callosum: evidence for an X chromosome lissencephaly locus. Ann Neurol 36:229, 1994. 165. Coban YK, Boran C, Omeroglu SA, et al.: Pai syndrome: an adult patient with bifid nose and frontal hairline marker. Cleft Palate Craniofac J 40:325, 2003. 166. Finnigan DP, Clarren SK, Haas JE, et al.: Extending the Pallister-Hall syndrome to include other central nervous system malformations. Am J Med Genet 40:395, 1991. 167. Bottani A, Schinzel A: A third patient with median cleft upper lip, mental retardation and pugilistic facies (W syndrome): corroboration of a hitherto private syndrome. Clin Dysmorphol 2:225, 1993. 168. Mitchel TN, Free SL, Williamson KA, et al.: Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol 53:658, 2003. 169. Henneveld HT, van Lingen RA, Hamel BC, et al.: Perlman syndrome: four additional cases and review. Am J Med Genet 86:439, 1999. 170. Myles WM, Flanders ME, Chitayat D, et al.: Peters’ anomaly: a clinicopathologic study. J Pediatr Ophthalmol Strabismus 29:374, 1992.

171. Happle R: Phylloid hypomelanosis and mosaic trisomy 13: a new etiologically defined neurocutaneous syndrome. Hautarzt 52:3, 2001. 172. Rodriguez JI, Palacios J, Omenaca F, et al.: Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am J Med Genet. 38:99, 1991. 173. Biesecker LG, Happle R, Mulliken JB, et al.: Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84:389, 1999. 174. Kato M, Das S, Petras K, et al.: Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 23:147, 2004. 175. Al-Dabbous R, Sabry MA, Farah S, et al.: The autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease: report of another Bedouin family. Clin Dysmorphol 7:127, 1998. 176. Brown GK, Otero LJ, LeGris M, et al.: Syndrome of the month. Pyruvate dehydrogenase deficiency. J Med Genet 31:875, 1994. 177. Guion-Almeida ML, Richieri-Costa A: Callosal agenesis, iris coloboma, and megacolon in a Brazilian boy with Rubinstein-Taybi syndrome. Am J Med Genet 43:929, 1992. 178. Ehara H, Kurimara A, Ohno K, et al.: New syndrome with Sakoda complex, bilateral anophthalmia, and cortical dysgenesis. Pediatr Neurol 18:445, 1998. 179. Say B, Poznanski AK: Cloverleaf skull associated with unusual skeletal anomalies. Pediatr Radiol 17:93, 1987. 180. Ozkinay FF, Akisu M, Kultursay N, et al.: Agenesis of the corpus callosum in Schinzel-Giedion syndrome associated with 47,XXY karyotype. Clin Genet 50:145, 1996. 181. Parent P, Moulin S, Munck MR, et al.: Le nanisme a tete d’oiseau ou syndrome de Seckel. Difficultes nosologiques. Arch Pediatr 3:55, 1996. 182. Shanske A, Caride DG, Menasse-Palmer L, et al.: Central nervous system anomalies in Seckel syndrome: Report of a new family and review of the literature. Am J Med Genet 70:155, 1997. 183. Arroyo HA, DiBlasi AM, Grinszpan GJ: A syndrome of hyperhydrosis, hypothermia and bradycardia possibly due to central monoaminergic dysfunction. Neurology 40:556, 1990. 184. Siber M: X-Iinked recessive microencephaly, microphthalmia with corneal opacities, spastic quadriplegia, hypospadias and cryptorchidism. Clin Genet 26:453, 1984. 185. Sharony R, Kidron D, Amiel A, et al.: Familial lethal skeletal dysplasia with cloverleaf skull and multiple anomalies of brain, eye, face and heart: a new autosomal recessive multiple congenital anomalies syndrome. Clin Genet 61:369, 2002. 186. Slee J, Knowles S, Goldblatt J: Siblings with a syndrome of hydrocephalus with patent aqueduct, growth retardation and associated anomalies. Clin Dysmorphol 8:11, 1999. 187. Smith PJ, Hindmarsh P, Kendall B, et al.: Dysgenesis of the corpus callosum and hypopituitarism. Acta Paediatr Scand 75:923, 1986. 188. Donnai D, Burn J, Hughes HE: Smith-Lemli-Opitz syndromes: do they include Pallister-Hall syndrome [letter]. Am J Med Genet 28:741, 1987. 189. Ferrier S, Nussle D, Friedl B, et al.: Marchesani’s syndrome (spherophakia-brachymorphism). Helv Paediatr Acta 35:185, 1980. 190. Geller JD, Topper SF, Hashimoto K: Diffuse neonatal hemangiomatosis: a new constellation of findings. J Am Acad Dermatol 24:816, 1991. 191. Plauchu H, Encha-Razavi F, Hermier M, et al.: Lissencephaly type III, stippled epiphyses and loose, thick skin: a new recessively inherited syndrome. Am J Med Genet 99:14, 2001. 192. Ciske DJ, Waggoner DJ, Dowton SB: Unique cardiac and cerebral anomalies with chondrodysplasia punctata. Am J Med Genet 75:59, 1998. 193. Stoll C, Huber C, Alembik Y, et al.: Dandy-Walker variant malformation, spastic paraplegia, and mental retardation in two sibs. Am J Med Genet 37:124, 1990. 194. Demaerel P, Kendell BE, Wilms G, et al.: Uncommon posterior cranial fossa anomalies: MRI with clinical correlation. Neuroradiology 37:72, 1995. 195. Chan AKJ, Levin AV, Teebi AS: Craniofacial dysmorphism, agenesis of the corpus callosum and ocular colobomas: Temtamy syndrome? Clin Dysmorphol 9:223, 2000.

Brain 196. Thakker Y, Donnai D: A new recessive syndrome of unusual facies and multiple structural abnormalities. J Med Genet 28:633, 1991. 197. Wongmongkolrit T, Bush M, Roessmann U: Neuropathologic findings in thanatophoric dysplasia. Arch Pathol 107:132, 1983. 198. Khabbaze Y, Karayalcin G, Paley C, et al.: Thrombocytopenia absent corpus callosum syndrome: third case of a distinct clinical entity. J Pediatr Hematol Oncol 23:469, 2001. 199. Barisic I, Peter B, Mikecin L: Further delineation of the Toriello-Carey syndrome: a case report of two siblings. Am J Med Genet 116A:188, 2003. 200. Fryns JP, Devriendt K, Legius E: Polysyndactyly and trigonocephaly with partial agenesis of corpus callosum: an example of the variable clinical spectrum of the Acrocallosal syndrome? Clin Dysmorphol 6:285, 1997. 201. Barth PG, Stam FC, von der Harten JJ: Tuberous sclerosis and dysplasia of the corpus callosum: case report of their combined occurrence in a newborn. Acta Neuropathol 42:63, 1978. 202. Van Biervliet JP, Hendrickx G, van Ertbruggen I: Intrauterine growth retardation with craniofacial and brain anomalies and arthrogryposis. Acta Paediatr Belg 30:97, 1977. 203. Zampino G, Colosimo C, Balducci F, et al.: Cerebro-facio-articular syndrome of Van Maldergem: confirmation of a new MR/MCA syndrome. Clin Genet 45:140, 1994. 204. Kraynack NC, Hostoffer RW, Robin NH: Agenesis of the corpus callosum associated with DiGeorge-velocardiofacial syndrome: a case report and review of the literature. J Child Neurol 14:754, 1999. 205. Chiyonobu T, Yoshihara T, Fukushima Y, et al.: Sister and brother with Vici syndrome: agenesis of the corpus callosum, albinism, and recurrent infections. Am J Med Genet 109:61, 2002. 206. Vles JSH, de Die-Smulders C, Van der Hoeven M, et al.: Corpus callosum agenesis in two male infants of a heterozygotic triplet pregnancy. Genet Couns 4:239, 1993. 207. Dobyns WB, Kirkpatrick JB, Hittner HM, et al.: Syndromes with lissencephaly. II: Walker-Warburg and cerebro-oculo-muscular syndromes and a new syndrome with type II lissencephaly. Am J Med Genet 22:157, 1985. 208. Kaplan LC: Congenital Dandy Walker malformation associated with first trimester warfarin: a case report and literature review. Teratology 32:333, 1985. 209. Wells TR, Falk RE, Senac MO, et al.: Acrocephalospondylosyndactyly— a possible new syndrome: analysis of the vertebral and intervertebral components. Pediatr Pathol 10:117, 1990. 210. Haan EA, Furness ME, Knowles S, et al: Osteodysplastic primordial dwarfism: report of a further case with manifestations similar to those of types I and III. Am J Med Genet 33:224, 1989. 211. Winter RM, Wigglesworth JS: Unusual association of cerebral and renal abnormalities. Clin Dysmorphol 2:71, 1993. 212. Kang WM, Huang CC, Lin SJ: X-linked recessive inheritance of dysgenesis of corpus callosum in a Chinese family. Am J Med Genet. 44: 619, 1992. 213. Kitamura K, Yanazawa M, Sugiyama N, et al.: Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 32:359, 2002. 214. Young ID, Trounce MI, Fitzsimmons JL, et al.: Agenesis of the corpus callosum and macrocephaly in siblings. Clin Genet 28:225, 1985. 215. Barkovich AJ, Peck WW: MR of Zellweger syndrome. AJNR Am J Neuroradiol 18:1163, 1997. 216. Zimmer EZ, Taub E, Sova Y, et al.: Tetra-amelia with multiple malformations in six male fetuses of one kindred. Eur J Pediatr 144:412, 1985. 217. Zollino M, Colosimo C, Zuffardi O, et al.: Cryptic t(12;12)(q44;p13.3) translocation in a previously described syndrome with polymicrogyria, segregating as an apparently X-linked trait. Am J Med Genet 117A:65, 2003. 218. Myrianthopoulos NC: Epidemiology of central nervous system malformations. In: Congenital Malformations of the Brain and Skull. Part I. Vinken PJ, Bruyn GW, Myrianthopoulos NC, eds. North Holland Biomedical, Amsterdam, 1977, p 139.

603 219. Larsen PD, Osborn AG: Computerized tomographic evaluation of corpus callosum agenesis and associated malformations. J Comput Tomogr 6:225, 1982. 220. Pinar H, Tatevosyants N, Singer DB: Central nervous system malformations in a perinatal/neonatal autopsy series. Pediatr Dev Pathol 1:42, 1998. 221. Shevell MI: Clinical and diagnostic profile of agenesis of the corpus callosum. J Child Neurol 17:896, 2002. 222. Grogono JL: Children with agenesis of the corpus callosum. Dev Med Child Neurol 10:613, 1968. 223. Chako A, Koul R, Sankhla DK: Corpus callosum agenesis. Saudi Med J 22:22, 2001. 224. Bodensteiner J, Schafer GB, Breeding L, et al.: Hypoplasia of the corpus callosum: a study of 445 consecutive MRI scans. J Child Neurol 9:47, 1994. 225. Jeret JS, Serur D, Wisniewski K, et al.: Frequency of agenesis of the corpus callosum in the developmentally disabled population as determined by computerized tomography. Pediatr Neurosci 12:101, 1986. 226. Couture A, Droulle P, Didier F: Les malformations ce´re´brales. In: Echographie du Foetus au Nouveaune´. Couture A, Veyrac C, Baud C, eds. Sauramps Me´dical Editions, Montpellier, 1994, p 267. 227. Rejjal A, Alaiyan S, Coates R, et al.: The prevalence of brain abnormalities in congenital choanal atresis. Neuropediatrics 25:85, 1994. 228. Glauser TA, Rorke LB, Weinberg PM, et al.: Congenital brain anomalies associated with hypoplastic left heart. Pediatrics 85:984, 1990. 229. Manhaes AC, Medina AE, Schmidt SL: Sex differences in the incidence of total callosal agenesis in BALB/cCF mice. Neurosci Lett 325:159, 2002. 230. Sidman RL, Rakic P: Development of the human central nervous system. In: Haymaker W, Adams RD, eds. Histology and Histopathology of the Nervous System. Charles C Thomas, Springfield, IL, 1982, p 42. 231. Rakic P, Yakovlev PI: Development of the corpus callosum and cavum in man. J Comp Neurol 132:45, 1968. 232. Richards LJ: Axonal pathfinding mechanisms at the cortical midline and in the development of the corpus callosum. Braz J Med Biol Res 35:1431, 2002. 233. Shu T, Richards LJ: Cortical axon guidance by the glial wedge during development of the corpus callosum. J Neurosci 21:2749, 2001. 234. Tear G, Harris R, Sutaria, et al.: Commissureless controls growth cone guidance across the CNS midline in Drosophila and encodes a novel membrane protein. Neuron 16:501, 1996. 235. Ozaki HS, Wahlsten D: Prenatal formation of the normal mouse callosum: a quantitative study with carbocyanine dyes. J Comp Neurol 323:81, 1992. 236. Barkovich AJ, Norman D: Anomalies of the corpus callosum: correlation with further anomalies of the brain. AJR Am J Roentgenol 151: 171, 1988. 237. Andermann E: Agenesis of the corpus callosum. In: Handbook of Clinical Neurology, vol 42, section I: Malformations. PJ Vinken, GW Bruyn, eds. Elsevier, North Holland Biomedical, Amsterdam, 1981, p 6. 238. Dobyns WB: Agenesis of the corpus callosum and gyral malformations are frequent manifestations of non-ketotic hyperglycinemia. Neurology 39:817, 1989. 239. Needham LK, Thelen K, Maness PF: Cytoplasmic domain mutations of the L1 cell adhesion molecule reduce L1-ankyrin interactions. J Neurosci 21:1490, 2001. 240. Howard H, Mount DB, Rochfort D, et al.: The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet 32:384, 2002. 241. Mathieu J, Bedard F, Prevost C, et al.: Motor and sensory neuropathies with or without agenesis of the corpus callosum: a radiological study of 64 cases. Can J Neurol Sci 17:103, 1990. 242. Ettlinger G, Blakemore CB, Milner AD, et al.: Agenesis of the corpus callosum: a further behavioural investigation. Brain 97:225, 1974. 243. Jeeves MA, Temple CM: A further study of language function in callosal agenesis. Brain Lang 32:325, 1987. 244. Schalomon PM, Wahlsten D: Wheel running behavior is impaired by both surgical section and genetic absence of the mouse corpus callosum. Brain Res Bull 57:27, 2002. 245. de Guise E, del Pecse M, Foschi N, et al.: Callosal and cortical contribution to procedural learning. Brain 122:1049, 1999.

604

Neuromuscular Systems

246. Jeeves M, Ludwig T, Moes P, et al.: The stability of compromised interhemispheric processing in callosal dysgenesis and partial commissurotomy. Cortex 37:643, 2001. 247. Lessard N, Lepore F, Villemagne J, et al.: Sound localization in callosal agenesis and early callostomy subjects: brain reorganization and/or compensatory strategies. Brain 125:1039, 2002. 248. Roser M, Corballis MC: Interhemispheric neural summation in the split brain with symmetrical and asymmetrical displays. Neuropsychologia 40:1300, 2002. 249. Roser M, Corballis MC: Interhemispheric neural summation in the split brain: effects of stimulus colour and task. Neuropsychologia 41: 830, 2003. 250. Forster B, Corballis MC: Interhemispheric transfer of colour and shape information in the presence and absence of the corpus callosum. Neuropsychologia 38:32, 2000. 251. Brown WS, Jeeves MA, Dietrich R, et al.: Bilateral field advantage and evoked potential interhemispheric transmission in commissurotomy and callosal agenesis. Neuropsychologia 37:1165, 1999. 252. Taylor M, David AS: Agenesis of the corpus callosum: a United Kingdom series of 56 cases. J Neurol Neurosurg Psychiatry 64:131, 1998. 253. Gupta JK, Lilford RJ: Assessment and management of fetal agenesis of the corpus callosum. Prenat Diagn 15:301, 1995. 254. Moutard M-L, Kieffer V, Feingold J, et al.: Agenesis of corpus callosum: prenatal diagnosis and prognosis. Childs Nerv Syst 19:471, 2003. 255. Lu WH, Chen CC, Chiu PC, et al.: Isolated complete agenesis of the corpus callosum. Acta Peadiatr Taiwan 44:5, 2003. 256. Bahadoran, Ballotti R, Ortonne J-P: Hypomelanosis, immunity, central nervous system: No more ‘‘and,’’ not the end. Am J Med Genet 116A:334, 2003. 257. Hunter AGW: Coffin-Lowry syndrome: a 20 year follow-up and review of long term outcomes. Am J Med Genet 111:345, 2002. 258. Cohen MM, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003.

15.7 Cavum, Cysts, and Absence of the Septum Pellucidum and Cavum Vergae Definition

A cavum is a fluid-filled cavity between the apposed sides of the septum pellucidum and/or vergae. The cavum vergae is more caudally placed and usually is connected to the cavum septum pellucidum. The cava are not connected to the ventricular system and should not be referred to as fifth or sixth ventricles. Cysts are defined usually as symptomatic enlargements of the cavum, but because it is sometimes difficult to show a causal relationship between the cyst and the symptoms, some have suggested a definition based on size and a convex contour of the cyst walls.1 Diagnosis

Most often a cavum is an incidental diagnosis at autopsy or on neuroimaging studies, and the prevalence is inversely related to the age of the patient. It has been reported in 100% of normal infants of less than 36 weeks gestation, and in a third of normal term infants.2 Estimates of prevalence in adults have varied widely from < 1–85%, although rates of up to 5% are probably realistic for the general population.3–6 Distinction between cavum septi pellucidi, cavum vergae, and cavum interpositum, which stems from a separation of the crura of the fornix, is generally clear on CT (Fig. 15-43). In case of doubt, MRI is useful (Fig. 15-44).7 Suggestions have been made for an association between a wide variety of clinical conditions and an increased prevalence of cava septi pellucidi and/or vergae. Examples include boxing,8 schizophrenia,9 developmental delay,7,10,11 dyslexia,12 and non-

Fig. 15-43. Axial CT scan showing midline cavum (arrows) between the lateral ventricles.

syndromic cleft lip with or without cleft palate.13 Children with cava septi pellucidi have been reported to show asymmetry and immaturity on EEGs and the differences are detectable by formal analysis.14 There appears to be some level of acceptance that continued postnatal appearance of a cavum may be a marker for some underlying disturbance of brain development and function. Given the wide and age-dependent variation in the estimated prevalence of cava, any such association studies require properly selected control subjects and should be considered in light of rates obtained in larger population series. In a MRI study of 505 non-psychotic individuals, Alder et al.6 found that anomalies of the septum pellucidum were about three times more common in the 0–9 years age group than across other decades, which did not show a trend in prevalence. Overall they obtained a 4.16% rate of cavum septum pellucidum with or without vergae, and there was no significant difference in prevalence between the sexes. Degreef et al.9 found a cavum septum pellucidum (large in two cases) in 14 of 62 (23%) patients with schizophrenia and in 1 of 46 (2%) of controls, whereas Gewertz et al.15 found a cavum in only 1 of 168 psychotic patients who had a cranial CT. In a study of children with developmental delay, Bodensteiner et al.10 found a cavum septum pellucidum in 3 of 124 (2.4%) of normal controls and 38 of 249 (15.3%) of subjects with developmental delay. A cavum vergae was noted in 20.5% and 19.3% of the respective groups. In their study of adult males with facial clefting, Nopoulous et al.13 noted an inverse relationship between the presence and size of the cavum septum pellucidum and IQ. Kim and Peterson16 noted that the cavum septum pellucidum was significantly smaller in children and adults with Tourette syndrome

Brain

Fig. 15-44. Axial MRI showing midline cavum septi pellucidi (arrows).

than among their control population, and that the prevalence of cavum vergae did not differ between the groups. It is this author’s opinion that additional studies with carefully selected subjects and age-matched normal controls, which include detailed, observer blinded, MRI assessment of adjacent areas of the brain, are required to assess the predictive value of the cavum septum pellucidum with respect to neuropsychiatric morbidity. There is consensus that in any such association the cavum is a marker of disturbed function in the adjacent areas of the brain, such as the limbic system, and that it is not a direct cause of the pathology. Cava are normally present during gestation and can provide important landmarks in the ultrasound assessment of the midline. Interpretation of what is considered to be enlargement of a cava is complicated by consideration of other potential causes of midline cysts, as well as issues surrounding normal variation and the uncertain clinical importance of an enlarged cavum. A careful search for associated CNS and extra-CNS anomalies is important. Sahinoglu et al.17 reported three cases of prenatal diagnosis of a dilated cavum vergae. One fetus had an associated meningomyelocele and ventriculomegaly, one required surgery for intracranial hypertension due to continued expansion of the cavum, and one remained asymptomatic. Cava have been noted in a number of reports of chromosome abnormalities and in a large number of syndromes (Table 15-9). The minimal clinical significance of cava has undoubtedly led to their being overlooked and underreported. The prevalence might be greater in syndromes involving midline defects of the CNS. However, for most syndromes there are inadequate data to determine whether a cavum occurs more often than would be expected in the general population.

605

Most authors consider that a cyst of the septum pellucidum (SPC) or cavum vergae is defined as a symptomatic enlargement of a cavum. This definition works well when severity of the symptoms parallels enlargement of the cyst or when symptoms are reduced/ cured by surgical intervention. However, in some instances, such as intermittent headache, the connection between an expanded cavum and the symptoms is less clear, and this has led some to seek different diagnostic criteria. Sener1 used a definition of the septal walls being
10 mm apart and showing a convex (laterally bowed) profile, but concluded that further studies were required to define diagnostic and interventional criteria for cysts of the septum pellucidum. Signs and symptoms that have been attributed to SPC are both chronic and acute and include changes in behavior, hydrocephalus, autonomic and sensorimotor (which may be asymmetric) dysfunction, intermittent or acute headache, papilledema and other neurophthalmologic signs, emesis, and syncope. Onset can be at any age. Lancon et al.55 were able to find 18 patients with SPC that met their strict diagnostic criteria of symptomatic expansion of an existing cavum in concert with neurologic symptoms, which were demonstrated to be relieved by intervention. The age at presentation ranged from 2 months to 61 years with a mean of 46.3 years and 56% presenting over the age of 34 years. Signs at presentation included headache (61%), behavioral and autonomic (67%; 5 of 6 children), sensorimotor/reflexes (56%), neurophthalmologic (50%), syncope (33%), emesis (33%), and papilledema (33%). These symptoms are non-specific and require that other possible intracranial pathology be excluded by detailed neuroimaging. Lancon et al.55 stress the importance of examining the optic chiasm for evidence of compression, and that MR venography should be considered in the presence of sensorimotor, behavioral or autonomic symptoms, or if anomalies in the size or signal characteristics of the basal ganglia and diencephalon are noted. Not all agree with the latter recommendation.56 A number of mechanisms have been proposed to account for the varied neurologic signs and symptoms associated with SPC55: 1) expansion of the cyst, obstructing the interventricular foramina causing hydrocephalus, and possibly compressing the origins of the internal cerebral veins; 2) distortion of adjacent vascular/venous systems of the deep cerebral veins, the internal capsule, and/or the lateral hypothalamus; 3) compression of cerebral nuclei in and around the hypothalamoseptal triangle; and 4) direct compression of the visual pathways. Intermittent signs are assumed to be due to periodic relief of interventricular foraminal obstruction. A case of cavum septum pellucidi obstructing a ventricular shunt has been reported.57 Absence of the septum pellucidum (ASP) is part of the septooptic dysplasia complex (Table 15-9) and usually is accompanied by other, more severe, CNS malformations, notably those involving the midline and/or ventricular system such as absent corpus callosum, holoprosencephaly, schizencephaly and Chiari II malformations.58 Apparently, longstanding hydrocephalus may lead to loss of the septum pellucidum.59 Newer imaging techniques have led to recognition that ASP can occur in otherwise neuroradiologically and clinically normal individuals60 and to its recognition in a number of syndromes (Table 15-9). The MRI hallmark of ASP is a squared-off and pointing appearance of the interior portions of the frontal horns at the level of the foramina of Monro.60 Etiology and Distribution

The development of the septum pellucidum is closely related to that of the corpus callosum and fornix, which it bridges together. The septum pellucidum is formed by the infolding halves of the neural

Table 15-9. Syndromes with cyst or cavum septum pellucidum or absent septum pellucidum as a feature Syndrome

Prominent Features

Causation Gene/Locus

Apert18

Severe craniofacial synostosis, marked syndactyly; developmental delay is common; CNS includes absent corpus callosum, limbic system, microgyria, polymicrogyria, heterotopia, ventriculomegaly, and high rate of abnormal septum pellucidum that may correlate with IQ

AD (101200) FGFR2, 10q25.3-q26

BRESHECK19

Microhydrocephaly with fused thalami, poor growth and mental retardation, alopecia, scaling skin, Hirschsprung, cleft palate, renal anomalies, microphthalmia

AR/XLR

Fetal phencyclidine20

Rhombencephalosynapsis, hypoplastic commissural systems, septo-optic dysplasia with absent septum pellucidum, absent posterior lobe of the hypothalamus, moderate hydrocephalus, abnormal pulmonary venous return, spinal segmentation defect. Mother took phencyclidine in first 6 weeks of pregnancy

In utero exposure?

Holzgreve-Wagner-Rehder21

Type II persistent bucopharangeal membrane, postaxial polydactyly, cleft palate, complex cardiac anomalies, renal agenesis, IUGR, absent septum pellucidum

Unknown (236110)

Marinesco-Sjogren22

Mental retardation, congenital cataracts, cerebellar ataxia, muscle wasting with neurogenic atrophy and vacuolar degeneration, distal weakness, ataxia, cerebellar atrophy mostly of vermis, skeletal anomalies including scoliosis, posterior vertebral scalloping, enlargement of intervertebral foramina, short metatarsals and metacarpals. Case report with arachnoid cyst and absent septum pellucidum

AR (248800), some SARA2, 5q31

Neish-Roberts: hypoplastic left heart23

Wide forehead, abnormal pinnae, bifid nasal tip, micrognathia, thin upper lip, hypoplastic left heart, camptodactyly of fingers and toes, non-obstructive hydronephrosis; absent septum pellucidum in one sib

AR

Oculo-encephalo-hepato-renal24

Epicanthus, nystagmus, ptosis, micrognathia, abnormal external genitalia, syndactyly, postaxial polydactyly, cystic renal dysplasia, cerebellar defects, mental retardation, postnatal growth failure, periodic breathing. Case reported with cerebral dysplasia and absent septum pellucidum.

Unknown

Porencephaly-cerebellar hypoplasia-heart defect25

Prominent metopic suture, bilateral epicanthus, high arched palate, absent septum pellucidum, hydrocephalus, bilateral cortical defects, dilated 4th ventricle, absent vermis, cerebellar hypoplasia, probable porencephaly in one sib, congenital heart defects

AR (601322)

Porencephaly/schizencephalyseptum pellucidum26

Absent septum pellucidum, porencephaly/schizencephaly, mental retardation, neurologic dysfunction including paraplegia

Unknown-case in utero benzol exposure

Septoopticdysplasia27

Septum pellucidum agenesis, optic nerve hypoplasia, hypothalamic/pituitary dysfunction; variable growth hormone deficiency, diabetes insipidus, trophic hormone deficiencies; seizures and developmental delay common; brain anomalies include agenesis of the corpus callosum, hydrocephalus, cerebral atrophy, porencephaly, schizencephaly. The association may be a component of other syndromes28 or seen occasionally in well-established syndromes.29,30

Heterogeneity (182230) some due to HESX1, 3p21.2-p21.1

Third ventricular obstruction31

Hydrocephalus with dilated lateral ventricles and narrowing of posterior 3rd ventricle, polygyria, choroid plexus atrophy, thin corpus callosum, absent septum pellucidum

Unknown

Velo-cardio-facial32

Long narrow face, retrognathia, prominent nose with hypoplastic lip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay; congenital heart; especially conotruncal defects. High prevalence of septal pellucidum anomalies.

AD (192430) del 22q11, del 10p

Walker-Warburg (HARDþ/E)33

Diffuse agyria, cobblestone appearance may be obscured by hydrocephalus, abnormal white matter, laminar heterotopia below cortex, absent septum pellucidum, severe midline to lateral cerebellar hypoplasia, brain stem hypoplasia, Dandy-Walker malformation, cephalocele, retinal dysplasia/non-attachment; microphthalmia, cataract, corneal opacity, hyaloid vessels, retinal corneal opacity, abnormal face; myopathic skeletal muscle with variable size and splitting of fibres with endomysial fibrosis

AR (236670) POMT1, 9q34.1

Prominent supraorbital ridges, heavy eyebrows, broad nasal root, hypertelorism, long mandible, pouting lower lip, basal cell carcinomata, jaw cysts, rib anomalies, palmoplantar pits, calcified falx

AD (109400) PTCH, 9q22.3 PTCH2, 1p32

Syndromes with Absent Septum Pellucidum

Syndromes with Cyst or Cavum Septum Pellucidum

Basal cell nevus34

(continued)

606

Table 15-9. Syndromes with cyst or cavum septum pellucidum or absent septum pellucidum as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Bertini: myoclonic epilepsymacular degeneration35

Hypotonia, congenital ataxia, mental retardation, progressive encephalopathy, recurrent infections, hypoplasia of corpus callosum and cerebellar vermis, septum pellucidum cyst

XLR, Xp22-Xpter

Cataracts-contractures-cortical dysplasia36

Postnatal growth and developmental failure, prominent supraorbital ridge, cataracts, large joint contractures, osteoporosis, cavum septum pellucidum, right temporal arachnoid cyst, cerebellar atrophy, multiple foci of cortical dysplasia in frontal and parietal lobes

AR

Cerebro-facio-thoracicdysplasia37

Mental retardation, macro/brachycephaly, absent corpus callosum, enlarged septum pellucidum, hypertelorism synophrys, bifid and synostosed ribs, narrow chest, elevated scapulas, hemivertebrae, short neck

AR (213980)

Chromosome anomalies38,39

Duplication (1)(q25-qter), (3)(q21-qter), (5)(11.2-q13.3); deletions (3)(pter-p15), (9)(pter-p21), (13)(q22-qter); mosaic trisomy 9, r(22)

Chromosome imbalance

Fetal alcohol40

Microcephaly, narrow palpebrae, smooth philtrum, thin upper lip. CNS anomalies include agenesis of the corpus callosum, cavum septum pellucidum, ventriculomegaly, hypoplasia of inferior olivary eminences, small brain stem, migrational abnormalities; holoprosencephaly an occasional finding with severe abuse.

In utero exposure

Fetal face41

Prominent forehead, wide mouth, small nose, hypertelorism, micropenis, variable mesomelic shortness, vertebral defects, oral clefts. Case with pellucidal cyst.

AD (180700) AR (268310) ROR2, 9q22

G42

Dysphagia, stridor, hypertelorism, prominent forehead, laryngotracheal cleft, tracheoesophageal fistula, hypospadias developmental delay, more severe in males

AD (145410) 22Q11.2 XLR (300000) MID1, Xp22.3

Growth failureencephalopathy-endocrine43

Postnatal onset microcephaly and growth failure, high bossed forehead, flat occiput, upslanting palpebral fissures, high palate, small pointed chin, cortical atrophy. One sib with septum pellucidum cyst, stereotypic movements

AR

Hall-Riggs: coarse face-skeletal dysplasia44

Progressive meta-epiphyseal disorder with severe retardation, flat nasal bridge, large lips, brachydactyly, short arms (microcephaly may be of postnatal onset)

AR (234250)

Macrocephaly-cavum septum pellucidum45

Macrobrachycephaly, developmental delay, cavum septum pellucidum, and cavum vergae

Uncertain

Microphthalmia-linear skin defects46

May have other CNS anomalies including septum pellucidum cyst, absent corpus callosum, colpocephaly, and hydrocephaly; microphthalmia, sclerocornea, linear dermal aplasia usually of the head and neck

XLD, male lethal (209801) del Xp22.3

Morning glory47

Indented and funnel-shaped optic disc with surrounding retinal pigment abnormality. Cases with enlarged optic disc and cavum vergae.

Unknown

Muller: cerebral malformation-hypertrichosis48

Hypertelorism, telecanthus, microphthalmos, small and low-set ears, hypertrichosis, camptodactyly, overlapping fingers, absent swallowing and suck; variable CNS in sibs including macrocephaly, absent corpus callosum, septum pellucidum cyst, cerebellar hypoplasia

AR (213820)

Nasopharyngeal teratoma49

Massive macrocephaly, broad and triangular flat face, hypertelorism, nasopharyngeal hairy polyp through cleft palate, diaphragmatic hernia, DandyWalker cyst, cavum septum pellucidum and vergae

Unknown

Neurofibromatosis 150

Cafe´-au-lait spots, neurofibromata, Lisch nodules, occasional plexiforum neuromas, pseudarthrosis, and diverse complications of tumors; two of five cases with large deletions had cavae

AD (162200) NF1, 17q11.2

Pseudo-TORCH51

Severe retardation and seizures, extensive and variable deep and superficial supratentorial and basal ganglia calcification, hepatosplenomegaly, petechial rash; similar to, and may be allelic with, Aicardi-Goutieres and Cree encephalitis; reported with pellucidal cysts

AR (251290)

Thrombocytopenia-absent radius52

Congenital thrombocytopenia, absent radius with preservation of thumbs, variable additional anomalies. Case with cerebellar hypoplasia, callosal hypoplasia, cavum septum pellucidum

AR (274000)

Sotos: cerebral gigantism53

Early overgrowth with large hands and feet, prominent and high forehead, downslanting palpebrae, long and prominent chin, high palate, somatomedian initially high and falls during first year, variable developmental delay

AD (117550) NSD1, 5q35

Weaver54

High broad forehead, broad nasal root, telecanthus, micrognathia, large ears, accelerated growth and bone age, hypotonia, camptodactyly, prominent finger pads

AR/AD (277590) Heterogeneity Some with NSD1, 5q35, mutations

607

608

Neuromuscular Systems

tube and is present by the third month of gestation.61 The cavum is apparent once the corpus callosum bridges the midline, and the septum pellucidum is usually, but not always, absent in agenesis of the corpus callosum. The cavum normally begins to close in a caudal to rostral sequence by 6 months gestation. A number of theories have been proposed for the origins of the cava. These include a stretching of the rapidly growing lamina terminalis, failure of fusion of the apposing halves of the neural tube, or a secondary cavitation at a site of hemispheric fusion due to cell death as fibers of the corpus callosum bridge the midline.61 Whatever the etiology, most cava probably are simple variations of normal development. Indeed Liss and Mervis62 demonstrated histologically three variations in development of the septum pellucidum: 1) a single midline membrane (50%); 2) two separate apposed membranes (25%); and 3) the two membranes separated by a space (25%). In some cases septal fenestrations were present. There is good evidence that at least some cava are acquired following head trauma. A cavum septum pellucidum has been noted in 18% of boxers.58 Borgdanoff and Natter63 found a cavum septum pellucidum in 5 of 80 (6.25%) of pediatric and 14 of 1914 (0.73%) of adult cranial CT examinations. Nine of the 14 adults were male, and of these, five had been boxers and one had suffered two significant episodes of head trauma as an adolescent. Nishimoto et al.64 observed the gradual post-traumatic development of a cavum septum pellucidum and vergae over a 33-month period in a 29-year-old woman and provided evidence for unidirectional flow of CSF from the 3rd ventricle to the posterior cavum vergae. A case involving a 26-month-old boy who developed progressive hydrocephalus and a cavum septum pellucidum and vergae secondary to venous sinus occlusion is interesting, as there was resolution of the complications with relief of the occlusion. The authors posit that venous hypertension, secondary to the occlusion, disrupted normal resorption of fluid by a pressure gradient involving septal capillaries and veins.65 It has also been suggested that cava may persist as a result of perinatal brain insult, such as meningitis.3 It is not known whether there is a relationship between the underlying developmental anatomy, as described by Liss and Mervis,62 and the propensity to acquire a cavum. The reason why a cavum should expand and become symptomatic is not known. As discussed by Lancon et al.,55 formation of a congenital cyst requires production of fluid that lacks an egress from the cavity, and it seems most likely that it would arise when the septal membranes are unfused and separated. The cyst fluid closely resembles CSF; the caval lining is the same as that of the ventricles62 and has been shown to be capable of secreting fluid.66 Given that some membranes have fenestrations, it is likely that some potential cysts decompress naturally, while others will rupture under tension, through a weakness, or with trauma, and thus self correct. Although there is consensus that hydrocephalus occurs secondary to obstruction by the expanding SPC, the case described previously, and three children in whom hydrocephalus preceded development of the SPC and did not resolve with drainage of the cysts, suggest that this is not always the case.67 True colloid cysts are occasionally seen in the septum pellucidum, but their neuroepithelial lining suggests an origin from cell nests of the invaginating diencephalic roof.68 A symptomatic endodermal cyst of the septum pellucidum has also been successfully treated.69 A set of monozygotic twins concordant for cysts has been reported.70 Absence of the septum pellucidum is estimated to occur with a frequency of 2 to 3 per 100,000,58 but this may well be an underestimate as most cases to date have been ascertained because of their association with other more significant CNS malformations. The etiology and pathogenesis of isolated ASP are unknown.

Prognosis, Treatment, and Prevention

The common cava is by definition asymptomatic, and, although a variety of neurologic complaints have been attributed to their presence, they do not respond to drainage of the cavum. The cavum likely represents a chance finding in the patient who is investigated for an unrelated problem, although it may prove to be a marker for some forms of developmental pathology or acquired trauma. True symptomatic cystic enlargement of a cava, which can result in hydrocephalus, increased intracranial pressure, and a wide spectrum of neurologic symptoms, is uncommon and will usually respond well to procedures that lead to drainage of the cyst. Treatment approaches have included cystoperitoneal, ventriculoperitoneal, cysto-ventriculo-subarachnoid, and cystoventricular shunting, and simple fenestration of the cysts. Externalized shunts run a higher risk of complications such as infection, are not always successful, and could result in an unnecessary continued peritoneal drainage of CSF in a patient without a primary hydrocephalus.56 The current consensus is to use a stereotactic, endoscopic approach to introduce a communication between the cyst and the ventricular system. This may be accomplished with insertion of a cyst-to-lateral-ventricle drain56,71 or by fenestration of the cyst.72,73 Extirpation of a cyst is rarely necessary. The prognosis for selectively and appropriately treated SPC is very good, and some cysts may be ‘‘cured’’ by spontaneous rupture.55,74 Of the 18 patients reviewed by Lancon et al.,55 four resolved spontaneously or at pneumoencephalogram, 10 were treated by craniotomy and fenestration of the cyst to the lateral ventricle, two by percutaneous fenestration, and two by cystoperitoneal shunt. Three recurrences in the craniotomy group were successfully treated by other approaches. At follow-up, 15 patients were asymptomatic, two were improved, and one had stabilized. The ASP by itself is of no significance and is not treatable. However, when found, it is necessary to look carefully for signs of an associated syndrome, notably septo-optic dysplasia, and to rule out additional CNS anomalies. References (Cavum Septum Pellucidum and Vergae) 1. Sener RN: Cysts of the septum pellucidum. Comput Med Imaging Graph 19:357, 1995. 2. Mott SH, Bodensteiner JB, Allan WC: The cavum septi pellucidi in term and preterm newborn infants. J Child Neurol 7:35, 1992. 3. Shaw GM, Alford EC Jr: Cava septi pellucidi et vergae: their normal and pathological states. Brain 92:213, 1969. 4. Garza-Mercado R: Giant cysts of the septum pellucidum. J Neurosurg 55:646, 1981. 5. Aldur MM, Gurcan F, Basar R, et al.: Frequency of septum pellucidum anomalies in non-psychotic population: a magnetic imaging study. Surg Radiol Anat 21:119, 1999. 6. Borgdanoff B, Natter HM: Incidence of cavum septum pellucidum in adults: A sign of boxer’s encephalopathy. Neurology 39:991, 1989. 7. Miller ME, Kido D, Homer F: Cavum vergae: association with neurologic abnormality and diagnosis by magnetic resonance imaging. Arch Neurol 43:821, 1986. 8. Casson IR, Seigal O, Sham, et al.: Brain damage in modern boxers. JAMA 251:2663, 1984. 9. Galarza M, Merlo AB, Ingratta A, et al.: Cavum septum pellucidum and its increased prevalence in schizophrenia: a neuroembryological classification. J Neuropsychiatry Clin Neurosci 16:41, 2004. 10. Bodensteiner JB, Schaefer GB, Craft JM: Cavum septi pellucidi and cavum vergae in normal and developmentally delayed populations. J Child Neurol 13:120, 1998. 11. Soto-Ares G, Joyes B, Lemaitre MP, et al.: MRI in children with mental retardation. Pediatr Radiol 33:334, 2003.

Brain 12. Lampl Y, Barak Y, Gilad R, et al.: Familial dyslexia associated with cavum vergae. Clin Neurol Neurosurg 99:142, 1997. 13. Nopoulos P, Berg S, VanDemark D, et al.: Increased incidence of a midline brain anomaly in patients with nonsyndromic clefts of the lip and/or palate. J Neuroimaging 11:418, 2001. 14. Kacinski M, Kubik A, Augustyn G, et al.: Quantitative analysis of bioelectric activity of both brain hemispheres in children with a cavum septum pellucidum. Przegl Lek 60 (Suppl 1):15, 2003. 15. Gewirtz G, Squires-Wheeler E, Sharif Z, et al.: Results of computerized tomography during first admission for psychosis. Br J Psychiatry 164:789, 1994. 16. Kim KJ, Peterson BS: Cavum septi pellucidi in Tourette syndrome. Biol Psychiatry 54:76, 2003. 17. Sahinoglu Z, Uludogan M, Delikara MN: Prenatal sonographic diagnosis of dilated cavum vergae. J Clin Ultrasound 330:378, 2002. 18. Renier D, Arnaud E, Cinalli G, et al.: Prognostic mental du syndrome d’Apert. Arch Pediatr 3:752, 1996. 19. Reish O, Gorlin RJ, Hordinsky M, et al.: Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate and kidney dysplasia/hypoplasia (BRESEK/BRESHECK). Am J Med Genet 68:386, 1997. 20. Michaud J, Misrahi EM, Urich H: Agenesis of the vermis with fusion of the cerebellar hemispheres, septo-optic dysplasia and associated anomalies. Acta Neuropath 56:161, 1982. 21. Legius E, Moerman PH, Fryns JP, et al.: Holzgreve-Wagner-Rehder syndrome: Potter sequence associated with persistent buccopharyngeal membrane. A second observation. Am J Med Genet 31:269, 1988. 22. Williams TE, Buchhalter JR, Sussman MD: Cerebellar dysplasia and unilateral cataract in Marinesco-Sjogren syndrome. Pediatr Neurol 14:158, 1996. 23. Neish AS, Roberts DJ: Hypoplastic left heart, nephromegaly, and distinctive facies in two siblings. Am J Hum Genet 50:153A, 1992. 24. Ehara H, Tamaoki Y, Eda I: A case in the spectrum of the oculoencephalo-hepato-renal syndrome. Pediatr Neurol 21:757, 1999. 25. Bonnemann CG, Meinecke P: Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 63:428, 1996. 26. Hosley MA, Abroms IF, Ragland RL: Schizencephaly: case report of familial incidence. Pediatr Neurol 8:148, 1992. 27. Burke JP, O’Keefe M, Bowell R: Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol 75:236, 1991. 28. Hayashi M, Sakamoto K, Kurata K, et al.: Septo-optic dysplasia with cerebellar hypoplasia in Cornelia de Lange syndrome. Acta Neuropathol 92:625, 1996. 29. Pagon RA, Stephan MJ: Septo-optic dysplasia with digital anomalies. J Pediatr 105:966, 1984. 30. Gieron-Korthals MA, Helal A, Martinez CR: Expanding spectrum of cocaine induced central nervous system malformations (Case report). Brain Dev 16:253, 1994. 31. Chow CW, McKelvie PA, Anderson RM, et al.: Autosomal recessive hydrocephalus with third ventricle obstruction. Am J Med Genet 35: 310, 1990. 32. van Amelsvoort T, Daly E, Robertson D, et al.: Structural brain anomalies associated with deletion at chromosome 22q11: quantitative neuroimaging study of adults with velo-cardio-facial syndrome. Br J Psychiatry 178:412, 2001. 33. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al.: Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 71:1033, 2002. 34. Gorlin RJ: Nevoid basal-cell carcinoma syndrome. Medicine 66:98, 1987. 35. des Portes V, Marchiani V, Bertini E, et al.: X-linked neurodegenerative syndrome with congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration, linked to Xp22.33-pter. Am J Med Genet 64:69, 1996. 36. Shotelersuk V, Desudchit T, Suwanwela N: Postnatal growth failure, microcephaly, mental retardation, cataracts, large joint contractures,

609

37. 38. 39.

40.

41. 42.

43.

44. 45.

46.

47.

48.

49.

50.

51.

52.

53. 54. 55. 56. 57. 58.

59. 60. 61. 62.

osteoporosis, cortical dysplasia, and cerebellar atrophy. Am J Med Genet 116A:164, 2003. Guion-Almeida ML, Richieri-Costa A, Saavedra D, et al.: Cerebrofaciothoracic syndrome. Am J Med Genet 61:152, 1996. Schinzel A: Catalogue of Unbalanced Chromosome Aberrations in Man, ed 2. Walter de Gruyter, Berlin, 2001. Honer WG, Basset AS, MacEwan GW, et al.: Structural brain imaging abnormalities associated with schizophrenia and partial trisomy of chromosome 5. Psychol Med 22:519, 1992. Bonnemann C, Meinecke P: Holoprosencephaly as a possible embryonic alcohol effect: another observation. Am J Med Genet 37: 431, 1990. Fehlow P, Walther F, Pfeifer T, et al.: Robin-Silverman-Smith (fetal face) syndrome. Klin Paediatr 207:354, 1995. Guion-Almeida ML, Richieri-Costa A: CNS midline anomalies in the Opitz G/BBB syndrome: report on 12 Brazilian patients. Am J Med Genet 43:918, 1992. Cohen LHF, Vamos E, Heinrichs C, et al.: Growth failure, encephalopathy, and endocrine dysfunction in two siblings, one with 5oxoprolinase deficiency. Eur J Pediatr 156:935, 1997. Silengo M, Rigardetto R: Hall-Riggs syndrome: a possible second affected family. J Med Genet 37:886, 2000. Sanchez O, Nastasi J, Escalona J, et al.: Two male siblings with cavum septum pellucidum, cavum vergae, macrocephaly, seizures and mental retardation. A new hereditary syndrome. Clin Dysmorphol 6:129, 1997. Kayserilli H, Cox TC, Cox LL, et al.: Molecular characterization of a new case of microphthalmia with linear skin defects (MLS). J Med Genet 38:411, 2001. Okada K, Sakata H, Shirane M, et al.: Computerized tomography of two patients with morning glory syndrome. Hiroshima J Med Sci 43:111, 1994. Muller F-M, Barth GM, Menger H, et al.: Cerebral malformation, seizures, hypertrichosis, distinct face, claw hands, and overlapping fingers in sibs of both sexes. Am J Med Genet 47:698, 1993. Aughton DJ, Sloan CT, Milad MP, et al.: Nasopharyngeal teratoma (‘hairy polyp’), Dandy-Walker malformation, diaphragmatic hernia, and other anomalies in a female infant. J Med Genet 27:788, 1990. Korf BR, Schneider G, Poussaint TY: Structural anomalies revealed by neuroimaging studies in the brains of patients with neurofibromatosis type 1 and large deletions. Genet Med 1:136, 1999. Knoblauch H, Tennstedt C, Brueck W, et al.: Two brothers with findings resembling congenital intrauterine infection-like syndrome (pseudo-TORCH syndrome). Am J Med Genet 120A:261, 2003. MacDonald MR, Schaefer GB, Olney AH, et al.: Hypoplasia of the cerebellar vermis and corpus callosum in thrombocytopenia with absent radius syndrome on MRI studies. Am J Med Genet 50:46, 1994. Wit JM, Beefier FA, Barth PG, et al.: Cerebral gigantism (Sotos syndrome): compiled data of 22 cases. Eur J Pediatr 144:131, 1985. Ardinger HH, Hanson JW, Harrod MJE, et al.: Further delineation of Weaver syndrome. J Pediatr 108:228, 1986. Lancon JA, Haines DE, Raila FA, et al.: Expanding cyst of the septum pellucidum. Case report. J Neurosurg 85:1127, 1996. Krauss JK, Mundinger F: Cavum septum pellucidum cysts. J Neurosurg 87:337, 1997. Mapstone TB, White RJ: Cavum septi pellucidi as a cause of shunt dysfunction. Surg Neurol 16:96, 1981. Barkovich AJ, Norman D: Absence of septum pellucidum: A useful sign in the diagnosis of congenital brain malformation. Am J Neuroradiol 9:1107, 1988. Sarwar M: The septum pellucidum: normal and abnormal. AJNR Am J Neuroradiol 10:989, 1989. Kuhn M, Swenson LC, Youssef HT: Absence of the septum pellucidum and related disorders. Comput Med Imaging Graph 17:137, 1993. Rakic P, Yakovlev PI: The development of corpus callosum and cavum septi in man. J Comp Neurol 132:45, 1968. Liss L, Mervis L: The ependymal lining of the cavum septi pellucidi: a histological and histochemical study. J Neuropathol Exp Neurol 23:355, 1964.

610

Neuromuscular Systems

63. Bogdanoff B, Natter HM: Incidence of cavum septum pellucidum in adults: a sign of boxer’s encephalopathy. Neurology 39:991, 1989. 64. Nishimoto H, Wada T, Kuroda K, et al.: A case of the development of cavum vergae after head trauma. No Shinkei Geka 31:297, 2003. 65. Sencer A, Sencer S, Turantan I, et al.: Cerebrospinal fluid dynamics of the cava septi pellucidi and vergae. Case report. J Neurosurg 94:127, 2001. 66. Lancon JA, Haines DE, Lewis AI, et al.: Endoscopic treatment of symptomatic septum pellucidum cysts: with some preliminary observations on the ultrastructure of the cyst wall: two technical case reports. Neurosurgery 45:1251, 1999. 67. Wester K, Krakenes J, Moen G: Expanding cava septi pellucidi and cava vergae in children: report of three cases. Neurosurgery 37:134, 1995. 68. Ciric I, Zivin I: Neuroepithelial cysts of the septum pellucidum. J Neurosurg 43:69, 1975. 69. Mishra GP, Sharma RR, Musa MM, et al.: Endodermal cyst of the septum pellucidum and pregnancy: a case report. Surg Neurol 53:583, 2000. 70. Craig WM, Miller RH, Holman CB: Cysts of the septum pellucidi. Interesting case reports. Proc Staff Meet Mayo Clinic 28:330, 1953. 71. Wester K, Pedersen PH, Larsen JL, et al.: Dynamic aspects of expanding cava septi pellucidi et vergae. Acta Neurochir (Wien) 104:147, 1990. 72. Jackowski A, Kulshresta M, Sgouros S: Laser-assisted flexible endoscopic fenestration of giant cyst of the septum pellucidum. Br J Neurosurg 9:527, 1995. 73. Donati P, Sardo L, Sanzo M: Giant cyst of the cavum septi pellucidi, cavum vergae and veli interpositi. Minim Invasive Neurosurg 46:177, 2003. 74. Kocer N, Kantarci F, Mihmalli I, et al.: Spontaneous regression of a cyst of the cavum septi pellucidi. Neuroradiology 42:360, 2000.

Table 15-10. Classification of hydrocephalus A. Hypersecretion 1. Choroid plexus papillomas—hydrocephalus of ventricles and basal cisterns B. Mechanical obstruction 1. At foramen of Monro a. Neoplasia b. Ventriculitis c. Ventricular hemorrhage d. Primary aplasia of foramen* 2. At the 3rd ventricle a. Stenosis* b. Neoplasia either by direct invasion or compression c. Obstruction by congenital cysts i. Choroid plexus{ ii. Neuroepithelial 3. At the aqueduct (the most common site of obstruction) a. ‘‘Congenital’’ stenosis/atresia, including membranous* b. ‘‘Acquired’’ stenosis/atresia (post necrosis, meningitis, hemorrhage) c. Direct occlusion by vascular malformation d. External compression i. Arteriovenous malformation—vein of Galen ii. Cysts in cisterna ambiens: arachnoid,{ glioependymal{

15.8 Hydrocephalus

4. At the cerebellar foramen a. Without caudal displacement of the cerebellum i. Neoplasia

Definition

ii. Dandy-Walker malformation{

Hydrocephalus is an increase in the volume of the intracranial cerebrospinal fluid (CSF)–containing space relative to that of the cerebral parenchyma and may result from both primary atrophy of cerebral parenchyma and fluid production that exceeds resorption and any compensatory mechanisms. The latter is the subject of this section and usually results in an increased pressure hydrocephalus, although normal, and even low-pressure hydrocephalus can occur. The former produces hydrocephalus ex vacuo, which may be complicated by a secondary pressure hydrocephalus, but is not covered in this section. A distinction should also be made from hydranencephaly (Section 15.10), in which only remnants of the cortex remain and the rest is replaced by fluidfilled sacs lined by leptomeninges, and from porencephaly (Section 15.11), in which the parenchyma contains one or more fluid-filled cavities that may result from either a primary abnormality of development or a secondary enclastic process. This section is concerned with congenital malformations that lead to hydrocephalus; several malformations that are often associated with hydrocephalus are covered in their own sections. However, Table 15-10 provides a general classification, as modified from Friede,l in order to provide an overall context. Those types considered in more detail in this section are noted.

iii. Retrocerebellar arachnoid cyst{

Diagnosis

In brains of lower animals and that of the early embryo, there is no connection between the CSF and meningeal spaces, and circulation is via the brain parenchyma. As the brain develops and thickens, this mechanism no longer suffices, and CSF circulation is dependent on the development and integrity of the cerebral foramina, subarachnoid space, and resorptive processes. In the

iv. Infratentorial subdural hematoma b. With caudal displacement of the cerebellum i. Acute cerebellar tonsillar herniation ii. Arnold-Chiari malformation(s){ 5. At the level of the subarachnoid space a. Non-canalization as a primary anomaly (speculative) b. Acquired fibrotic obstruction (most common cause) i. Organized fibropurulent exudate ii. Organized subarachnoid hemorrhage iii. Organized necrotic debris or protein exudates iv. Abnormal storage such as mucopolysaccharidoses c. Abnormalities of arachnoid granulations/villi i. Congenital absence of granulations* ii. Acute hemorrhagic block (speculative) C. Functionally impaired CSF resorption 1. Altered CSF colloid osmotic pressure (no firm evidence) 2. Increased venous pressure (perhaps on transient basis) 3. Large arteriovenous shunts (scattered case reports) D. Hydrocephalus associated with bony dysplasia* *Discussed in this section. {

Discussed in sections 15.13–15.14.

Brain

normal brain there is a marked excess of resorptive capacity over normal levels of CSF production,2 and an increased production of CSF is matched by a concomitant increased resorption.3 There is also some evidence of a fall in CSF production with increasing pressure, although production continues in the face of high pressures.1,4 The production of CSF is under stimulatory sympathetic and inhibitory cholinergic enervation, and several other CSF compounds and their receptors also play a controlling role.5 The traditional view that there is a continuous flow of CSF from the choroid plexus to the arachnoid (pachionian) granulations, and that hydrocephalus results from an excess of CSF production over resorption, has been recently challenged by a review of the extant literature,6 clinical experience,7 and newer neuroimaging and experimental approaches.7–9 Johnson and Papaiconomou7 suggest that the extracranial lymphatic system may play a far greater role in CSF absorption than was previously credited. Protein tracers injected into brain interstitial space or ventricles exit the cranium via perineural extensions of the subarachnoid space and appear in spinal lymph nodes and lymphatic vessels. The cribiform plate and nasal mucosa may be important components of this pathway.7 Greitz et al.9 have examined the possibility that CSF is reabsorbed into the venous system of the brain. Flow-sensitive MR methods have shown that what was interpreted as the bulk flow of CSF in standard radionuclide cisternography is due to pulsatile mixing of the tracer, combined with its dilution by the egress of new CSF at the foramina of Lushka and Magendie.8 Notwithstanding the relative impermeability of the blood–brain interface, there is evidence that there is no such brain–blood barrier,9 and indeed that there is an active transport involved at that interface.10 Cardiac systole causes cerebral arterial expansion, compression of cerebral veins, and an increased sinus flow, thus forcing CSF into the spinal cord. The latter is reversed during diastole, again tending to collapse the cerebral veins. It has been hypothesized that pressure on the venous outlets causes inflation of the veins, leading to less resistance and increased flow, and that compression of the pachionian granules into the veins may cause them to act as valves, again aiding venous circulation.9 Thus, these investigators propose a return to the original views of the early 1900s that hydrocephalus is an essentially vascular process, which Greitz et al.9 propose to group as primary and secondary hemodynamic disturbances. They call the former, which presents as communicating hydrocephalus, restricted arterial pulsation type, and it arises from any cause of reduced arterial pulsations, such as diminished arterial compliance, and decreased compliance of the arachnoid space (e.g., arachnoiditis, Chiari malformations). Intracranial pressure is normal to slightly increased with intermittent high pressure waves. Expansion of the ventricles is considered due to a rise in the normal ventricular to subarachnoid gradient, which is transmitted into the brain parenchyma. Secondary or venous congestion hydrocephalus is the typical obstructive, high-pressure hydrocephalus. In this case there is an excess of CSF production over resorption because of a block to outflow (e.g., aqueductal stenosis, tumor mass); the resulting mass effect of the expanding ventricles compresses the cortical veins, raising intracranial blood volume, and thus pressure. This hemodynamic concept of hydrocephalus provides a basis for understanding cases of hydrocephalus that occur with extracranial lesions, such as a tumor compressing the superior vena cava.11 Notwithstanding the varied causes and mechanisms of hydrocephalus, its diagnosis rests on recognition of the signs and symptoms of increased intracranial pressure, and/or decreased cerebral blood volume and flow, which vary with the age of the patient and the severity of involvement.

611

Increased use of routine and high-risk obstetric ultrasound has meant that increasing numbers of fetuses are being diagnosed as having ventriculomegaly; both bilateral and unilateral. The prenatal diagnosis of unilateral ventriculomegaly requires that both cerebral hemispheres be well visualized as both acoustic noise in the cortex proximal to the transducer and some reverberation artifacts in the distal hemisphere may lead to a false-positive diagnosis.12 Although the fetal cranial sutures are open, in the presence of hydrocephalus, significant ventricular enlargement and parenchymal compromise may occur before there is evidence of an abnormal increase in biparietal diameter. Thus, the diagnosis of fetal hydrocephalus rests on intracranial measurements, including comparison of the lateral ventricle to hemisphere ratio (LV/H) with nomograms,13 a search for separation of the choroid plexus from the ventricular wall (dangling choroid), and direct measurement of the ventricular diameters. A lateral ventricular atria diameter of >10 to 15 mm (from 15 to 35 weeks) and/or a choroid separation of >3 and  8 mm is an accepted definition of mild ventriculomegaly.14 It must be emphasized that mild to moderate in utero ventriculomegaly is often non-progressive and ultimately will not require treatment. Providing genetic counseling to couples whose fetus has been found to have mild ventriculomegaly is fraught with uncertainty (vide infra). Mention should be made of what some term as benign external hydrocephalus in which the postnatal presentation is with macrocephaly, a squared forehead, symmetrical enlargement of the frontal horns, and enlarged subarachnoid spaces over the anterior part of the cerebral hemispheres.15 It is interesting that the prenatal presentation of this condition is with mild and asymmetric posterior ventriculomegaly, a normal biparietal diameter, with either contralateral, ipsilateral, or bilateral posterior enlargement of the subarachnoid spaces.15 The condition is most often idiopathic but it may accompany skeletal dysplasia, intraventricular hemorrhage, and storage disorders. Most, but not all, cases of hydrocephalus that occur because of a congenital malformation will present by childhood, during which time the sutures and cranium remain elastic and subject to expansion. Thus, the most important signs of untreated hydrocephalus in the infant and child are those of macrocrania and, more importantly, an occipitofrontal circumference (OFC) that upwardly crosses centiles. Raised intracranial pressure in the adult occurs in an enclosed space with relatively little capacity to accommodate changes in pressure, and the classic presentation is that of headache, vomiting, and papilledema. More unusual presentations, including endocrine disturbance and secondary amenorrhea, may occur.16 The presentation of hydrocephalus in childhood is extremely varied. Almost one-half may be asymptomatic, but a large proportion will have some combination of irritability, headache, and vomiting.17 More subtle presentation with mild developmental delay, personality change, unsteady gait, seizures, or endocrine dysfunction may occur in the older child.18 The most important clinical signs include increasing head circumference, a tense fontanel, widened sutures that may be visible on routine skull radiographs, distended scalp veins and sparse hair, loss of upward gaze, and a retracted or rigid neck (Fig. 15-45).17 As the cranium expands it often assumes a characteristic shape, with prominent frontal and rounded parietal regions. Normally, when in the sitting position, an infant’s anterior fontanel is sunken and pulsates. With increasing pressure, it begins to bulge and lose its pulsation. Again, a more gradual presentation with a disinterested dull affect, increased deep tendon reflexes, especially in the lower limbs, and papilledema and other neurologic signs may occur.19

612

Neuromuscular Systems

Fig. 15-45. Facial view of a 5-month-old infant with a large head secondary to hydrocephaly. The infant had a number of other malformations as well, and chromosome analysis showed mosaicism for trisomy 9. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

A number of neuro-ophthalmologic signs, including abducens, trochlear, and occasionally oculomotor palsies, amblyopia due to long-standing papilledema, and optic atrophy, as well as loss of upward gaze, the ‘‘setting sun’’ sign, may be seen.20 The setting sun sign is characterized by downward displacement of the eyes with exposure of the sclera. Some have argued that this is due to the effect of increased intracranial pressure on the orbital roofs while others have argued that it is due to direct pressure on the quadrigeminal plate.4 Corbett20 reviewed the chronology of this dorsal midbrain syndrome, which is seen most characteristically with aqueduct stenosis and aneurysm of the vein of Galen. It begins with dissociation between the pupillary response during accommodation and its response to light, followed by lid retraction and paresis of upward gaze, the ‘‘setting sun’’ sign. He concurs with the view that aqueductal dilation leads to an increase in periaqueductal pressure, which in turn decreases local cerebral blood flow and causes fiber dysfunction. Thus, actual fiber stretching would not be required. It bears emphasizing that almost one-half of the children with clinical signs of hydrocephalus are asymptomatic and, more importantly, that up to 15% of children with symptoms will have no clinical signs of increased intracranial pressure. This has led Kirkpatrick et al.17 to advocate a high index of suspicion for hydrocephalus and to advocate early use of direct measurement of intracranial pressure. This view is supported by unusual case presentations, for example, a child whose only signs were the sudden onset of episodic torticollis and screaming, and who required long-term intracranial pressure monitoring to demonstrate the increased intracranial pressure.21 Routine skull radiographs may show relative macrocrania, splayed sutures, changes in the position of the torcular, thinning of the calvarium and supraorbital ridges, flattening of the cranial base, and, in long-standing cases, digital impressions (Fig. 15-46).

Fig. 15-46. Lateral radiograph of infant with hydrocephalus showing macrocranium, widened sutures, and large fontanel.

Neuroimaging techniques, including ultrasonography in the young infant, radionuclide flow studies, CT (Fig. 15-47), and MRI, will readily establish the diagnosis and generally detail the site of the abnormality. Specific neuroimaging findings will Fig. 15-47. Axial cranial CT scan showing enlarged lateral and third ventricles in a patient with aqueductal stenosis.

Brain

usually allow distinction between true hydrocephalus and hydrocephalus ex vacuo. In the former the temporal horns are dilated relative to the bodies of the lateral ventricles, and there is dilation of the anterior and posterior recesses of the 3rd ventricle and a short mamillopontine distance.22,23 Finally, there is a decreased ventricular angle and increased frontal horn radius, as opposed to an increased ventricular angle and decreased frontal horn radius seen in the latter.22 If the question remains unclear, a number of invasive studies may provide further information.22 The importance of distinguishing between severe (or ‘‘maximum’’) hydrocephalus and hydranencephaly is discussed in the section on hydranencephaly (Section 15.10). Venkataramana et al.24 reported that brain stem auditory evoked responses were abnormal in up to 95% of untreated children with hydrocephalus. Total absence of response was more common in communicating hydrocephalus. The formation of cerebral gyri allows an enlarging cortex to be contained within a confined space. Early hydrocephalus that expands the cranium provides a larger cavity to accommodate the growing brain and may be associated with numerous irregular convolutions (Fig. 15-48). This ‘‘polymicrogyria’’ does not show the microscopic pathology of true polymicrogyria, and indeed thinning of the cortex to as little as 2 cm can occur, at least initially, without significant loss of cortical parenchyma. Specific malformations, as listed in Table 15-10 as causing hydrocephalus, and which are not covered in other sections of the chapter, are now considered in more detail. 15.8.1 Aplasia of the Foramen of Monro

Friede1 questioned whether true aplasia occurs, but several putative cases have been reported. Involvement is of the lateral

613

ventricles and, when only one foramen is involved, will present the uncommon picture of unilateral hydrocephalus and herniation across the midline. Several cases have been diagnosed in utero, and all have presented early.25–27 Obstruction at this level may be characteristic of the Chudley-McCullough syndrome (Table 15-11). 15.8.2 Stenosis of the Third Ventricle

In this uncommon condition, obstruction at the level of the third ventricle leads to dilation of the lateral ventricles, while the third ventricle remains narrow. Obstruction at this level can occur on a genetic basis and may represent a spectrum of stenosis involving the third ventricle and/or aqueduct and/or fourth ventricle.28 15.8.3 Congenital Aqueduct Stenosis/Atresia

This is the most common lesion causing congenital hydrocephalus and may occur alone or as a component of a number of syndromes (Table 15-11). There continues to be significant confusion concerning the descriptive pathologic anatomy, uncertainty as to the underlying pathogenic mechanisms, and even questions as to whether aqueductal stenosis is a primary cause of, or rather is secondary to, hydrocephalus.29 Thus, although the concept of distinguishing stenosis due to malformation from that secondary to acquired obstruction may be helpful intellectually, in most cases the differentiation cannot be made. The aqueduct is the narrowest portion of the CSF spaces, and the adult shape, which is not significantly different from that of the newborn, results from gradual narrowing due to growth of the surrounding tissue. The embryology is summarized in several sources.1,4 The normal aqueduct is characterized by marked

Fig. 15-48. Left: Medial view of the right cerebral hemisphere with dilation of the lateral ventricle (LV) due to aqueductal stenosis. M, midbrain; A, anterior. Right: Coronal section from the cerebral hemispheres from a 5-month-old infant with severe dilation of the cerebral ventricles (V) and marked atrophy of the cerebral cortex. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Table 15-11. Syndromes with hydrocephalus as a feature Syndrome

Prominent Features

Causation Gene/Locus

Variable expression, Dandy-Walker, cerebellar hypoplasia, cleft palate, congenital heart defect, rigidly extended fingers lacking flexion creases

AD (147800)

Achondroplasia47

Rhizomelic short stature, low nasal bridge, prominent forehead, trident hand, short cranial base, small foramen magnum, narrowed lumbar interpeduncular distance, short tubular bones; megalencephaly may relate to mild undetected hydrocephalus

AD (100800) FGFR3, 4p16.3

Acrania48

Absent calvarial bones; brain anomalies include absent pituitary, hydrocephalus, holoprosencephaly, cerebellar hypoplasia; often misinterpreted prenatally as encephalocele; cleft lip/palate, congenital heart defects, omphalocele, and NTD often concurrent

Unkown

Acrofacial dysostosisintermediate severity49

Malar, maxillary, and mandibular hypoplasia; downslanting palpebrae, absent eyelashes; lateral and typical facial clefts; macrostomia; abnormal ears; mesomelic dysostosis; congenital heart; hydrocephaly, polymicrogyria

Unknown

Acrofacial dysostosis-type Rodriguez50

Severe acrofacial dysostosis, congenital heart defects, absent lung lobation, small kidneys; variable limb anomalies include short limbs, absent fibulae, oligodactyly; hypoplastic scapulae; hydrocephalus, agenesis of the corpus callosum

AR (201170)

Acromesomelic frontonasal dsplasia51

Epibulbar dermoid, cleft nose, notched alae, midline cleft lip/palate, renal anomalies, pre- and post-axial polydactyly, delayed development; CNS includes absent corpus callosum, Dandy-Walker, hydrocephalus, encephalocele

Unknown

Albinism-eye defectshydrocephalus52

Developmental delay, trigonocephaly, oculocutaneous albinism, megalocornea, retinal coloboma, congenital hydrocephalus

Unknown

al-Gazali: anterior segmentskeletal anomalies53

IUGR, large and clouded cornea, downslanting palpebrae, cleft lip, small mouth, contractures at large joints, talipes equinovarus, congenital heart defect, osteopenia, long ulnas and fibulas, bowed radius; 1 of 4 had hydrocephalus

AR

al-Gazali: webbed neck-face dysmorphia54

Growth and developmental delay, short webbed neck, low-set ears, downslanting palpebrae, arched eyebrows, hypoplastic supraorbital ridges, large nose, pectus carinatum/excavatum, cardiac septal defects, 5th finger clinodactyly; 1 of 4 had hydrocephaly

AR

Amelo-cerebrohypohydrotic55

Can show normal early development, variable regression, and seizures; can have ataxia, amelogenesis imperfecta, broad thumbs, and great toes; CNS includes hypoplasia of cerebellar vermis and dilation of the lateral ventricles

AR (226750)

Aminopterin-like56

Cranial ossification defect, upswept frontal hair, hypertelorism, prominent nasal root, low and rotated ears, digital defects, variable delay (obstruction at 3rd ventricle)

Possible AR

Aminopterin, prenatal57

Parietal/frontal bone defects, brachycephaly, widow’s peak, upswept hair, narrow palpebrae, prominent long nose, short stature, anomalies of palate, ears, distal limbs, digits

Prenatal drug exposure

Amniocentesis trauma58

Few reports have appeared of fetal damage following 2nd-trimester amniocentesis. This case of hydrocephalus and subarachnoid cyst followed non-ultrasound guided testing.

Physical trauma

Amniotic bands59

Disruptions may involve craniofacies, trunk, or limb, and clefts often do not follow the normal plains of embryologic fusion. Cases have been described with internal anomalies, including of the brain with aqueduct dysgenesis

Disruption (217100)

Aniridia-renal anomalies60

Partial aniridia, glaucoma, hypertelorism, hypotonia, mental retardation, frontal bossing, short stature, renal anomalies. Similar to that described by de Hauwere et al.113

AR (206750)

Anophthalmia-cleft lip/ palate61

Cutis aplasia, macrocephaly, hypopituitarism, hydrocephalus with ‘‘grape-cluster’’ ventricular system

Anophthalmia-nasal proboscis62

Macrocephaly, hydrocephalus, craniosynostosis, anophthalmia, and proboscis-like nose; 1 of 2 unrelated girls had frontal encephalocele

Unknown (605627)

Anterior chamberhydrocephalus-heart defect63

Peters anomaly, persistent hyaloid artery, unilateral absent lens, obstructed aqueduct of Sylvius, enlargement of the lateral and 4th ventricles, cerebellar, pontine, and medullary atrophy, porencephaly, tricuspid valve dilation, atrial septal defect, lethal

Unknown

Antley-Bixler296

Brachycephaly, craniosynostosis, large fontanelle, midface hypoplasia, proptosis, choanal atresia/stenosis, radioulnar stenosis, femoral bowing, less frequent internal anomalies, hydrocephaly in 17%, case with AC-I

AR (207410) POR, 7q11.2

Aase-Smith

46

(continued)

614

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Apple peel atresia-ocular anomalies-microcephaly64

Marked microcephaly, developmental delay, variable eye anomalies include anterior chamber and microphthalmia, apple peel jejunal atresia; postnatal growth failure and hydrocephalus

AR (243605)

Aqueductal stenosisautosomal dominant65

Mild hydrocephalus in mother and two sons; no mutation in L1CAM

AD

Aqueductal stenosisautosomal recessive66

Inherited aqueductal stenosis is usually X-linked recessive but is sometimes inherited as an autosomal recessive trait.

AR (236600) 6q25-6qter

Aqueduct stenosis-basilar impression67

Clinically different from typical XLR aqueductal stenosis in that onset was in adulthood and associated with basilar impression.

XLR? (307000?)

Atelosteogenesis type III68

Broad forehead, hypertelorism, flat nasal bridge, cleft palate, bowed and rhizomelic limbs, absent or hypoplastic fibulae, multiple joint dislocations, platyspondyly, scoliosis, coronal and sagittal vertebral clefts and segmentation defects, short humeri with distal tapering; abnormal size, ossification and morphology of phalanges; 50% neonatal mortality due to respiratory and feeding problems, and hydrocephalus

AD (108721) FLNB, 3p14.3

Axenfield-Riegerleptomeningeal calcification69

Mild mental retardation, short stature, Axenfeld-Rieger eye anomaly, leptomeningeal calcification, non-obstructive hydrocephalus; one sib each with epilepsy, sensorineural deafness, significant recurrent bilateral iridocyclitis

AR

Axial mesodermal dysplasia70

A spectrum of distal vertebral, lower limb, urogenital, and usually anal stenosis/ atresia; case patient also had epibulbar dermoid, pre-auricular tags, heart defect, webbed neck, and hydrocephalus

Unknown

Barnicoat: ‘‘overgrowth’’polysyndactyly71

Birth weight and OFC >97%, coarse appearance, flat nasal bridge, short neck, large shoulder cavernous hemangioma, slender long bones, four limb bilateral postaxial polydactyly, 3-4 zygodactyly of hands

Unknown

Basal cell nevus72

Prominent supraorbital ridges, heavy eyebrows, broad nasal root, hypertelorism, long mandible, pouting lower lip, basal cell carcinomata, jaw cysts, rib anomalies, palmoplantar pits, calcified falx

AD (109400) PTCH, 9q22.3 PTCH2, 1p32

Beemer: dense bones73

Dense bones, ambiguous genitalia, bulbous nose with broad root and bridge, cardiac lesions, minor face dysmorphia, communicating hydrocephalus

AR (209970)

Bellini: epimetaphyseal dysplasia-mental retardation74

Moderate mental retardation, disproportionate short stature, knee contractures with wedge-shaped epiphyses, primarily lower limb metaphyseal dysplasia, platyspondyly; one brother with sparse hair, hydrocephalus

AR/XLR

Bijlsma: aqueductal stenosis75

Cleft palate, hypoplastic mandible, long fingers, club feet, finger contractures, myopia, narrow palpebrae. Father with camptodactyly, mother with cleft lip

Unknown

Bone fragility-proptosis76

Postnatal compression fractures, demineralization and diaphyseal fractures, orbital synostosis, frontal bossing, growth failure, enamel hypoplasia

Unknown

BRESHECK77

Microhydrocephaly with fused thalami, growth and mental retardation, alopecia, scaling skin, Hirschsprung, cleft palate, renal anomalies, microphthalmia

AR/XLR

Brooks: XLMR-distinctive face78

Triangular face, bifrontal narrowing, cupped and low-set ears, malar flattening, deep-set eyes, short palpebrae, epicanthus inversus, bulbous/beaked nose, short and flat philtrum, mild joint contractures at knees/elbows, spasticity, variable nystagmus/mild optic atrophy, enlarged ventricles; one case partial agenesis corpus callosum

XLR

Campomelia-ankyloglossia79

Multiple rib fractures, tongue adhesions to palate, cleft palate, micrognathia, severe angulation of long bones, digital contractures.

Unknown

Campomelic dysplasia80

Macrocephaly, micrognathia, flat nasal bridge, cleft palate, laryngomalacia, bowed femur and tibia, narrow chest, cardiac and renal defects common, ambiguous genitalia in most males; characteristic radiographic changes; hydrocephalus in ~10%

AD (114290) SOX9, 17q24q-25

Cardiac fibromahydrocephalus-cleft lip/ palate81

Myocardial fibromas causing death, cleft lip/palate, cyst of the olfactory lobe, mild communicating hydrocephalus, thin corpus callosum

Unknown

Cardio-facial-cutaneous82

Facial appearance resembles Noonan syndrome; sparse, friable, curly hair; bitemporal narrowness; dry and hyperkeratotic skin; frequent ptosis, strabismus and nystagmus; pulmonary stenosis most common congenital heart defect

Uncertain (115150)

(continued)

615

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Carpenter-Hunter: micromelia-polysyndactyly83

Severe short-limbed dwarfism, encephalocele, marked hypertelorism, microphthalmia, absent external nares, cleft palate, micrognathia, narrow chest, cardiac malformation, cystic dysplasia of the kidneys and pancreas, post-axial polydactyly of hands and feet, duplicated tibia, hydrocephalus, pachygyria

Unknown

Cataract-ossified pinnae84

Short stature, downslanting palpebrae, palate mass, large ears, deafness, distal wasting/contractures radiographic lucencies, severe mental retardation

Unknown

Caudal appendage-short terminal phalanges85

Monozygous twin with ‘‘tail,’’ short stature, short terminal phalanges, mixed deafness, developmental delay, initial normal OFC, arrested hydrocephalus, then microcephaly

Unknown

Centromere instabilityimmunodeficiency86

Facial dysmorphia, skin and respiratory infections, hypogammaglobulinemia, decreased T cells, chromosome centromeric instability, multiradial formation

AR (242860) Some DNMB3B, 20q11.2

Cephalothoracic lipodystrophy-deafness87

Barraquer-Simons-type cephalothoracic lipodystrophy in a woman with deafness and hydrocephalus

Unknown

Cerebellar hypoplasia-brain stem calcification88

Sib fetuses with cerebellar aplasia, dilated ventricles, aqueductal stenosis in one, necrosis and calcification in the brain stem and cortex, cortex contained foamy macrophages and prominent vascularity

AR

Cerebroarthrodigital89

Extreme IUGR, microcephaly or hydrocephaly, severe arthromyodysplasia, budlike digits with hypoplastic to absent nails, long bone shortness, sacral vertebral anomalies, little active range of motion, postnatal growth failure

Unknown

Cerebro-oculo-nasal90

Macrobrachycephaly, craniosynostosis, anophthalmia, nares separated by a midline groove, nasal skin appendages, low-set ears. The other girl had a single maxillary central incisor, case reported with agenesis of the corpus callosum; other CNS not well documented but may include hydrocephalus, frontal encephalocele, holoprosencephaly, Dandy-Walker cyst

Unknown

Chondrodysplasia-callosal agenesis-thrombocytopenia91

Rhizomelia, hypertension, thrombocytopenia, flat nasal root, anteverted nasal tip, wide metaphyses, platyspondyly, deficient dorsal ossification centers of vertebrae, agenesis of the corpus callosum, severe hydrocephalus

Unknown (166990)

Chromosome aberrations92,93

Reported in a wide range of deletions and duplications (over 50 in ref 93), generally with associated malformations, developmental delay, and dysmorphic features

Chromosome imbalance

Chromosome 14 maternal disomy94

Macrocephaly, short to tall stature, obesity common, normal or impaired intelligence, communicating hydrocephalus that may resolve, premature puberty, small testes, hyperextensible joints

Maternal disomy

Chudley-McCullough: hydrocephalus-deafness95

Normal intellect, non-dysmorphic, obstruction at foramen of Monro, severe bilateral sensorineural hearing loss; recent reports with ACC suggest it is same as Hendriks syndrome137

AR (604213)

Ciliary akinesia/ dyskinesia96,97

Abnormal function of cilia cause respiratory infection, bronchiectasis, and sperm dysfunction; mental retardation and hydrocephalus (ependymal cell dysfunction) run in some families; Kartagener syndrome has associated abnormalities of laterality

AR (242650), DNAH5, 5p15-p14 DNAH11, der 7 DNAI1, 9p21-p13 CILD2, 19q13.3-qter

Clefting-corneal opacity98

Growth and developmental delay, cleft lip/palate, hypertelorism, colobomas, optic atrophy, spasticity, cardiac murmur, overlapping fingers and toes (aqueduct stenosis)

AR

Coffin-Lowry99

Mental retardation, prominent forehead and supraorbital ridges, downslanting palpebrae, hypertelorism, low nasal bridge with thick septum, small and anteverted nares, full and patulous lips, everted lower lip; soft, hyperextensible, and tapering fingers; non-specific radiographic changes, progressive kyphoscoliosis; true hydrocephalus uncommon

XLD (303600) RDS6KA3, Xp22.2

Craniofacial conodysplasia100

Macrocephaly, frontal bossing, flat nasal bridge, telecanthus, midface hypoplasia, prognathism, acrodysostosis, hypertonia, short proximal phalanges of thumbs and middle phalanges of 2nd and 5th fingers, stenotic foramen magnum, spinal cord atrophy

AD

Craniofacial dyssynostosis101

Variable developmental delay, premature fusion of the lambdoid and posterior sagittal sutures, dolichocephaly, protuberant forehead; one each of seven original patients had congenital heart defect, agenesis of the corpus callosum, and hydrocephalus (same as craniotelencephalic dysplasia?)

AR (218350)

(continued)

616

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Craniomicromelia

IUGR, short limbs, absent coronal sutures, short palpebrae, pinched nose, hypoplastic alae, microstomia, cleft palate, large fontanels, absent 2nd finger phalanges, occipital protrusion containing cerebellum

AR (602558)

Craniosynostosis-bifid thumb-micropenis103

Craniosynostosis, low-set and posteriorly rotated ears, hypotelorism, prominent eyes, epicanthus, short and anteverted nose, flat nasal bridge, bifid thumbs, limited extension at the knees, small 5th finger, bi-lobed lungs, small penis with bifid scrotum, polymicrogyria, hypoplastic frontal lobes, arhinencephaly, cerebellar herniation, hydrocephalus

Unknown

Craniosynostosis-choanal atresia-dysphagia104

Normal intelligence, exophthalmos, choanal atresia, severe swallowing difficulties, gastroesophageal reflux, ventriculomegaly; one case ankylosis of temporomandibular joint and maxillomandibular synechiae, other cleft soft palate

AR

Craniotelencephalic dysplasia

See Craniofacial dyssynostosis102

102

106

Crouzon

Craniofacial dysostosis due to suture synostosis, exophthalmos, prominent and beaked nose, prognathism maxillary hypoplasia (communicating hydrocephaly of unknown cause)

AD (123500) FGFR2, 10q26

Cutis marmoratamacrocephaly107

Congenital reticular vascular pattern seen in association with hemihypertrophy, hemiatrophy, aplasia cutis congenita, cavernous hemangiomas of the skin, developmental delay; macrocephaly, seizures, and other associations are uncommon and include digital and congenital heart defects; hydrocephalus reported

Unknown (602501)

Cytomegalovirus-prenatal infection108

Asymptomatic to severe CNS changes. May include IUGR, microcephaly, intracranial calcification, hydrocephaly, chorioretinal changes, deafness

Prenatal infection

Czeizel: omphalocele-cleft palate109

Omphalocele, cleft palate/uvula, uterus bicornis; one of three femal sibs had hydrocephalus

AR (258320)

Daish: tall stature-joint hypermobility110

Tall stature, kyphoscoliosis, floppy mitral valve, joint hypermobility, susceptible to luxation

Uncertain (236660)

Da Silva: mental retardationmicrocephaly111

Severe retardation, postnatal growth failure, preauricular skin tag, camptodactyly nasal skin tag, club feet, increased tone, pulmonary infections, lethal

AR (217990)

DeHauwere: iris dysplasia112

Mesodermal iris dysplasia telecanthus/hypertelorism, psychomotor delay, short stature, hypotonia ventricular and cisternal enlargement, possible agenesis of the corpus callosum

AD or SLD

Devi: endocardial fibroelastosis-cataracts113

Congenital cataracts, endocardial fibroelastosis (lethal), postnatal communicating hydrocephalus; two unrelated males

Unknown (600559)

Diaphragmatic herniapulmonary hypoplasiahydrocephalus114

Right diaphragmatic defect, pulmonary aplasia or hypoplasia, borderline developmental delay, atrial septal defect, aqueduct stenosis, ventriculomegaly

AR

Disseminated hemagiomatosis115

Congenital multiple hemangiomas of skin and viscera, and sometimes fundi, brain stem, cerebellum, and cortex; complications include larger cavernous hemangiomas causing high-output cardiac failure and/or thrombocytopenia, subglottic hemangiomas, and obstruction by intracranial capillary hemangiomas causing hydrocephalus

Unknown (106070)

Dwarfism-microcephalyhydrocephaly116

Sloping forehead with marked microcephaly, no developmental progress, short and cupped ribs, mildly flat vertebrae, post mortem hydrocephalus; one sib with absent corpus callosum

AR

Dysmorphic facies-sex discrepancy117

Low-set ears, hypertelorism, flat nose, microretrognathia, female external genitalia, no uterus or vagina, testicular tissue in gonads, vas deferens present, 46,XX karyotype

Unknown

El-Khazen: lethal osteopetrosis118

Prenatal-onset increased bone density, brittle bones, hydrocephalus, marked gliosis of cortex and white matter, extensive neuronal loss, axonal swellings, some calcifications, hypoplastic cerebellum

AR (259720)

Enamel hypoplasia-cataractsaquedate stenosis119

Normal intelligence, anterior and posterior subcapsular lenticular opacities with radial spoke opacities in the lens cortex, enamel hypoplasia, anterior overbite, aqueduct stenosis noted on neuroimaging

Unknown (600907)

Epidermal nevus120

Nevus unius lateris, icthyosis hystrix, acanthosis nigricans, nevus sebaceous, hemangiomas, hemihypertrophy, pigment changes

Unknown (163200)

Fine: ocular anomalies-cleft palate-asymmetry121

Asymmetry of skull and body, cataract, glaucoma, low-set and abnormal pinnae, small mouth and mandible, hypoplastic genitalia, absent corpus callosum (aqueductal stenosis)

Unknown

(continued)

617

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Wide sutures, small eyes, abnormal external ears, flat nose, cleft palate, syndactyly hands/feet, abnormal pubic rami, laryngeal stenosis, absent/dysplastic kidneys, genital anomalies, abnormal gyri

AR (219000) FRAS1, 4q21

Fried: XLMR-spastic diplegia123

Mental retardation, spastic diplegia; congenital or possibly postnatal regression with loss of muscle tone wasting; ventricular dilation, calcification of the basal ganglia

XLR Xp22

Fukuyama: cerebro-oculomuscular124

Less severe than Walker-Warburg, developmental delay, small areas of agyria, pachgyria/polymicrogyria microscopically as in type II lissencephaly, mild cerebellar foliation defects, minor or absent eye defects, progressive facial and limb muscular dystrophy and contractures, raised CK; founder mutation in Japanese

AR (253800) Fukutin, FCMM, 9q31-q33

Game: hydrocephalusabnormal lungs125

Growth retardation, hypoplastic and/or hypersegmented lungs, intestinal malrotation, omphalocele, bowed tibiae and hypoplastic/absent fibula, rocker-bottom or clubbed feet

AR (236640)

Gaucher-like disease126

Neurologic deterioration, supranuclear gaze palsy, hydrocephalus, aortic stenosis, mitral valve calcification

AR (231005) acid b-maltase, D409Hm

Gibson: absent radiusanogenital anomalies127

Hydrocephalus, absent radial rays, hypospadias; report of fetus; maternal uncle reported with medially deviated and short forearms, imperforate anus; this is within spectrum of X-linked VATER with hydrocephalus

XLR (312190)

Goldblatt: spondylocostal metaphyseal dysplasia128

Very short limbs, macrocephaly due to hydrocephalus, narrow thorax, left cystic dysplastic kidney, short digits, metaphyseal cupping of long bones, phalanges and metacarpals of hands, platyspondyly with anterior beaking, short ribs, cupped costochondral junctions, squared scapulae and iliac wings, lambdoid and posterior sagittal synostosis

Unknown

Goldenhar129

Variable asymmetric lower face, with mandibular hypoplasia, microtia, preauricular tags and pits, epibulbar dermoids, macrostomia, upper vertebral anomalies; variety of CNS defects in low frequency

Sporadic, occasionally AD (164210)

Greig: cephalopolysyndactyly130

Macrocephaly, high forehead, frontal bossing, hypertelorism, broad nasal base, postaxial and/or preaxial polydactyly of hands, broad thumbs, hallux often duplicated, 1-3 toe syndactyly with occasional post-axial polydactyly, possible agenesis of the corpus callosum, and a few cases with mild communicating hydrocephalus

AD (175700) GLI3, 7p13

Haar-Dyken: athetotic hemiplegia131

Congenital, unilateral, hypertonic, hemiparesis, later onset athetoid posturing, dysarthria, contralateral cerebral atrophy; case with mild communicating hydrocephalus, aqueduct stenosis, macrocephaly

AD

Habel: microstomiahydrocephalus132

Frontal bossing, hirsutism, nasal obstruction (apparent), microphthalmia, carp mouth, low-set ears, profound mental retardation, postnatal growth failure, micropolygyria, early death

t(1;2)(q42.3;q37.1)

Hajdu-Cheney133

Coarse face, short neck, hirsutism, lax joints, acro-osteolysis, bathrocephaly, vertebral anomalies, normal intelligence; CNS anomalies include hydrocephalus (7/49) and syringomyelia

AD (102500)

Hayashi: leprechaunismlike134

Megalencephaly, hydrocephaly, unusual appearance, severe growth failure, hypoglycemia, no hyperinsulinemia, cardiac defect, decreased cortical neuronal density, fronto-parietal dysplasia. Single case

Unknown

Hemihypertrophyhemimegalencephalypolydactyly135

Hemimegalencephaly, cutis marmorata, hemihypertrophy of face and limbs, 3-4 syndactyly and post-axial polydactyly of hands, polydactyly of left foot with 2-3 toe syndactyly, wide-sandal gap. Single case

Unknown

Hendriks: deafness-callosal agenesis-arachnoid cyst136

Normal intelligence, sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cysts, hydrocephalus

AR

Heptacarpo-octatarsodactyly137

Cleft lip/palate, hypertelorism, macroglossia, horseshoe kidney, congenital heart defect, micropenis, internal hydrocephalus, ependymal cysts

Unknown

Hersh: mirror hands and feet-brain anomalies138

Sagittal synostosis, flat nasal bridge, bulbous nasal tip, hypoplastic alae, hamartomatous enlargement of parotid glands, stenotic ear canals, pelvic kidneys, ventricular septal defects, fusion and platyspondyly of cervical vertebrae, hydrocephalus, callosal agenesis

Unknown (135750?)

Hydrocephalus-angiopathyhypercholesterolemia139

Normal initial development, acute hydrocephalus in infancy, neurologic deterioration, seizures, high lipoprotein(a) and cholesterol; perivascular calcifications in Sylvian fissure, brain stem, cisterna magna; subpial gliosis and other changes

Unknown

Fraser: cryptophthalmos

122

(continued)

618

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Hydrocephalus-cataractmicrophthalmos140

Hydrocephalus, congenital cataract, microphthalmia; possible Walker-Warburg variant

Unknown

Hydrancephalic hydrocephalus-proliferative vasculopathy141

Late 2nd trimester hydramnios, multiple upper and lower limb major joint contractures, maximum hydrocephalus, with vascular glomeruloids, cytoplasmic inclusions, calcified necrotic foci in cortex

AR (225790) some due to mitochondrial dysfunction

Hydrocephalus-Sprengel shoulder-skeletal142

Mild mental retardation or psychosis, arachnoid or cerebellar cysts, hydrocephalus, abnormal white matter, Sprengel shoulder anomaly, brachydactyly of variable type

AD (600991)

Hydrolethalus143

Cleft lip/palate, small tongue and mandible, abnormal nose and ears, malformed respiratory tract, genitourinary and heart anomalies, polydactyly, stillbirth/ neonatal death

AR (236680) 11q23-q25

Hypoglossia-hypodactyly144

Normal intelligence, small jaw, intraoral band from palate to floor of mouth, variable limb reduction from absent digits to distal limb, association with bilateral facial and abducens nerve palsies; some may have followed early CVS; case with aqueduct stenosis, hydrocephalus, and histologic brain stem changes

Possibly vascular (103300)

Ichthyosis-biliary atresia145

Ichthyosis congenita, biliary atresia, neonatal death of brother from umbilical hemorrhage; sister with hydrocephalus

AR (242400)

Influenza, prenatal146

Possible rare complication of maternal infection; microphthalmia, malformed pinnae, diaphragmatic hernia, costovertebral defects; ependymal damage, aqueduct forking, hydrocephalus, heterotopias; agenesis of the corpus callosum, cerebellum, pontine and inferior olivary neurons, optic and olfactory nerves; immunohistochemical evidence of influenza virus antigens in brain

Unproven association

Jeune: thoracic dysplasia147

Hypoplastic rib cage with short ribs, ‘‘trident’’ pelvis, postaxial polydactyly, short stature, dental anomalies, renal microcysts and failure, mild dilation of lateral ventricles

AR (208500) 15q13

Jonas: pontine hypoplasiacallosal agenesis148

Macrocephaly, frontal bossing, deep-set eyes, short palpebrae, Duane retraction anomaly, hydronephrosis, patent ductus arteriosus, agenesis of corpus callosum, hypoplastic pons; mild, focal, subcortical white matter changes; communicating hydrocephalus

AR

Kabuki149

Mental retardation, short stature, prominent ear lobes, everted lateral 1/3 of the lower lid, long palpebrae, broad nasal tip, cleft/high-arched palate, short 5th finger, fetal finger pads, cardiac and renal anomalies, variety of minor anomalies; case with hydrocephalus

Uncertain (147920)

See Ciliary akinesia/dysgenesis96

Kartagener 150

Kraues-Kivlin: Peters plus

Central corneal leukoma with abnormal posterior stroma and Descemet membrane, iris synechia, unusual facies, disproportionate short limbs; digital cardiac and renal anomalies; case with communicating hydrocephalus

AR (261540)

Larsen151

Normal intelligence, prominent forehead, flat face, low nasal bridge, hypertelorism, dislocation at large joints, varus or valgus foot deformities, long tapering fingers

AD (150250) LAR1, 3p21.1-p14.1 AR (245600)

Ligneous conjunctivitis152

Palpebral pseudomembranes become nodular masses of amorphous, hyalinized ground substance; mucous membranes of mouth, tongue, nasopharynx, tracheobronchial tree, and the female genital tract may be involved; minority have obstructive hydrocephalus

AR (217090) Plasminogen 1 deficiency, 6q26

Lockwood: short-arthritislipodystrophy153

Late childhood growth failure, broad nasal bridge, cupped optic discs, mild generalized lipodystrophy, osteoporosis, short pelvis, bilateral coxa valga, mild platyspondyly, short metacarpals, degenerative arthritis of hips and knees, arrested hydrocephalus

Unknown

Lurie-Kletsky: callosal agenesis-diaphragmatic defect154

Fetal hydrops, microcephaly, scalp defect, short palpebrae, posterior diaphragmatic defect, agenesis of corpus callosum, ventriculomegaly

Unknown

Marshall-Smith155

Accelerated linear and skeletal growth with prenatal onset, poor weight gain, dolichocephaly, prominent eyes, anteverted nose, broad proximal and middle phalanges, narrow distal phalanges, respiratory problems often lethal, absent corpus callosum, hypoplasia inferior vermis, pachygyria

Unknown (602535)

MASA (X-linked hydrocephaly spectrum)156

Mental retardation, adducted thumbs, shuffling gait with aphasia or speech delay, agenesis of corpus callosum, spastic paraplegia, hydrocephalus. Same gene as X-linked hydrocephalus, X-linked paraplegia type 1

XLR (303350) L1CAM, Xq28 (continued)

619

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Metatropic dwarfism-lethal variant157

Normal face, expanded joints, cleft soft palate, cataracts, wide metaphyses, short and narrow diaphyses, intrauterine fractures, unossified epiphyses, normal vertebrae

AR (250600)

Microgastria-upper limb reduction158

Microgastria, variable upper limb defects, asplenia/splenogonadal fusion; case reports in association with iris coloboma, orbital cyst, fused thalami, arhinencephaly, agenesis of corpus callosum, several internal anomalies, hypothalamic hamartoma; anophthalmia, porencephalic cyst, hydrocephalus

Unknown (156810)

Microphthalmia-linear skin defects159

May have other CNS anomalies including septum pellucidum cyst, ACC, colpocephaly and hydrocephaly; microphthalmia, sclerocornea, linear dermal aplasia usually of the head and neck

XLD male lethal (309801) del Xp22.3

Mizoguchi: hydrocephalustrigonocephaly160

Communicating hydrocephalus, trigonocephaly, spastic gait in 3rd decade, dementia starting in 5th decade

AD

Morning glory-sphenoidal encephalocele161

Characteristic optic nerve, hypertelorism, microphthalmia, other eye anomalies, midline cleft, pituitary/hypothalamic dysfunction, hydrocephalus, absent corpus callosum, sphenoidal encephalocele

Unknown

MULIBREY nanism162

Muscle hypotonia, liver enlargement, brain defects including large ventricles, and cysternae, eyes with yellow pigmentation of retina. Growth failure, triangular face, pericardial constriction, long shallow sella turcica, fibrous dysplasia of bones

AR (253250) TRIM37, 17q22-q23

Muscle wasting-cataractscalcified pinnae163

Severe mental retardation, calcification pinnae, posterior polar cataracts, progressive muscle wasting (mostly of hands) and joint contractures, cystic areas in head of humeri and upper femora

Unknown (259050)

Mutchinick164

Microcephaly, hydrocephalus, growth and developmental delay, high forehead, ptosis, downslanting palpebrae, prominent nose, high nasal bridge, protruding ears; 1 of 8 cases with ACC

AR

Nephropathyventriculomegaly165

Protein losing nephropathy with grossly elevated MSAFP levels; nephrin mutations excluded, mild ventriculomegaly and echogenic kidneys on prenatal ultrasound

AR

Nephrosis-neuronal migrational defect166

Mental retardation, aqueduct stenosis, periventricular neuronal heterotopias, spastic tetraplegia, seizures, proliferative glomerulonephritis, periodic hypertension

Uncertain

Neurocutaneous melanosis167

Classical and variant forms of cutaneous pigmented nevi and leptomeningeal melanosis with malignant change, intracranial anomalies and cysts, arachnoid villi infiltration in some cases

Unknown

Neurofibromatosis168

Cafe´-au-lait spots, neurofibromata, Lisch nodules, occasional plexiforum neuromas, pseudoarthrosis, and diverse complications of tumors; macrocephaly is common

AD (162200) NF1, 17q11.2

Noonan169

Variable mental retardation and short stature, ptosis, downslanting palpebrae, low/abnormal ears, short/webbed neck, pectus malformation, pulmonary valve stenosis/dysplasia; hydrocephalus in about 5%

AD (163950) PTPN11, 12q24.1

Ochoa-urofacial170

Hydronephrosis, hydroureter, intravesicular ureteral stenosis, urethral valve stenosis; crying or smiling causes a lateral displacement of the mouth, nasal flattening, deepening of the nasolabial sulcus; case with aqueduct stenosis

AR (236730) 10q23-q24

Oculocerebrocutaneous171

Orbital cysts, microphthalmia, lid coloboma, skin defects, skeletal anomalies, agenesis of the corpus callosum, multiple cysts of brain

Unknown (164180)

Ohdo: tetra-amelia; ectodermal dysplasia172

Tetra-amelia, upslanting palpebrae, absent scalp hair and eyebrows, absent lacrimal puncti, prominent nose, large and downturned mouth, bilateral preauricular pits, ventriculomegaly, increased subarachnoid space

AR (273390)

Oral-facial-digital type I173

Midline cleft/notched upper lip, multiple oral frenulae, lobulated tongue with hamartomas, asymmetric brachysyndactyly; CNS includes hydrocephaly, porencephaly, cerebellar vermis hypoplasia, Dandy-Walker cysts, neuronal migration defects, and agenesis of the corpus callosum

XLD (311200), male lethal CXORF5, Xp22.3-p22.2

Oral-facial-digital type II174

Short stature, hypertelorism, low nasal bridge, broad and bifid nasal tip, hypertrophied oral frenula, cleft and lobulate tongue, cleft palate; brachysyndactyly, pre- and post-axial polydactyly of hands; pre-axial foot polydactyly; usually normal intelligence; CNS includes porencephaly, hydrocephaly, callosal agenesis

AR (252100)

Oral-facial-digital type Gabrielli175

Severe developmental delay, low-set ears, preauricular pits, hypertelorism, blepharophimosis, bulbous nose, multiple oral frenula, long philtrum, split upper lip, micrognathia, cleft palate, bilateral postaxial polydactyly of hands and feet, fusion of posterior arches of C2 and C3 and of atlas to occiput, clefts of cervical and thoracic vertebrae, hypoplastic odontoid, dilated lateral ventricles

Unknown

(continued)

620

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Orstavik: aplasia cutisretinal-brain176

Aplasia cutis on scalp and abdomen, broad bulbous nose, small chin, long philtrum, hypoplasia to absence of fingers with the nails attached to metacarpals, ventricular dilation and cerebral atrophy, variable thalamic calcification; male had agenesis of the corpus callosum

AR

Osteogenesis imperfecta, lethal type177

Prenatal onset hydrocephalus may be due to either fractures at foramen magnum or sub-arachnoid haemorrhage (may reflect severe type II osteogenesis imperfecta).

Most AD (166210) COL1A1, 7q22.1 COL1A2, 17q21.31-q22

Osteogenesis imperfectaretinopathy-mental retardation178

Postnatal growth and developmental retardation, blue sclera, optic atrophy, retinopathy, fractures, wormian bones, large fontanel, seizures, congenital heart defect

AR

Osteoglophonic dwarfism179

Multiple metaphyseal lucencies, craniosynostosis, flat-beaked vertebrae, marked growth failure, delayed dentition, hypertelorism, abnormal face, obstructive hydrocephalus

AD (166250)

Oto-palato-digital II180

Mandibular hypoplasia, cleft palate, malar hypoplasia, downslanting palpebrae, narrow ribs, bowed forearms and legs, absent fibulas and carpals, pelvic hypoplasia; case reported with cerebellar hypoplasia and hydrocephalus

XLR (304120) FLNA, Xq28

Palmer-Pagon: hydrocephalus-low umbilicus181

Mild facial signs with short and bulbous nose, wide palpebrae, low position of umbilicus, congenital heart defect, mild speech delay, ventricular dilation

Unknown

Pena-Shokier without IUGR182

Small and immobile mouth, low and angulated ears, choanal atresia, pterygia, camptodactyly; macrocephaly; posterior fossa cyst and hydrocephalus in one case

XLR or AR

Polyasplenia-caudal deficiency-absent corpus callosum183

Laterality associated defects, imperforate anus, renal anomalies, lumbosacral agenesis, lower limb anomalies; cases reported with meningocele, hydrocephalus; one case with absent corpus callosum and white matter neuronal heterotopias and abnormal cortical architecture

Uncertain

Polymicrogyriahydrocephaluscraniosynostosis184

Craniosynostosis, scaphocephaly, severe mental retardation, lethal early; low-set ears, eyebrow hypoplasia, short nose, long philtrum, small mouth, small genitalia. Single case

Unknown

Porencephaly-cerebellar hypoplasia-heart defect185

Prominent metopic suture, bilateral epicanthus, high arched palate, absent septum pellucidum, hydrocephalus, bilateral cortical defects, dilated 4th ventricle, absent vermis, cerebellar hypoplasia, probable porencephaly in one sib, congenital heart defects

AR (601322)

Port-wine nevi-mega cisterna magna186

Glabellar port-wine stain, mega cisterna magna; 2 of 5 affected persons had congenital communicating hydrocephalus, agenesis of posterior vermis

AD

Proliferative vasculopathyhydranen/hydrocephaly187

Ventriculomegaly/hydranencephaly; proliferative blood vessels in spinal cord, brain stem, retina, and cerebral mantle; decreased number of primitive neuroectodermal cells, maturing neurons and glia; no gyral pattern; hypoplastic muscles, joint contractures, pterygia; possibly a destructive vascular process; cerebro-oculo-muscular spectrum?

AR (225790)

Proteus188

Marked and asymmetric overgrowth can lead to a range of complications; shagreen patches, linear verrucous epidermal nevi, intradermal nevi, lipomas, hemangiomas, patchy dermal hypoplasia, hyperplastic and pebbly plantar overgrowth; frequent ocular problems; CNS abnormalities uncommon, partial absent corpus callosum, lissencephaly, hydrocephalus

Uncertain (176920) Some PTEN, 1q11-q25, mutations claimed, but cases questioned296

Pseudomarfanism189

Ectopia lentis arachnodactyly, mild osteopetrosis, hypertelorism, high palate, malocclusion, communicating hydrocephalus

AD

Reuss: cystic kidneysventiculomegaly190

Polyhydramnios elevated amniotic fluid a-fetoprotein level, normal-sized dense kidneys with corticomedullary and medullary cysts with amorphous eosinophilic material, unexplained ventriculomegaly

AR (219730)

Rhombencephalosynapsis191

Facial signs can include marked low-set ears, hypertelorism, strabismus, long philtrum; CNS includes absent incisuria cerebelli posterior, velum medullare anterius, and nuclei fastigii; fusion dentate nuclei and cerebellar hemispheres; survivors show neurologic signs including ataxia, dysarthria, and mental retardation

Unknown

Riccardi: Dandy-Walker malformation192

Hydrocephalus, cerebellar agenesis, Dandy-Walker malformation; maternal greatgreat uncle with hydrocephalus

Unknown

Rogers: anophthalmia tracheoesophageal fistula193

Prominent forehead, open fontanel, bilateral anophthalmia, high palate, glandular hypospadias, tracheoesophageal fistula, arrested hydrocephalus. Single case.

Unknown (continued)

621

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Complete absence of upper and lower limbs, severe pulmonary hypoplasia; one case with cleft lip and hydrocephalus; see also Zimmer tetra-amelia

AR (273395)

Sagittal synostosis-DandyWalker195

Developmental delay, sagittal synostosis, Dandy-Walker malformation, hydrocephalus

AD (123155)

Schinzel-Giedion: hirsutismmidface retraction196

High cranium, midface retraction, choanal atresia, cardiac and renal anomalies, hirsutism, sclerosis of skull base, wormian bones, mental retardation, subependymal pseudocysts, intraventricular bands

AR (269150)

Sengers: obesityhypogenitalism197

Mental retardation, short stature, obesity, hypogenitalism

XLR

Sensorineural deafnesshypospadias-digit synostosis198

Mental retardation, truncal obesity, small kidneys, sensorineural deafness, hypospadias, synostosis of the 4th and 5th metacarpals and metatarsals, high rate of digital arches, dilated ventricles, mildly underdeveloped occipital lobes and cerebellum

Unknown

Shprintzen-Goldberg: arachnodactylycraniosynostosis199

Mental retardation, hypotonia, craniosynostosis, low-set ears, exophthalmos, maxillary and mandibular hypoplasia, prominent lateral palatine ridges, abdominal hernias, arachnodactyly, camptodactyly; significant overlap with Melnick-Needles and spectrum of syndrome uncertain; possible case with cloverleaf skull, hydrocephaly, and hypoplastic corpus callosum

AD (182212), some FBN1, 15q21.1

Siber: microphthalmia200

Microphthalmia, corneal opacities, hypospadias; one sib had more extensive brain anomalies noted at autopsy

XLR (309800)

Slee: hydrocephalus-growth failure-digital201

Severe polyventricular hydrocephalus, patent aqueduct of Sylvius, cleft palate, overlapping fingers; CNS variable and includes partial/complete callosal agenesis, hypoplastic mid- and hindbrain, cerebellar agenesis; lethal

Uncertain

Split foot-congenital hearthydrocephalus202

Developmental delay, depressed and broad nasal bridge, downslanting palpebrae, low-set ears, torticollis, left foot ectrodactyly, secundum atrial septal defect, thin corpus callosum, dilated 3rd and lateral ventricles

Unknown

Temtamy: callosal agenesiscolobomas-retardation203

Macrodolichocephaly, low-set and simple ears, narrow face, hypertelorism, complete colobomas, beaked nose, micrognathia, dental anomalies, dilated aorta, mild brachydactyly of digits 2-5 of hands and feet, dilated lateral and 4th ventricles and slightly dilated sulci

AR

Tetralogy of Fallot-unusual facies-hydrocephalus204

Developmental delay, midface hypoplasia, short palpebrae, cyanotic heart disease, variable hypertelorism and hydrocephalus

AR

Thakker-Donnai205

IUGR, Klippel-Feil, long and downslanting palpebrae, hypertelorism, short nose with blunt tip, small downturned mouth, vertebral anomalies, short esophagus, diaphragmatic hernia, congenital heart defect; one sib with hydrocephalus, the other with callosal agenesis

AR (227255)

Third ventricular obstruction206

Hydrocephalus with dilated lateral ventricles and narrowing of posterior 3rd ventricle, polygyria, choroid plexus atrophy, thin corpus callosum, absent septum pellucidum

Unknown

Thrombocytopeniaalloimmune207

Equivalent of rhesus disease; involves platelet antigens (usually HPA1a); hydrocephalus secondary to thrombocytopenia mediated, in utero, intracerebral hemorrhage; recurrence risk of >80%

Immune sensitization

Tibial aplasia-ectrodactyly208

Pregnancy complicated by early twin resorption, left forearm hypoplasia, absent thumb, syndactyly, bilateral lower limb hypoplasia, idiopathic hydrocephalus. Single case

Twin vascular interaction possible

Tibial aplasia-polysyndactylyimperforate anus209

Imperforate anus, femoral hypoplasia, unilateral tibial aplasia, ipsilateral pre-axial polysyndactyly, vertebral and rib anomalies, ventriculomegaly

Unknown

Tibial hypoplasiapolydactyly-retrocerebellar cyst210

Tibial aplasia/hypoplasia, cleft lip, postaxial polydactyly of hands, pre- or postaxial polydactyly of feet, short radii, colonic malrotation, diaphragmatic agenesis, ventriculomegaly (one sib), retrocerebellar arachnoid cyst (two sibs)

AR (601027)

Tranebjaerg: XLMR-ataxiaapraxia211

Mental retardation, ataxia, apraxia, club feet, seizures, dilation of cerebral ventricles

XLR

Trigonocephaly212

Patients presented with isolated metopic fusion and communicating hydrocephalus, hypothesized to be due to developmental anomaly of cortical veins; onset of spastic gait in 3rd decade

AD

Tollner: polydactyly-visceral anomalies213

Hypertelorism, bilateral cleft lip/palate, macroglossia, hepatosplenomegaly, accessory lobe of right lung, horseshoe kidney, complex congenital heart defect, heptadactyly of hands, pre-axial polysyndactyly of feet, micropenis, hydrocephalus, ependymal cysts, polygyria, leptomeningeal fibrosis. Single case.

Unknown

Rosenak: tetra-amelia

194

(continued)

622

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Short palpebral fissures, telecanthus, Robin sequence, small nose, abnormal auricles, excess nuchal skin, larynx anomaly, hypospadias, brachydactyly, microcephaly, mental retardation

AR (217980)

Toxoplasmosis215

IUGR, developmental delay, hydrocephalus, microcephaly, intracranial calcifications, choreoretinitis, hearing loss

Prenatal infection

VATER, VACTERL216

Typical association of vertebral, anal, cardiac, tracheoesophageal, renal and limb (radial) anomalies; increasingly noted with aqueductal stenosis

Sporadic some XLR (192350)

Van Biervliet: thoracic dystrophy217

IUGR, multiple joint contractures, narrow thorax, small mouth and mandible, appear older than age, developmental delay, aqueduct stenosis

AR

Varicella, fetal218

Risk about 2% with maternal infection at 13–20 weeks; mild mental retardation, eye defects, skin scarring distributed over dermatomes, limb hypoplasia; most reported brain lesions seem clastic but hydrocephalus reported

In utero infection

Ventriculo-radial-renal219

Progressive prenatal hydrocephalus, absent radial rays, horseshoe kidney/crossed renal ectopia; elevated amniotic fluid g-glutamyltranspeptidase, total protein

AR (602200)

Vitamin A, prenatal220

Spontaneous abortion, microtia, microophthalmia, anophthalmia, congenital heart, limb reduction defects, thymic hypoplasia, jaw hypoplasia, hydrocephalus

In utero exposure

Waaler: costovertebral dysplasia221

Sprengel anomaly, kyphoscoliosis, rib anomaly and minor vertebral changes, hypertelorism, enamel hypoplasia, prominent mandible, communicating hydrocephalus

AD (143250)

Walker-Warburg (HARDþ/E)222

Diffuse agyria, cobblestone appearance may be obscured by hydrocephalus, abnormal white matter, laminar heterotopia below cortex, absent septum pellucidum, severe midline > lateral cerebellar hypoplasia, brain stem hypoplasia, Dandy-Walker malformation, cephalocele, retinal dysplasia/non-attachment; microphthalmia, cataract, corneal opacity, hyaloid vessels, retinal corneal opacity, abnormal face; myopathic skeletal muscle with variable size and splitting of fibers with endomysial fibrosis

AR (236670) POMT1, 9q34.1

Wallace: dwarfism-midline cleft223

Short-limbed dwarfism, short ribs, midline cleft lip/palate, pulmonary hypoplasia, disrupted endochondrial ossification, aqueductal stenosis

AR?

Weaver: craniosynostosis224

Coronal and lambdoid fusion, cranial bone defects, hypertelorism, clefting, arthrogryposis, growth and developmental delay, esophageal reflux and apnea

Unknown

Winter: IUGRhydrocephalus-skeletal225

Severe IUGR, rhizomelia, small face and ears, blue sclerae, beaked and pinched nose, small hands, zygodactyly of 4th and 5th toes, bifid 5th left toenail, small penis, retarded bone age; radiologic changes including metaphyseal flaring, platyspondyly, pelvic anomalies, wormian bones; enlarged 3rd and lateral ventricles, small 4th ventricle, normal aqueduct, probable cerebellar vermis dysgenesis/agenesis

Unknown, AR?

Winter: thoracic dysplasia226

Short ribs, mild rhizomelia, pelvis of newborn was not trident. Could be same as Jeune asphyxiating thoracic dysplasia

AR (273730)

Winter-Wigglesworth227

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, severe hydrocephalus, poorly formed hemispheres; microscopic renal changes

Unknown

X-linked laterality defect228

Variable visceral situs inversus, complex congenital heart disease, splenic malformations; CNS less common and includes arhinencephaly, hydrocephalus, meningomyelocele, cerebellar hypoplasia

XLR (304750) ZIC3, Xq24-q27

XLMR-corpus callosum dysgenesis229

Microcephaly, wide anterior fontanel, frontal bossing, telecanthus, broad nasal root, downturned mouth, short broad hands, brachydactyly; absent corpus callosum, interhemispheric cyst, cortical gyral dysplasia

XLR (304100)

X-linked myotubular myopathy230

Congenital lethal myopathy with hypotrophic muscle fibers, central nuclei and surrounding clear area lacking myofibrils; several cases with communicating hydrocephalus

XLR (310400) Myotubukarin, Xq28

Zaglul-Odita: multiple hernia231

Moderate mental retardation, hypotonia, low-set ears, downslanting palpebrae, hypotelorism, mild ptosis, anteverted nares, retrognathia, high-arched palate; herniae of diaphragm, stomach, lungs, inguinal region; bladder diverticulae; hydrocephalus and mild cerebellar atrophy

Unknown

Toriello-Carey

214

(continued)

623

624

Neuromuscular Systems

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Zimmer: tetra-amelia

Polyhydramnios, amelia, severe facial clefting, no nose, ocular anomalies, hydrocephalus, absent ophthalmic and possible olfactory nerves

XLR (301090)

Zolotukhina: nasal proboscismultiple anomalies233

Low-set ears, hypertelorism, downslanting and short palpebrae, micophthalmia, blind-ending proboscis, cleft alveolus, ectrodactyly/polydactyly, band-like sacral protrusion, cerebral atrophy probable hydrocephalus

Unknown

232

variation in shape and histology along its length: triangular at the rostral opening, round to oval under the superior colliculi, ‘‘U’’shaped below the posterior colliculi, and forming a deep midline slit in the floor throughout the caudal portion. The walls may fuse at their dorsal margin at various points along this slit, thus forming a small ventral channel, seen in some cross sections, below the main passage. This normal phenomenon has been misinterpreted as pathologic aqueductal forking when associated with aqueductal stenosis.1 Attempts have been made, on the basis of histopathology, to distinguish atresia/stenosis due to malformation from blockage that is acquired (mainly postinflammatory). The appearance of the former was considered to be represented by lack of any evident channel or by multiple small irregular channels, whereas in the latter the original outline of the lumen was represented by residual nests of ependyma, and the canal was filled by gliosis. However, Drachman and Richardson30 reported a patient in whom the two types of pathology were noted at different levels of the aqueduct. Evidence from animal experimentation also shows clearly that infectious agents can produce aqueductal occlusion without producing gliosis.31 Thus, histopathology does not truly aid in the differentiation of the causes of aqueductal stenosis. Perez-Figares et al.5 have proposed that primary abnormalities in the subcommissural organ, which secretes glycoproteins that aggregate along the floor of the aqueduct, 4th ventricle, and central canal as Reissner’s membrane, may cause aqueductal stenosis. There is some consensus that 0.15 cm2 represents the lower limit of normal for lumen area, but both normal-sized ventricles with smaller areas and ventriculomegaly in the presence of apparently larger areas have been reported.1,29 Perhaps the length of stenosis plays a role in this regard. The age of onset and severity of congenital aqueductal stenosis are extremely variable. In general, the signs and symptoms are as described previously. However, the ‘‘bobble-head’’ doll phenomenon, which consists of to-and-fro head movement at 2–3 hz, is considered characteristic of 3rd ventriculomegaly due to obstruction at the level of the aqueduct. Although this sign has been considered due to pressure on the dorsal medial nucleus of the thalamus, Coker32 has argued that it results from interference with the red nucleus. Standard diagnostic techniques will demonstrate obstruction at the level of the aqueduct with ventriculomegaly involving the third and lateral ventricles (Fig. 15-47). The specific findings with MRI, including those of a membranous obstruction, have been described.33 Narrowing of the aqueduct is directly visible in its position ventral to the tectum, the appearance of which varies with the level of the stenosis. With stenosis at the level of the intercollicular sulcus, the tectum is often thinned. Stenosis at the level of the superior colliculi causes lateral compression of the tectum due to dilated temporal lobes and foreshortening due to downward compression from the dilated suprapineal recess of the 3rd ventricle. Uncommonly, the obstruction may consist of a thin web of loose fibroglial tissue with or without ependymal rests.34 The age

of onset in these patients is generally older than in the total group with aqueductal stenosis, and complaints often relate to disturbances of gait and changes in levels of consciousness and behavior. Presentation at age 12 years with bobble-head movement has been reported.35 The membrane always occurs in the caudal portion of the aqueduct and, with appropriate imaging techniques, can be seen to bulge into the 4th ventricle. The histopathology is not distinctive, and this may simply represent the minimal end of the spectrum of aqueductal stenosis. Recognition remains important, as simple fenestration may be sufficient treatment.34 In light of the known occurrence of aqueductal stenosis in neurofibromatosis, it is interesting that three of four patients with membranous stenosis reported by Turnbull and Drake34 had cafe´-au-lait spots. That aqueductal stenosis could be genetic was first recognized by Bickers and Adams36 in 1949, and a number of reviews have been published since.28,37 Most families have shown an X-linked pattern of inheritance,38 although several families compatible with autosomal recessive inheritance have been reported (Table 15-11).39 Our understanding of the X-linked form (XLH) has expanded rapidly since the discovery that it was due to mutations in L1, a member of the Ig superclass of cell adhesion molecules. The gene has a number of roles including axonin-1 binding affecting neurite growth, ankrin binding in the function of the cytoskeleton, and a kinase-related influence on intracellular secondary messangers.40 It is now clear that mutations in L1CAM can result in the various components of X-linked hydrocephalyMASA spectrum (Table 15-11). Aqueductal stenosis is not always present, even in those with hydrocephalus, and there does appear to be some genotype–phenotype correlation. The most severe expression, associated with marked hydrocephalus and a high prenatal and postnatal mortality, is seen in patients with nonsense mutations in the extracellular domain, which disrupts all functions of the gene. Missense mutations in the extracellular domain, followed by all types of intracellular domain mutations, cause respectively less severe effects, and it has been suggested that the hydrocephalus in such cases my be ex vacuo due to diminished white matter.40 The estimated birth prevalence of XLH is 1/30,000,41 and to date there is no evidence of genetic heterogeneity. The mental retardation that accompanies L1CAM mutations is not influenced by early shunting, is present even in the absence of hydrocephalus, and therefore must have a more intrinsic cause. There are no absolute criteria that distinguish the sporadic genetic case from those with other etiologies. The presence of adducted thumbs, due to abnormalities of the extensors and abductors of the thumb, affect about 25% of XLH cases and can be a useful sign. However, caution is required because adducted thumbs can be seen in severe hydrocephalus on the basis of the bipyramidal syndrome.28,37 Although new mutations are considered to be rare, most are private, and mutation screening in the absence of an X-linked family history or tissue from an affected male is problematic.41

Brain

15.8.4 Deficient Arachnoid Granulations

Arachnoid granulations are not visible at birth, but may be seen with a hand lens by age 6 months and with the naked eye by 18 months. Patients present with signs of communicating hydrocephalus, and the diagnosis requires pathologic confirmation.1,42 The condition appears to be extremely rare, although some degree of underascertainment seems likely. The fact that any granulations that are found in these patients are dysplastic supports a developmental rather than an acquired cause. Deficient granulations can readily explain hydrocephalus if they are the site of major CSF absorption. Under the hemodynamic model, the absence of their valve effect would lead to increased venous collapse, and hence an increased resistance to flow. 15.8.5 Associated with Skeletal Dysplasias

The nature of hydrocephalus associated with skeletal dysplasias has been controversial. Achondroplasia is certainly the most studied example, and it was long considered that the mild to moderate dilation observed in most cases was self-limited and perhaps due to hypoplasia of the base of the skull with compression at the level of the foramen magnum. However, although it has been increasingly recognized that the small foramen magnum may compromise the cord and medulla and contribute to the increased mortality in achondroplasia and some other chondrodystrophies, its surgical relief does not alter the ventricular dilation. Although a few patients with achondroplasia have obstructive hydrocephalus, the overwhelming majority have a communicating type.43 Radioisotope cisternography shows evidence of failure of CSF absorption at the level of the sagittal sinus, and, together with evidence of abnormally wide sulci (which become normal with relief of the hydrocephalus), support a hydrodynamic etiology of hydrocephalus due to elevated sinus venous pressure.43,44 The level of venous obstruction appears to be at the point of exit from the skull and may be ultimately selfcorrecting, as the skull base grows and anastomotic venous channels develop. One can speculate that similar venous obstruction could be responsible for hydrocephalus in related chondrodystrophies and conditions causing osteosclerosis.45 Syndromes in which hydrocephalus or ventriculomegaly can be attributed to other CNS malformations, such as holoprosencephaly, Dandy-Walker cyst, Chiari malformation and other intracranial cysts, are treated in their respective sections. Many syndrome descriptions refer to varying degrees of ‘‘ventriculomegaly,’’ often in the face of microcephaly (which can be accompanied by hydrocephalus), and representing ex vacuo/atrophic hydrocephalus. An attempt has been made to exclude such syndromes from Table 15-11, but it is certain that some of the conditions that have been included will lack true hydrocephalus, and some may have been mistakenly excluded. Distribution and Etiology

As discussed by De Lange,4 the prevalence of hydrocephalus is reported to range from 0.1 to 3.5 per 1000, and such figures can only be interpreted in the context of how the data were obtained and what types of cases were included. Rates for spina bifida are known to show geographic, ethnic, and temporal variation, and hydrocephalus associated with spina bifida should therefore always be reported separately. Other factors aside from true biologic population variation, which may contribute to differing rates, may include whether a survey relies on registry reporting or active case ascertainment, whether all births or only live births are in-

625

cluded, and whether the survey is limited to specific age groups. There was some temporal decline in the prevalence of congenital hydrocephalus from 1940 to 1960 that may reflect the parallel decline in the rates of neural tube defects. Stein et al.234 found some evidence of an association with lower socioeconomic status, a higher rate among Puerto Ricans, but a similar rate in blacks and whites, and no association with age or parity. Rates for isolated congenital hydrocephalus cluster in the range of 0.5–0.8 per 1000.4 In a low-risk population, mild prenatal ventriculomegaly occurs at a rate of about 1.48 per 1000 births.235 Unilateral prenatal ventriculomegaly is detected in about 1 in 1400 pregnancies (0.07%), and in two-thirds of cases it is an isolated finding.236 The etiology of hydrocephalus is varied and to a large extent outlined in Table 15-10. Again, the prevalence of each specific type of hydrocephalus and the different causative factors will be influenced by many of the same variables mentioned previously. For example, the perivascular granulomas caused by prenatal toxoplasmosis infection may obliterate the aqueduct. Martinovic et al.237 provided evidence that 15 of 38 infants in Belgrade who had congenital hydrocephalus had contracted toxoplasmosis in utero. Rates of seropositivity in women vary from about 33% in New York City and London to 85% in Paris. Hagberg et al.238 used a modified optimality concept to study factors of history that might play a role in the etiology of hydrocephalus. In this approach, details normally available from the prenatal, perinatal, and postnatal medical records are simply assigned a dichotomous optimal or nonoptimal scoring. In a manner similar to numerical taxonomy, which is perhaps more familiar to dysmorphologists, there is no preconceived weighting of an item’s importance. The authors carried out a case control study of 128 term and 50 preterm children of whom they considered 73 had definite prenatal, 33 definite perinatal, and 72 undefined onset of their hydrocephalus. This compares with previous reports that term infants have 70% prenatal, 25% perinatal, and 5% postnatal, and preterm infants 40%, 60%, and 4%, respectively, causes for their hydrocephalus. Patients in the prenatal group showed significantly higher odds ratios than did the perinatal or control groups for prenatal nonoptimal factors. These included problems in prior pregnancies, recurrent abortion, twinning, and reduced pregnancy interval. Conversely, the perinatal group had increased odds ratios for perinatal factors. The profile of those children with unknown cause was similar to those of term children with a prenatal cause. The rates of the broad categories of congenital hydrocephalus are similar in different surveys, although the exact etiology is usually unknown. Table 15-12 compares data from the studies of Burton239 and of Renier et al.240 Causes of prenatal onset unilateral hydrocephalus include atresia or obstruction of the foramen of Monro, gliosis secondary to inflammation, an association with hemihypertrophy, and it is seen occasionally with absent corpus callosum, but most cases Table 15-12. Proportions of hydrocephaly by various causes Burton75

Renier et al.76

Cause

No.

Percent

No.

Percent

Aqueductal

42

Communicating

39

38.9

88

42.9

36.1

77

Dandy-Walker

37.6

10

9.3

26

12.7

Other anatomic

17

15.7

14

6.8

626

Neuromuscular Systems

remain idiopathic.12 Most cases in adults have an acquired cause but some may represent chance discovery of an asymptomatic unilateral hydrocephalus of prenatal onset. The proportion of aqueductal stenosis that has a genetic basis is difficult to determine, and initial estimates of 2% were not based on firm data. Renier et al.240 considered 6/42 and Burton239 4/88 cases had family histories compatible with X-linked inheritance. Current estimates are that L1CAM mutations account for about 5% of all non-syndromic congenital hydrocephalus.41 The spectrum of the L1CAM-associated X-linked hydrocephaly–MASA gamut accommodates previously reported X-linked families with partial midline fusions and absent corpus callosum.37 Landrieu et al.29 cited animal experiments that demonstrate, in both mutant and virally infected mice, that initial communicating hydrocephalus can lead to aqueductal stenosis. They describe an affected patient (from an extensive family) with X-linked aqueductal stenosis who had a minimal aqueductal measurement of 0.33 cm2. When considering the genetic contribution to aqueductal stenosis, it should be remembered that many X-linked cases are stillborn and that autosomal recessive cases have been reported. There are several non-X-linked animal models of hydrocephalus, notably in rats (H-Tx) and mice, and progress in discovering and understanding the genes in these other species may come to shed light on the etiology in humans. Mice homozygous for mutations in the forkhead/winged helix (Mf1) gene have skeletal and eye anomalies and hydrocephalus associated with abnormal differentiation of arachnoid cells.241 Heterozygous mice, and humans with mutations in the equivalent gene (FOXC1/FREAC3 on 6p25), have Axenfeld-Rieger malformation (iridogoniodysgenesis type 1),242 and testing of human syndromes (Table 15-11) with resemblance to the Mf1 / mouse would be of interest. Other mouse models include Otx2 þ/ (human OTX2 on 14q21-q22) where the pups present with severe lethal hydrocephalus and edematous periventricular white matter243; Tal2 / (human TAL2 on 9q31) in which there is dysgenesis of the midbrain tectum and apparent obstruction of the foramen of Monro244; and Hy3 mice homozygous for mutations in Hydin, which is limited in its expression in the brain to the ciliated lining of the ventricles.245 The latter model appears to underlie developmental anomalies of the subcommissural organ with aqueductal stenosis.5,246 Mice homozygous for a disruption of the nuclear factor 1-A gene (Nfia) (human NFIA on 1p31.3-p31.2) usually die within 2 weeks of birth with absent corpus callosum and early signs of hydrocephalus.247 The few Nfia -/- survivors have an almost normal life span, callosal agenesis, neurologic and fertility deficits, and severe communicating hydrocephalus. Prognosis, Treatment, and Prevention

In discussing the prognosis and treatment of patients with hydrocephalus it is important to consider the age at diagnosis, the type of treatment, the etiology, and whether there are associated intracranial or extracranial malformations. An important group of patients are those in whom the diagnosis is made by prenatal ultrasound done on a routine basis or because of family history or a gestational problem. Not atypical is the report from one center that 38% of its referrals for prenatal assessment were for fetal ventriculomegaly.15 Recent years have seen several reviews of fetal ventriculomegaly (FV) in which the authors have provided guidelines for proper prenatal assessment, stressed variables that can have an impact on prognosis, and compiled summaries of reported series so as to have better information available for expectant parents.14,235,248,249 First and foremost it is critical that the ventricular system is assessed accurately and completely using appropriate landmarks and tech-

nique.235 The echogenic characteristics of the ventricular walls may provide some information as to the underlying etiology, and thus the prognosis. For example, increased echogenicity suggests intraventricular hemorrhage, whereas a thick and irregular appearance that is accompanied by mild atrial dilation can suggest a neuronal migrational defect.249 Studies suggest that measurement of ventricular size can be reliable and reproducible. Mean measurements have ranged from 5.6 to 7.4 mm,14 and generally have shown little variation across gestation from 15 to 35 weeks. Different surveys have found that 10 mm represents anywhere from 2.5 to
4 SD above the mean, but there is consensus that it is a reasonable cut-off for defining FV. Although the mean diameter in males has ranged from 0.1 to 0.6 mm above that in females, and many studies have noted an excess of males with mild FV, the use of a higher figure (e.g., 12 mm) for males has not met with general acceptance.14 The upper limit for the diameter of the 3rd ventricle is 3.5 mm by ultrasound and 4 mm with MRI, and the respective values for the 4th ventricle are 4.8 mm and 7 mm, respectively.249 Mild FV, as defined earlier as >10 to 15 mm, is generally considered to have a better prognosis than that exceeding 15 mm, and it is certainly more common and has attracted most of the attention in recent reports. Therefore, it is interesting to note that in their review Kelly et al.235 found a mean of 40% of cases of FV had an associated malformation, and that the rate was 43% if the summary was limited to those with mild FV. Furthermore, the rate of associated chromosomal anomalies has not always differed between the two groups.250 Perhaps the most important variable in estimating prognosis is whether the FV is isolated or whether it is associated with other CNS and/or extracranial malformations, which will sometimes define a syndrome. Given that fetal imaging is unable to detect all associated anomalies, it can only be said that the fetus has sonographically isolated ventriculomegaly (SIV). A review of studies on the accuracy of the detection of additional anomalies in the face of FV found that 12.8% of fetuses with SIV had another malformation that was detected at follow-up or after birth.14 However, the rates of non-detection vary greatly between individual studies (e.g., 0/27251 to 10/14252). Notwithstanding the small study sizes, the differences seem unlikely to be solely due to chance, and variables that could affect the rate of non-detection would be important to consider when counseling families. There is some evidence that fetuses with minimal ventriculomegaly (<12 mm) are less likely to have associated anomalies and will do better.248,251,253 Critical is the actual gestational age at the time the FV is detected. Several significant CNS malformations are not subject to reliable sonographic diagnosis below 20 weeks gestation. Of the 10 undetected anomalies in the study of Greco et al.,252 there were five with absence of the corpus callosum, one with lissencephaly, and one with heterotopias. Given the greater difficulty in detecting associated CNS malformations in earlier gestations, there seems little to justify attempting to diagnose FV by transvaginal ultrasonography at between 14 to 18 weeks, except where there is a high recurrence risk of a known syndrome.254 Studies also vary widely in the proportion of fetuses subject to amniocentesis for karyotyping, and in the proportion studied for fetal infections such as toxoplasmosis, cytomegalovirus, and parvovirus B19. Variation in the frequency of associated chromosome anomalies can reasonably be attributed to the small sample size in most studies. In summarizing the literature, Kelly et al.235 concluded that 9% of 491 fetuses with mild FV had a chromosome anomaly and that the rate fell to 4% if cases with

Brain

other malformations were excluded. This is comparable to the 14/ 324 (4.3%) reported by Wax et al.14 The use of ancillary fetal MRI can also affect the status of a fetus with SIV but has been used in relatively few series to date. In one such study the addition of MRI provided additional information in 32.8% of 51 cases and provided a diagnosis in 21.3%.255 A further potential variable is the natural history of the ventriculomegaly. A summary to date of mild FV suggests that about 29% will resolve, 57% remain stable, and 14% progress. The prognosis of the first group is not guaranteed to be normal; it has been suggested to be superior,253,256 although some have argued that some of such cases do not merit the diagnosis of FV.257 Those fetuses in which the ventriculomegaly progresses, both isolated and in association with additional anomalies, appear to have a worse prognosis,256 and the data from Pilu et al.248 suggest females with FV may be at greater risk for a poor developmental outcome. Finally, in addition to the caveats outlined previously, outcome data are variably compromised by underlying case heterogeneity, notably whether or not patients with meningomyeloceles have been excluded, a generally limited period of follow-up, and lack of constant and formal developmental evaluations.249 However, Wax et al.14 found favorable outcomes in 168/199 (84.4%) of cases that had normal chromosomes, and Kelly et al.235 estimated an overall 90% favorable outcome. Where delay does occur in SIV with normal chromosomes it is most often in the mild range. By contrast to SIV, Wax et al.14 noted that 20/108 (18.5%) of fetuses with additional ultrasound anomalies had a chromosome abnormality and that 18/ 40 (45%) had developmental delay. Clearly there is a dichotomy based on the presence or absence of associated anomalies. However, some circumspection is necessary until more long-term information is available for children who had SIV. For example a small study of five children with mild FV, followed at the ages of 4 to 9 years, found one with ADHD, one with autism, and two with learning disablity.258 Another small controlled study of 22 pairs of children at a mean postnatal age of about 22 months found that children who had FV were at significantly increased risk of developmental delay.259 Guidelines for the management of FV include a detailed pregnancy and family history, an ultrasound search for intracranial and extracranial anomalies including the soft signs of aneuploidy and/or evidence of an NTD, serial ultrasounds to continue the search for anomalies and to follow the course of the FV, screening for teratogenic infections, consideration of fetal karyotyping, and fetal MRI. A search for potential causes of fetal intracranial hemorrhage has been suggested by some235 but has a relatively low yield and perhaps can be reserved for cases where the ultrasound is suggestive of a bleed. It has been suggested that unilateral, prenatal ventriculomegaly may have a generally better prognosis than its bilateral counterpart, and that it should be considered separately. Wax et al.14 summarized cases from the literature and none of 47 had a significant anomaly detected postnatally; 1 of 30 had a chromosome anomaly; and 3 of 51 were developmentally delayed. A review of 55 cases from the recent literature12,26,27,236 is perhaps not quite as optimistic. At least five cases underwent spontaneous resolution; a further 32 were considered normal at follow-up; 18 had a variety of associated findings and/or developmental delay. Included in the latter patients were three with atresia of the foramen of Monro, four with a syndrome, two with prenatal intracranial bleeds, four with associated intracranial developmental pathology, one with toxoplasmosis, and four with idiopathic neurologic impairment. Two patients had died and three pregnancies were terminated. The lack of any associated anomalies and a stable or resolving ventriculomegaly was highly associated with a good outcome, with the converse suggestive of a

627

poor prognosis. Thus, management requires a careful ultrasound and/or MRI search for associated CNS or non-CNS anomalies and continued monitoring during pregnancy and after delivery. Not all patients will require intervention.12 Overall the developmental outlook for children with congenital hydrocephalus is poor, and fetuses in which the diagnosis of hydrocephalus is made before 32 weeks gestation do worse than those in whom the diagnosis is made later in pregnancy. This suggests that there could be a role for the in utero shunting of early progressive hydrocephalus. In addition some animal studies have suggested some benefit from in utero shunting. Studies of human fetuses and animal experimentation have shown hydrocephalusrelated changes in brain histology, including impaired myelinization and neuronal migration, axonal damage and degeneration, neuronal loss, decreased synapses, and gliosis.260 In a rat model, Del Bigio261 and co-workers have shown white matter injury due to elevated calcium and activation of proteolytic calpains. Blood flow is seen to increase with shunting and normalization of pressure; but while there was some recovery of myelinization and lamination, there was only partial recovery of synapses and neuronal size. Experimental studies have also shown early initial changes in cellular membrane lipids, followed by decreased levels of intracellular metabolites, thus resulting in cellular swelling and loss of osmolytes and neurotransmitters.262 The outcomes from initial attempts to install in utero shunts in humans have been disappointing, but at least in part this might be attributable to the inclusion of patients with additional CNS pathology. A voluntary international registry was established, and it formulated guidelines for the selection of patients for in utero placements of shunts. Patients with additional CNS anomalies were to be excluded.260 Forty-one patients were reported to the registry, and they had a mean gestational age at diagnosis of 25 þ/ 2.7 weeks and at treatment of 27 þ/ 2.6 weeks.263 Twenty-two percent were later found to have undetected associated CNS malformations that included holoprosencephaly, Dandy-Walker cyst, porencephaly, and Arnold-Chiari malformation. Of the 83% who survived surgery and were born alive, 53% had serious and 12% mild to moderate handicap. Although survival was somewhat improved, normal development was limited to patients with isolated aqueductal stenosis, a group that has faired at least as well in historical samples. Thus, fetal shunt procedures were largely abandoned in the late 1980s when reviews showed either no improvement or worse outcome in fetuses which were treated prenatally as compared to those treated postnatally.260,263 However, von Koch et al.260 have pointed out that with improved fetal MRI imaging to detect associated CNS malformations, and advances in cytogenetic and molecular prenatal diagnosis, it may be time to reevaluate the role of surgical intervention in a selected subpopulation of fetuses with early progressive hydrocephalus. They argue that the worse prognosis in fetal as compared with neonatal and pediatric diagnosed cases reflects in utero damage that is irreversible by the time of postnatal surgery. Although the argument is quite compelling, it is possible that the earlier onset in the fetal cases is in itself a marker for a more severe underlying CNS pathology, which has an inherently poorer prognosis and will be unaltered by fetal intervention. The answer will only come from a properly designed randomized comparison of intervention with non-intervention. Early induction of labor in the face of advancing hydrocephalus is a balance between the risks of prematurity and the hope that earlier shunting will prevent further brain damage, which would be irreversible at term. There is some consensus to

628

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deliver at about 32 weeks or beyond, depending on lung maturity and clinical aspects surrounding the hydrocephalus. Of children with congenital hydrocephalus unassociated with spina bifida, about 24% are stillborn and 17% die as neonates.234 Eighty-four percent of the 108 children reported by Renier et al.240 were treated at less than 3 months and were followed from 1 to 10 years. Of the 75 1iving at the time of study, 28% had an IQ >80, and in 50% it was < 60. The OFC, ventricular size, and age at surgery were not prognostic of outcome; lack of associated malformations, shunt infections and failures, a developmental quotient of >80 at 6 months, and aqueductal stenosis not due to an X-linked gene or to toxoplasmosis predicted a good outcome. Aqueductal stenosis had an 80% survival to age 10 years and almost one-half had a normal IQ compared with 60% and 20%, respectively, for communicating hydrocephalus. Shunt infections in the perinatal period are often due to gram-negative organisms and can be extremely damaging. Renier et al.240 reported that only 5% of neonates with infected shunts had a normal IQ at the mean follow-up of 7 years, and that half had died by the age of 10 years. In a survey of 1450 cases treated for hydrocephalus, Mori et al.22 confirmed a poor outcome (IQ < 50) was more common in congenital cases, and that associated CNS malformations, seizures, and an increased OFC at birth were predictors of a poor outcome. Fernell et al.264 studied 47 patients in whom hydrocephalus was present at birth from among a group of 202 children with infantile hydrocephalus. Patients with spina bifida were excluded. Thirteen were not shunted, five because it was not required and eight, all of whom died, because of the severity of their problems. Eight of the 34 who were shunted died. Of those over age 2 years, 27% had cerebral palsy, 55% had seizures, and 45% had delayed development, most with an IQ < 50. Only 11 had no major dysfunction. The presence of additional malformations was again a poor prognostic sign. Donders et al.265 reviewed previous studies regarding the importance of early medical variables as predictors of long-term outcome. Problems with earlier studies included variable and often ill-defined sample selection, lack of definition of outcome measures, variation in the medical parameters included in the studies, and inadequate statistical evaluation. The authors reported a multivariate analysis of a mixed group of 48 patients treated before age 1 year and who were between 5.6 and 8.6 years at follow-up. They found that neonatal and infancy problems, most commonly anoxia (and/or early seizures) and ocular defects, were highly predictive of a performance and verbal IQ of < 71. A lacunar skull deformity was associated with a low verbal score. As discussed, the expanding cranium can allow for significant ventricular enlargement and cortical thinning without any actual loss of parenchyma. However, very high-grade ventriculomegaly with cortical thinning and poor response to shunting has been associated with a poor prognosis.264 Young et al.266 used pneumoencephalography to estimate mantle thickness at the time of assessing IQ in 147 patients aged 3 to 20 years. Forty-two of 59 children with isolated hydrocephalus, mostly aqueductal stenosis, had an IQ >80, and 41 had a cerebral mantle of >2.8 cm. Above 2.8 cm there was no correlation with IQ. Ten of those with an IQ < 80 and a mantel < 2.8 cm were treated either late or inadequately. The thickness of the cerebral mantle at the time of diagnosis and the time of the study were both related to early treatment. All patients who were treated before 6 months had a mantle of >2.8 cm, although seven had an IQ < 80. The authors argued that early shunting improved prognosis. Although the case is not proven in that other factors influencing early detection and

presentation could apply, it would appear reasonable to advocate early recognition and treatment of isolated hydrocephalus. However, whereas 41/48 children with isolated hydrocephalus were considered normal, only one-half of 39 children with spina bifida and a mantle of >2.8 cm had an IQ >80. Previous studies of untreated survivors have shown no correlation with mantle thickness and IQ. There are also reports of patients with a normal IQ and mantle thickness of 0.5 cm at the time of treatment.267 Pediatric patients with treated isolated hydrocephalus may show a pattern of motor dysfunction, notably of gait, cognitive problems, especially in non-verbal performance,268 and hypothalamic disturbance resulting in growth failure and short stature. Specific difficulties in coordination, mathematics, and reading269 could result in difficulties with social integration and consequent maladaptive behavior. Difficulties with visuospatial processing and memory have also been described.268 However, Hommet et al.,268 in a study that included eight adults with isolated aqueductal stenosis, found no discrepancy between verbal and non-verbal performance or verbal versus visuospatial memory, and no abnormalities on the Vineland Adaptive Behavioral Scale. Overall, those patients with aqueductal stenosis outperformed those with spina bifida. That shunting can have an immediate benefit was shown in an older population by Czepko et al.270 who performed neuropsychological testing before and 4 to 8 months after shunt placement. Of the 45 treated patients, 81.4% showed improved functioning, 7% were unchanged, and 11.6% declined. Poor prognostic signs included cerebral atrophy and symptomatology that had been present for more than a year. Castro-Gago et al.271 have suggested that measurement of CSF oxypurine values can be used to select patients who require shunting and to follow the status of those who have been shunted. Values of CSF xanthine, hypoxanthine, and total oxypurine were significantly elevated over those in normal controls and in children with self-compensated hydrocephalus. The elevated values returned to normal with treatment and were considered to reflect tissue and cellular hypoxia. A discussion of the indication for specific placements and types of shunts is beyond the scope of this discussion; the reader is referred to standard neurosurgical references. Ventriculoperitoneal and cystoperitoneal shunts have been the standard method of CSF diversion for over 40 years, but while they can be highly effective, they are also plagued by a long list of potential complications, some of which are rather common. Among the difficulties that can arise, which include slit 3rd ventricle, craniosynostosis, lumbar canal stenosis, subdural hematomas, sylvian aqueduct syndrome, chronic tonsilar herniation, non-resorptive peritoneal ascites, trapped 4th ventricle, and renal and/or cardiac failure with ventriculoatrial shunts,272 infection and various types of shunt failure are the most important. Newer techniques of manufacture have reduced material failures, but shunt obstruction and migration still occur. Development of anti-siphon valves to prevent transmission of negative pressure from the pleural space may allow the safer use of ventriculopleural drainage when other approaches may be precluded by complications such as peritoneal adhesions, peritonitis, or persistent ascites.273 However, shunt obstruction is an ongoing risk to patients; in a series of 1564 children followed by Vinchon et al.274 for a mean of 10.7 years, they observed that 70.7% required at least one revision. They found that children whose shunt failure was detected and repaired while they were asymptomatic showed a lower rate of shunt infection and recurrent shunt failure than those children whose shunt replacement occurred after they became symptomatic.

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The rate of shunt infection has varied from < 1–30%, and a rate of about 10% has been treated as acceptable.275 About 90% of infections occur in the first 6 months after surgery,276 many in the first 2 months, and infection introduced at the time of surgery is believed to be the main source. Several centers have shown a reduction in rates of infection in parallel with changes in type of shunt and surgical protocols.275-277 Staphlococcus epidermidis is the causative agent in most cases, but Caboulives et al.276 completed a meta-analysis with the conclusion that there were inadequate data on which to base a recommendation for or against prophylactic antibiotics. A prospective randomized trial of a standard shunt versus an antibiotic impregnated shunt (AIS) had infection in 10/60 of the controls and 3/50 of the AIS group.278 All the control group infections, but none of those in the AIS group, were with S. epidermidis. Complications and infections are much more common in preterm and term neonates than in older children. For example, Bruinsma et al.279 had a 46.4% rate of infection in 28 patients who were < 37 weeks gestation at the time of surgery, as compared to 19.6% in those under 6 months at the time of surgery. A not infrequent complication of shunting is the development of shunt dependence, the requirement for a shunt even after the initial cause for the hydrocephalus has been resolved. As discussed earlier, the cerebral veins are thought to play an important role in the regulation of cerebral blood flow and in CSF dynamics. One hypothesis for shunt dependence is that chronic drainage by the shunt leads to persistent venous dilation, and that the venous role is subverted and hard to regain, even after the shunt is removed.9 Initial work with programmable valves, which can be used to reduce venous drainage and increase intraventricular pressure, suggest that this approach may allow a greater proportion of shunts to be removed.280 Close monitoring is required with this approach. Historically, several other approaches to the relief of hydrocephalus, such as aqueductal stenting and 3rd ventriculostomy, have been attempted and largely abandoned because of the surgical complexity and high associated morbidity. However, the development of fiberoptic endoscopy opened up the option of 3rd ventriculostomy, in which a stoma is created in the floor of the 3rd ventricle, allowing the CSF to drain into the subarachnoid space of the interpeduncular cistern. Initial enthusiasm has been tempered somewhat by the reality of complications and failures.272 However, in carefully selected patients it has significant advantages and may be the treatment of choice. Brockmeyer et al.281 attempted 98 ventriculostomy procedures on 97 patients, of which 26 were abandoned because of the anatomy found at surgery, inability to perform the cisterotomy, or bleeding. Of the 71 patients who had a completed procedure, 49% were successful, either in avoiding a shunt or in allowing a shunt to be removed. Although the numbers were small, the greatest rate of success was with aqueductal stenosis, posterior fossa and tectal plate tumors, and the slit ventricle syndrome. A prior history of having a shunt was the only factor significantly associated with failure. Greitz et al.9 suggest that chronic ventricular dilation causes compression of the subarachnoid space and restricted arterial pulsation, thus converting an obstructive hydrocephalus into a communicating hydrocephalus, which is not aided by the 3rd ventriculostomy. Cinalli272 has emphasized the importance of accurately diagnosing aqueductal stenosis, so as to diminish failure rates. Whereas some authors have suggested radiologic criteria that would exclude certain patients from ventriculostomy, he has argued that those criteria change with insertion of the endoscope and removal of a

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small amount of CSF, and that a decision as to whether or not to proceed to ventriculostomy can be made at the time of surgery. The decrease in ventricular size is less, and slower to occur, with ventriculostomy than with a shunt,272 and continuous intracranial monitoring has been suggested as an effective way to follow these patients in the postoperative period and to deal with the intracranial hypertension that can occur.282 To date there is no randomized controlled trial of ventriculostomy versus shunting. Retrospective studies do not show significant differences in mortality, neurologic or endocrine dysfunction, behavior or social status.272 Data from series suggest that 80% of patients with isolated aqueductal stenosis treated by 3rd ventriculostomy have an IQ of over 80.283 Failures occur with the procedure, including sealing of the stoma, but in selected cases may be  25% at 6 years.272 Cinalli272 disagrees with those who state that age  1 year is a factor in treatment failure. The slit ventricle syndrome is an uncommon complication of treatment that merits brief mention because it may go unrecognized and have serious consequences. Following successful shunting, the ventricles assume a normal or even reduced size. A small number of patients present, usually 3 to 5 years after their first early shunt, with chronic or intermittent headache, nausea and vomiting, and occasionally loss of consciousness in the absence of ventriculomegaly. This slit ventricle syndrome was believed to be due to periodic shunt blockage resulting from the narrowly apposed ventricular walls, but the true situation is likely more complex and may relate to changes in intracranial CSF space and compliance, secondary to chronic CSF drainage.284 The underlying problem may be an excess drainage of CSF, and Greitz et al.9 believe that this causes a reduction of systolic expulsion of CSF through the foramen magnum with a corresponding reduction in diastolic venous counter pressure, thus creating a communicating hydrocephalus. Epstein et al.285 reported 20 cases from among 2000 patients. In 6 of the 20, ventricular size was normal when asymptomatic, but moderately increased while symptomatic, thus documenting intermittent shunt malfunction. They stressed the importance of doing diagnostic studies while the patient is symptomatic. The remaining 14 children had a relatively small calvarium and elevated CSF pressure in the face of normal shunt function. They hypothesized that initial shunting led to collapse of the skull and fusion of the sutures, and those patients benefited from craniectomies. There has been moderate success in treating slit ventricle by ventriculostomy.281 To a large extent prevention of hydrocephalus awaits increased knowledge and understanding of its many prenatal, perinatal, and postnatal causes, including infections and trauma. Ultimately, public health measures aimed at preventing prenatal infection and at improving prenatal and obstetric care can be expected to have their impact. Hydrocephalus associated with perinatal hemorrhage has a generally poor prognosis and is an important complication of prematurity. Several preventive and therapeutic approaches have been attempted including streptokinase, urokinase, plasminogen activator, steroids, hyaluronidase, and selective venous dilators.260 Meta-analysis has shown no benefit, and an increased need for ventilator support, with phenobarbitone,286 and no evidence to date of benefit from intraventricular streptokinase.287 A phase 1 trial of drainage, irrigation with artificial CSF, and prior intravenous plasminogen activator has shown a downward trend in mortality, and single and multiple disabilities.288 Alloimmune thrombocytopenia affects about 0.01% of pregnancies, and about 10–20% of those will suffer either a prenatal or perinatal intracranial bleed that may lead to hydrocephalus. Maternal treatment with high-dose immunoglobulin and/or corticosteroids may significantly reduce this risk.289

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Appropriate counseling and advice regarding prenatal diagnosis should be provided to the family at risk for recurrence of a specific syndrome. In the absence of a specific syndrome, including proven X-linked hydrocephalus, empiric recurrence risk data must be applied. However, even in the absence of a syndrome diagnosis, it is important to distinguish isolated hydrocephalus from that associated with other CNS malformations. The 205 patients reported by Burton239 had 353 siblings, of whom 5 were also affected. This included 4 males of 123 siblings of male index cases with aqueductal stenosis who also had other matrilineal male-affected relatives. This provided a 6% risk to siblings, and a 12% risk to male siblings, of males with aqueductal stenosis. There was one recurrence among 154 siblings of patients with communicating hydrocephalus, 0/54 with Dandy-Walker malformation, and 0/22 in the ‘‘other’’ category. Howard et al.290 provide a 4.5% recurrence risk for a male sibling and 2% for a female sibling of a male propositus with aqueductal stenosis, and a 1% risk for all siblings of a female propositus. Varadi et al.291 followed 261 pregnancies of 362 couples who had been referred because of a personal or family history of a child with hydrocephalus. They considered children with neural tube defects, other associated malformations, and no associated anomalies as distinct groups. Parents of one previous child with isolated hydrocephalus experienced a 5/89 (5.6%) recurrence rate. In two instances, both propositus and sibling were male. Hydrocephalus was not broken down into communicating versus aqueductal. The higher recurrence rates are likely due in part to the prenatal/ prospective nature of the study, and may also reflect relatively small numbers. Haverkamp et al.292 recently proposed a genetic etiology for 13 of 35 (37%) of their cases of aqueductal stenosis. However, they included both members of two sibling sets in the total (11/33 more appropriate), assumed that all four cases of VACTERL syndrome with hydrocephalus were mendelian, and included a case of Krabbe disease, as well as four cases of ‘‘phenotypic abnormalities not classified’’ in the genetic total. A cautious approach is needed if using these types of data in genetic counseling. Summarizing data to date, male siblings of a male propositus with aqueductal stenosis have a 12% risk, female siblings a 6% risk, and the siblings of a female propositus a 2% risk for hydrocephalus.292 Adams et al.293 addressed and summarized the question as to whether relatives of propositi who have isolated hydrocephalus are at greater risk for neural tube defects. They found that in 74 families in which there were 159 siblings, three (1.83%) had hydrocephalus and one (0.63%) had spina bifida. Seven of 846 first cousins had spina bifida, one anencephaly, and three isolated hydrocephalus. Thus, there was no increased incidence of neural tube defects over that expected in the general Northern Ireland population. Other studies have suggested an increased risk, and differences may reflect endemic versus nonendemic neural tube defects and the possibility of unrecognized neural tube defects in the index patients with hydrocephalus. Journel et al.294 examined the question from the opposite perspective and studied the rate of hydrocephalus among the relatives of propositi with neural tube defects. Three of 691 siblings had hydrocephalus, whereas rates of 1/460 and 1/430 were found in uncles and cousins, respectively. This was considered to be somewhat increased over expected, but unfortunately there were no control groups or local data on the frequency of hydrocephalus. Finally, a cautious approach to the prospective prenatal ultrasound diagnosis of hydrocephalus is emphasized. As discussed

in some detail, a fetus with a mild ventriculomegaly may not have true and/or progressive hydrocephalus and has a generally good prognosis. Second, ventriculomegaly may become apparent after the usual 20-week window for prenatal diagnosis. Friedman et al.295 reported two patients with X-linked aqueductal stenosis who had normal studies at 17–18 weeks, ventriculomegaly by 22 weeks, and an increased biparietal diameter by 30 weeks. References (Hydrocephalus) 1. Friede RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 203. 2. Bell, WO: Cerebrospinal fluid reabsorption. Concepts Pediatr Neurosurg 10:214, 1990. 3. Mortensen OA, Weed LH: Absorption of isotonic fluids from subarachnoid space. Am J Physiol l08:458, 1934. 4. De Lange SA: Progressive hydrocephalus. In: Handbook of Clinical Neurology. Congenital Malformations of the Brain and Skull, Part I. PJ Vinkin, GW Bruyn, eds. North Holland Publishing, Amsterdam, 1977, p 525. 5. Perez-Figares JM, Jimenez AJ, Rodriguez EM: Subcommissural organ, cerebrospinal fluid circulation, and hydrocephalus. Microsc Res Tech 52:591, 2001. 6. Mawera G, Asala SA: The function of arachnoid villi/granulations revisited. Cent Afr J Med 42:281, 1996. 7. Johnston M, Papaiconomou C: Cerebrospinal fluid transport: a lymphatic perpspective. News Physiol Sci 17:227, 2002. 8. Greitz D, Hannerz J: A proposed model of cerebrospinal fluid circulation; observations with radionuclide cisternography. AJNR Am J Neuroradiol 17:431, 1996. 9. Greitz D, Greitz T, Hindmarsh T: A new view on the CSF-circulation with the potential for pharmacological treatment of childhood hydrocephalus. Acta Pediatr 86:125, 1997. 10. Reed DJ, Woodbury DM: Kinetics of iodide, sucrose, inulin, and radio-iodinated serum albumin in the central nervous system and cerebrospinal fluid of the rat. J Physiol 169:816, 1963. 11. Kollar CD, Johnston IH, Sholler GF: Communicating hydrocephalus secondary to a cardiac tumour compressing the superior vena cava. Child Nerv Syst 17:117, 2001. 12. Sherer DM, Allen TA, Ghezzi F: Prenatal diagnosis of moderate unilateral hydrocephalus subsequently not requiring neonatal decompression. Am J Perinatol 12:50, 1995. 13. Johnson ML, Dunne MG, Mack, LA, et al.: Evaluation of fetal intracranial anatomy by static and real time ultrasound. J Clin Ultrasound 8:311, 1980. 14. Wax J, Bookman L, Cartin A, et al.: Mild fetal ventriculomegaly: diagnosis, clinical associations, and outcomes. Obstet Gynecol Surv 58: 407, 2003. 15. Girard NJ, Raybaud CA: Ventriculomegaly and pericerebral CSF collection in the fetus: early stage of benign external hydrocephalus? Child Nerv System 17:239, 2001. 16. Lowry DW, Lowry DL, Berga SL, et al.: Secondary amenorrhea due to hydrocephalus treated with endoscopic ventriculostomy. Case report. J Neurosurg 85:1148, 1996. 17. Kirkpatrick M, Engleman H, Minns RA: Symptoms and signs of progressive hydrocephalus. Arch Dis Child 64:124, 1989. 18. Di Rocco C, Caldarelli M, Ceddia A: ‘‘Occult’’ hydrocephalus in children. Child Nerv Syst 5:71, 1989. 19. Bromberger P, James HE, Saunders B, et al.: Sudden infant apnea and insidious hydrocephalus. Child Nerv Syst 4:241, 1988. 20. Corbett JJ: Neuro-ophthalmologic complications of hydrocephalus and shunting procedures. Semin Neurol 6:111, 1986. 21. Bech RA, Juhler M: Unusual manifestations of disturbed CSF dynamics in hydrocephalic chidren. Child Nerv Syst 16:446, 2000. 22. Mori K, Shimada J, Kurisaka M, et al.: Classification of hydrocephalus and outcome of treatment. Brain Dev 17:338, 1995. 23. Barkovich AJ, Edwards MSB: Applications of neuroimaging in hydrocephalus. Pediatr Neurosurg 18:65, 1992.

Brain 24. Venkataramana NK, Satishchandra P, Hegde AS, et al.: Evaluation of brainstem auditory evoked responses in congenital hydrocephalus. Child Nerv Syst 4:334, 1988. 25. Gaston BM, Jones BE: Perinatal unilateral hydrocephalus: atresia of the foramen of Monro. Pediatr Radiol 18:328, 1989. 26. Senat MV, Bernard JP, Schwarzler P, et al.: Prenatal diagnosis and follow-up of 14 cases of unilateral venriculomegaly. Ultrasound Obstet Gynecol 14:327, 1999. 27. Durfee SM, Kim FM, Benson CB: Postnatal outcome of fetuses with the prenatal diagnosis of asymmetric hydrocephalus. J Ultrasound Med 20:179, 2001. 28. Chow CW, McKelvie PA, Anderson RMCD, et al.: Autosomal recessive hydrocephalus with third ventricle obstruction. Am J Med Genet 35: 310, 1990. 29. Landrieu P, Ninane J, Ferriere G, et al.: Aqueductal stenosis in X-linked hydrocephalus: a secondary phenomenon? Dev Med Child Neurol 21: 637, 1979. 30. Drachman DA, Richardson EP: Aqueductal narrowing, congenital and acquired: a critical review of the histologic criteria. Arch Neurol 5:552, 1961. 31. Johnson RT, Johnson KP: Hydrocephalus following viral infection: the pathology of aqueductal stenosis developing after experimental mumps virus infection. J Neuropathol Exp Neurol 27:591, 1968. 32. Coker SB: Bobble-head doll syndrome due to trapped fourth ventricle and aqueduct. Pediatr Neurol 2:115, 1986. 33. Barkovich AJ, Newton TH: MR of aqueductal stenosis: evidence of a broad spectrum of tectal distortion. AJNR Am J Neuroradiol 10:471, 1989. 34. Turnbull IM, Drake CG: Membranous occlusion of the aqueduct of sylvius. J Neurosurg 24:24, 1966. 35. Bhattacharyya KB, Senapati A, Basu S, et al.: Bobble-head doll syndrome: some atypical features with a new lesion and review of the literature. Acta Neurol Scand 108:216, 2003. 36. Bickers DS, Adams RD: Hereditary stenosis of aqueduct of sylvius as a cause of congenital hydrocephalus. Brain 72:246, 1949. 37. Viseskul C, Gilbert EF, Opitz JM: X-linked hydrocephalus: further observations. Z Kinderheilkd 119:11, 1975. 38. Edwards JH: The syndrome of sex-linked hydrocephalus. Arch Dis Child 36:486, 1961. 39. Vanlieferinghen P, Chazal J, Francannet C, et al.: Ste´nose conge´nitale de l’aqueduc de sylvius a transmission re´cessive autosominque. J Ge´ne´t Hum 35:251, 1986. 40. Kamiguchi H, Hlavin ML, Yamasaki M, et al.: Adhesion molecules and inherited diseases of the human nervous system. Ann Rev Neurosci 21:97, 1998. 41. Schrander-Stumpel C, Fryns J-P: Congenital hydrocephalus: nosology and guidelines for clinical approach and genetic counselling. Eur J Pediatr 157:355, 1998. 42. Gilles FH, Davidson RI: Communicating hydrocephalus associated with deficient dysplastic parasagittal arachnoid granulations. J Neurosurg 35:421, 1971. 43. Yamada H, Nakamura S, Tajima M, et al.: Neurological manifestations of pediatric achondroplasia. J Neurosurg 54:49, 1981. 44. Steinbok P, Hall J, F1odmark O: Hydrocephalus in achondroplasia: the possible role of intracranial venous hypertension. J Neurosurg 71:422, 1989. 45. MacDonald IM, Hunter AGW, MacLeod PM, et al.: Growth and development in thanatophoric dysplasia. Am J Med Genet 33:508, 1989. 46. Patton MA, Sharma A, Winter RM. The Aase-Smith syndrome. Clin Genet 28:521, 1985. 47. Hall JG, Horton W, Kelly T, et al.: Head growth in achondroplasia: use of ultrasound studies [letter to the editor]. Am J Med Genet 13:105, 1982. 48. Kurata H, Tamaki N, Sawa H, et al.: Acrania: report of the first surviving case. Pediatr Neurosurg 24:52, 1996. 49. Goldstein DJ, Mirkin LD: Nager acrofacial dysostosis: evidence for apparent heterogeneity. Am J Med Genet 30:741, 1988. 50. Rodriguez JI, Palacios J, Urioste M: New acrofacial dysostosis syndrome in 3 sibs. Am J Med Genet 35:484, 1990.

631 51. Verloes A, Gillerot Y, Walczak E, et al.: Acromelic frontonasal ‘‘dysplasia’’: further delineation of a subtype with brain malformation and polydactyly (Toriello syndrome). Am J Med Genet 42:180, 1992. 52. Dube P, Der Kaloustian VM, Demczuk S, et al.: A new association of congenital hydrocephalus, albinism, megalocornea, and retinal coloboma in a syndromic child: a clinical and genetic study. Ophthalmic Genet 21:211, 2000. 53. al-Gazali LI, Bakir M, Sadaghatian MR, et al.: Anterior segment anomalies of the eye associated with multiple skeletal abnormalities and early lethality: confirmation of an autosomal recessive syndrome. Clin Dysmorphol 8:87, 1999. 54. al-Gazali LI, Aziz SAA, Salem F: A syndrome of short stature, mental retardation, facial dysmorphism, short webbed neck, skin changes and congenital heart disease. Clin Dysmorphol 5:321, 1996. 55. Musumeci SA, Elia M, Ferri R, et al.: A further family with epilepsy, dementia and yellow teeth: the Kohlschutter syndrome. Brain Dev 17: 133, 1995. 56. Fraser FC, Anderson RA, Mulvihill JI, et al.: An aminopterin-like syndrome without aminopterin (ASSAS). Clin Genet 32:28, 1987. 57. Reich EW, Cox RP, Decker MH, et al.: Recognition in adult patients of malformations induced by folic-acid antagonists. Birth Defects Orig Artic Ser XIV(6B):139,1978. 58. Chong SKF, Levitt GA, Lawson J, et al: Subarachnoid cyst with hydrocephalus-a complication of mid-trimester amniocentesis. Prenat Diagn 9:677, 1989. 59. Baker DW, Vinters HV: Hydrocephalus with cerebral aqueductal dysgenesis and craniofacial anomalies. Acta Neuropathol 63:170, 1984. 60. Sommer A, Rathbun MA, Battles ML: A syndrome of partial aniridia, unilateral renal agenesis, and mild psychomotor retardation in siblings. J Pediatr 85:870, 1974. 61. Leichtman LG, Wood B, Rohn R: Anophthalmia, cleft lip/palate, facial anomalies, and CNS anomalies and hypothalamic disorder in a newborn: a midline developmental field defect. Am J Med Genet 50:39, 1994. 62. Richeri-Costa A, Guin-Almeida ML: Mental retardation, structural anomalies of the central nervous system, anophthalmia and abnormal nares: A new MCA/MR syndrome of unknown cause. Am J Med Genet 47:702, 1993. 63. Gunderson CA, Stone R, Peiffer R, et al.: Corneal coloboma, aphakia and retinal neovascularization with anterior segment dysgenesis (Peters’ anomaly). Ophthalmologia 210:361, 1996. 64. Slee J, Goldblatt J: Further evidence for a syndrome of ‘‘apple peel’’ intestinal atresia, ocular anomalies and microcephaly. Clin Genet 50:260, 1996. 65. Verhagen WIM, Bartels RHAM, Fransen E, et al.: Familial congenital hydrocephalus and aqueduct stenosis with probably autosomal dominant inheritance and variable expression. J Neurol Sci 158:101, 1998. 66. Zlotogora J, Sagi M, Cohen T: Familial hydrocephalus of prenatal onset. Am J Med Genet 49:202, 1994. 67. Sajid MH, Copple PJ: Familial aqueduct stenosis and basilar impression. Neurology 18:260, 1968. 68. Stern HJ, Graham J Jr, Lachman RS, et al.: Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II. Am J Med Genet 36:183, 1990. 69. Moog U, Bleeker-Wagemakers EM, Crobach P, et al.: Sibs with AxenfeldRieger anomaly, hydrocephalus, and leptomeningeal calcifications: A new autosomal recessive syndrome? Am J Med Genet 78:263, 1998. 70. Russell LJ, Weaver DD, Bull MJ: The axial mesodermal dysplasia spectrum. Pediatrics 67:176, 1981. 71. Barnicoat AJ, Salman M, Chitty L, et al.: A distinctive overgrowth syndrome with polysyndactyly. Clin Dysmorphol 5:339, 1996. 72. Lo Muzio L, Nocini PF, Savoia A, et al.: Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet 55:34, 1999. 73. Beemer FA, Ertbruggen IV: Peculiar facial appearance, hydrocephalus, double-outlet right ventricle, genital anomalies and dense bones with lethal outcome. Am J Med Genet 19:391, 1984. 74. Bellini F, Chiumello G, Rimoldi R, et al.: Wedge-shaped epiphyses of the knees in two siblings: a new recessive rare dysplasia? Helv Paediatr Acta 39:365, 1984.

632

Neuromuscular Systems

75. Bijlsma JB: MR, cleft palate, aqueduct stenosis, contractures. Synd Ident VI(1):4, 1980. 76. Cole OEC, Carpenter TO: Bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: a newly recognized type of osteogenesis imperfecta. J Pediatr 110:76, 1987. 77. Reish O, Gorlin RJ, Hordinsky M, et al.: Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/ BRESHECK). Am J Med Genet 68:386, 1997. 78. Brooks SS, Wisniewski K, Brown WT: New X-linked mental retardation (XLMR) syndrome with distinct facial appearance and growth retardation. Am J Med Genet 51:586, 1994. 79. Stevenson RE: Campomelia, prenatal fractures, and ankyloglossia superior. Proc Greenwood Genet Center 1:47, 1982. 80. Cameron FJ, Hageman RM, Cooke-Yarborough CM, et al.: A novel germ line mutation in the SOX9 causes familial campomelic dysplasia and sex reversal. Hum Mol Genet 5:1625, 1996. 81. de Leon GA, Zaeri N, Donner RM, et al.: Cerebral rhinocele, hydrocephalus, and cleft lip and palate in infants with cardiac fibroma. J Neurol Sci 99:27, 1990. 82. Lazalde B, Sa´nchez-Urbina R, Nun˜o-Arana I, et al.: Autosomal dominant inheritance in Cantu´ syndrome (congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly): Am J Med Genet 94:421, 2000. 83. Carpenter BF, Hunter AGW. Micromelia, polysyndactyly, multiple malformations, and fragile bones in a stillborn child. J Med Genet 19:311, 1982. 84. Collacott RA, O’Malley BP, Young IO: The syndrome of mental handicap, cataracts, muscle wasting and skeletal abnormalities: report of a second case. J Ment Defic Res 30:301, 1986. 85. Lynch SA, Lee SG, Murday VA: Caudal appendage, short terminal phalanges, deafness, cryptorchidism and mental retardation: a new syndrome? Clin Dysmorphol 3:340, 1994. 86. Valkova G, Ghenev E, Tzancheva M: Centromeric instability of chromosomes 1, 9 and 16 with variable immune deficiency: support of a new syndrome. Clin Genet 31:119, 1987. 87. Spranger S, Spranger M, Tasman AJ, et al.: Barraquer-Simons syndrome (with sensorineural deafness): A contribution to the differential diagnosis of lipodystrophy syndromes. Am J Med Genet 71:397, 1997. 88. Turnpenny P, Ashworth M, Harding B, et al.: Hydrocephalus, severe hypoplasia, and brain stem calcification—a new autosomal recessive syndrome. Eur J Hum Genet 4:132A, 1996. 89. Spranger JW, Schinzel A, Myers T, et al.: Cerebroarthrodigital syndrome: a newly recognized formal genesis syndrome in three patients with apparent arthromyodysplasia and sacral agenesis, brain malformation and digital hypoplasia. Am J Med Genet 5:13, 1980. 90. Ercal D, Say B: Cerebro-oculo-nasal syndrome: another case and review of the literature. Clin Dysmorphol 7:139, 1998. 91. Faye-Petersen OM, Ward K, Carey JC, et al.: New syndrome? Osteochondrodysplasia with rhizomelia, platyspondyly, callosal agenesis, thrombocytopenia, hydrocephalus, and hypertension. Am J Med Genet 40:183, 1991. 92. Schinzel A: Catalogue of Unbalanced Chromosome Aberrations in Man, ed 2. Walter de Gruyter, New York, 2001. 93. POSSUM1, Version 5.6. The Murdoch Institute Royal Children’s Hospital, Melbourne, Australia. 94. Penman Splitt M, Goodship J: Another case of maternal uniparental disomy chromosome 14 syndrome. Am J Med Genet 72:239, 1997. 95. Ostergaard E, Pedersen VF, Skriver EB, et al.: Brothers with ChudleyMcCullough syndrome: sensorineural deafness, agenesis of the corpus callosum, and other structural brain abnormalities. Am J Med Genet 124A:74, 2004. 96. De Santi MM, Magni A, Valletta EA, et al.: Hydrocephalus, bronchiectasis, and ciliary aplasia. Arch Dis Child 65:543, 1990. 97. al-Shroof M, Karnik AM, Karnik AA, et al.: Ciliary dyskinesia associated with hydrocephalus and mental retardation in a Jordanian family. Mayo Clin Proc 76:1219, 2001. 98. Anyane-Yeboa K, Mackay C, Taterka P, et al.: Cleft lip and palate, corneal opacities and profound psychomotor retardation: a newly recognized genetic syndrome? Cleft Palate J 20:246, 1983.

99. Hunter AGW. Coffin-Lowry Syndrome: A 20 year follow-up and review of long term outcomes Am J Med Genet 111:345, 2002. 100. Beals RK, Piatt JH, Zonana J: Craniofacial conodysplasia. J Pediatr Orthop 15:633, 1995. 101. Morton JEV: Craniofacial dyssynostosis: A further clinical report. Am J Med Genet 79:8, 1998. 102. Barr M Jr, Heidelberger KP, Comstock CH: Craniomicromelic syndrome: a newly recognized lethal condition with craniosynostosis, distinct facial anomalies, short limbs, and intrauterine growth retardation. Am J Med Genet 58:348, 1995. 103. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management, ed 2. Oxford University Press, New York, 2000. 104. Orstavik KH, Tangsrud SE, Nordshus T, et al.: Severe craniofacial malformations and deglutition dysfunction in a brother and sister: new syndrome. Am J Med Genet 78:260, 1998. 105. Fransen E, Van Camp G, Vits L, et al.: L1-associated diseases: clinical geneticists divide, molecular geneticists unite. Hum Mol Genet 6:1625, 1997. 106. Hanieh A, Sheen R, David OJ: Hydrocephalus in Crouzon’s syndrome. Child Nerv Syst 5:188, 1989. 107. Clayton-Smith J, Kerr B, Brunner H, et al.: Macrocephaly with cutis marmorata, haemangioma and syndactyly—a distinctive overgrowth syndrome. Clin Dysmorphol 6:291, 1997. 108. al-Ali HY, Yassen SA, Raof TY: Follow-up of pregnant women with active cytomegalic virus infection. East Mediterr Health J 5:949, 1999. 109. Czeizel A: New lethal omphalocele-cleft palate syndrome? Hum Genet 64:99, 1983. 110. Daish P, Hardman MJ, Lamont MA: Hydrocephalus, tall stature, joint laxity, and kyphoscoliosis: a new inherited disorder of connective tissue? Case report. J Med Genet 26:51, 1989. 111. Naritomi K, Tohma T, Goya Y, et al.: Delineation of the da Silva syndrome. Am J Med Genet 49:313, 1994. 112. Van Daele SG, Van Coster RN, Meire F, et al.: Fibrotic eye muscles, axenfeld anomaly, flat face, and mild developmental retardation: a new example of the Chitty syndrome. Am J Med Genet 65:205, 1996. 113. Devi AS, Eisenfeld L, Uphoff D, et al.: New syndrome of hydrocephalus, endocardial fibroelastosis, and cataracts (HEC syndrome). Am J Med Genet 56:62, 1995. 114. Bieber FR, Dawson AE, Holmes LB: Etiologic complexities of diaphragmatic defects: right diaphragmatic hernia, pulmonary hypoplasia/ agenesis, and hydrocephalus in sibs. Am J Med Genet 41:164, 1991. 115. Capin DM, Gottlieb SM, Rosman NP: Central nervous system hemangiomatosis in early childhood. Pediatr Neurol 17:365, 1997. 116. Juberg RC, Van Ness MB: A new syndrome of hereditary short limbed dwarfism with microcephalus. Clin Genet 7:111, 1975. 117. Becker K, Seller MJ, Pal K, et al.: A 46,XX fetus with external female and internal male genitalia, facial dysmorphic features and mildly dilated lateral ventricles of the brain—a new syndrome? Clin Dysmorphol 10: 215, 2001. 118. El Khazen N, Faverly D, Vamos E, et al.: Lethal osteopetrosis with multiple fractures in utero. Am J Med Genet 23:811, 1986. 119. Seow WK, Needleman HL, Smith LEH, et al.: Enamel hypoplasia, bilateral cataracts, and aqueductal stenosis: a new syndrome? Am J Med Genet 58:371, 1995. 120. Goldberg LH, Collins SAB, Siegel DM: The epidermal nevus syndrome: case report and review. Pediatr Dermatol 4:27, 1987. 121. Ayme´ S, Philip N: Fine-Lubinsky syndrome: a fourth patient with brachycephaly, deafness, cataract, microstomia and mental retardation. Clin Dysmorphol 1996; 5:55 122. Boyd PA, Keeling JW, Lindenbaum RH: Fraser syndrome (cryptophthalmos-syndactyly syndrome): a review of eleven cases with post mortem findings. Am J Med Genet 31:159, 1988. 123. Strain L, Wright AF, Bonthron DT: Fried syndrome is a distinct X linked mental retardation syndrome mapping to Xp22. J Med Genet 34:535, 1998. 124. Kimura S, Sasaki Y, Kobayashi T, et al.: Fukuyama-type congenital muscular dystrophy and the Walker-Warburg syndrome. Brain Dev 15:182, 1993.

Brain 125. Game K, Friedman JM, Paradice B, et al. Fetal growth retardation, hydrocephalus, hypoplastic multilobed lungs, and other anomalies in 4 sibs. Am J Med Genet 33:276, 1989. 126. Stone DL, Tayebi N, Coble C, et al.: Cardiovascular fibrosis, hydrocephalus, ophthalmoplegia, and visceral involvement in an American child with Gaucher disease. J Med Genet 37:e40, 2000. 127. Gibson CC, Genest DR, Bieber FR, et al.: X-linked phenotype of absent radius and anogenital anomalies. Am J Med Genet 45:743, 1993. 128. Goldblatt J, Knowles S: A unique lethal spondylocostal metaphyseal dysplasia: a case report. Clin Dysmorphol 7:115, 1998. 129. Aleksic S, Budzilovich G, Greco MA, et al.: Intracranial lipomas, hydrocephalus and other CNS anomalies in oculoauriculo-vertebral dysplasia (Goldenhar-Gorlin syndrome). Child Brain 11:285, 1984. 130. Marafie MJ, Temtamy SA, Rajaram U, et al.: Greig cephalopolysyndactyly syndrome with dysgenesis of the corpus callosum in a Bedouin family. Am J Med Genet 66:261, 1996. 131. Haar F, Dyken P: Hereditary nonprogressive athetotic hemiplegia: a new syndrome. Neurology 27:849, 1977. 132. Laing IA, Lyall EGH, Hendry LM, et al.: ‘‘Typus Edinburgensis’’ explained. Pediatrics 88:151, 1991. 133. Ramos FJ, Kaplan BS, Bellah RD, et al.: Further evidence that the Hajdu-Cheney syndrome and the ‘‘Serpentine fibula-polycystic kidney syndrome’’ are a single entity. Am J Med Genet 78:474, 1998. 134. Hayashi M, Kurati K, Suzuki K, et al.: Megalencephaly, hydrocephalus and cortical dysplasia in severe dwarfism mimicking leprechaunism. Acta Neuropathol (Berl) 95:431, 1998. 135. Reardon W, Harding B, Winter RM, et al.: Hemihypertrophy, hemimegalencephaly, and polydactyly. Am J Med Genet 66:144, 1996. 136. Hendriks YMC, Laan LAEM, Vielvoye GJ, et al.: Bilateral sensorineural deafness, partial agenesis of the corpus callosum, and arachnoid cysts in two sisters. Am J Med Genet 86:183, 1999. 137. Tollner U, Horst J, Manzke E, et al.: Heptacarpo-octatarsodactyly combined with multiple malformations. Eur J Pediatr 136:207, 1981. 138. Hersh JH, Dela Cruz TV, Pietrantoni M, et al.: Mirror image duplication of the hands and feet. Am J Med Genet 59:341, 1995. 139. Manzur AY, Poskitt KJ, Norman MG, et al.: Hydrocephalus, mineralizing angiopathy, hypercholesterolemia, and hyperlipoprotein (a). Pediatr Neurol 13:257, 1995. 140. Cennamo G, Gangemi M, Magli A: Hydrocephalus combined with congenital cataract and microphthalmia. J Pediatr Ophthalmol Strabismus 16:382, 1979. 141. Castro-Gago M, Pintos-Martinez E, Forteza-Vila J, et al.: Congenital hydranencephalic-hydrocephalic syndrome with proliferative vasculopathy: a possible relation with mitochondrial dysfunction. J Child Neurol 16:858, 2001. 142. Ferlini A, Ragno M, Gobbi P, et al.: Hydrocephalus, skeletal anomalies, and mental disturbances in a mother and three daughters: a new syndrome. Am J Med Genet 59:506, 1995. 143. Salonen R, Herva R, Norio R: The hydrolethalus syndrome: delineation of a ‘‘new,’’ lethal malformation syndrome based on 28 patients. Clin Genet 19:321, 1981. 144. Gillerot Y, Van Maldergem L, Chef R, et al.: Hypoglossia-hypodactyly syndrome with hydrocephalus: a clue to the aetiology? J Med Genet 28:490, 1991. 145. Gould AA: Ichthyosis in an infant: hemorrhage from umbilicus: death. Am J Med Sci, 27:356, 1854.(cited in POSSUM1) 146. Conover PT, Roessmann U: Malformational complex in an infant with intrauterine influenza viral infection. Arch Path Lab Med 114:535, 1990. 147. Singh M, Ray D, Paul VK, et al.: Hydrocephalus in asphyxiating thoracic dystrophy. Am J Med Genet 29:391, 1988. 148. Jonas REJ, Kimonis VE, Morales A: Possible new autosomal recessive syndrome of partial agenesis of the corpus callosum, pontine hypoplasia, focal white matter changes, hypotonia, mental retardation, and minor anomalies. Am J Med Genet 73:184, 1997. 149. Kasuya H, Shimizu T, Nakamura S, et al.: Kabuki make-up syndrome and report of a case with hydrocephalus. Child Nerv Syst 14:227, 1998. 150. Frydman M, Weinstock AL, Cohen HA, et al.: Autosomal recessive Peters anomaly, typical facial appearance, failure to thrive, hydro-

633

151. 152.

153. 154.

155. 156. 157. 158.

159.

160. 161.

162.

163.

164.

165. 166.

167.

168.

169. 170. 171. 172.

173.

174.

175.

cephalus, and other anomalies: further delineation of the KrauseKivlin syndrome. Am J Med Genet 40:34, 1991. Caksen H, Kurtoglu S: Larsen syndrome associated with severe congenital hydrocephalus. Genet Couns 12:369, 2001. Schuster V, Mingers AM, Seidenspinner S, et al.: Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous deficiency. Blood 90:958, 1997. Lockwood J, Feingold M: Case report 86. Synd Ident 8:17, 1982. Lurie IW, Kletsky SK: Syndrome identification case report #145: agenesis of the corpus callosum, hydrocephaly, diaphragmatic hernia, and hydrops fetalis. Dysmorphol Clin Genet 4:63, 1990. Williams DK, Carlton DR, Green SH, et al.: Marshall-Smith syndrome: the expanding phenotype. J Med Genet 34:842, 1997. Boyd E, Schwartz CE, Schroer RJ, et al.: Agenesis of the corpus callosum associated with MASA syndrome. Clin Dysmorphol 2:332, 1993. Shanske AL, Baden M, Fernando M, et al.: A possible lethal variant of metatropic dwarfism. Birth Defects Orig Artic Ser 18(3B):135, 1982. al-Gazali LI, Bakir M, Dawodu A, et al.: Recurrence of the severe form of microgastria-limb reduction defect in a consanguineous family. Clin Dysmorphol 8:253, 1999. Kayserilli H, Cox TC, Cox LL, et al.: Molecular characterization of a new case of microphthalmia with linear skin defects (MLS). J Med Genet 38:411, 2001. Mizoguchi K, Nishimura Y, Honda N: A family of hereditary communicating hydrocephalus with trigonocephaly. Brain Nerve 38:917, 1986. Lees MM, Hodgkins P, Reardon W, et al.: Frontonasal dysplasia with optic disc anomalies and other midline craniofacial defects: a report of six cases. Clin Dysmorphol 7:157, 1998. Voorhess ML, Husson GS, Blackman MS: Growth failure with pericardial constriction, the syndrome of MULIBREY nanism. Am J Dis Child 30:1146, 1976. Lindor NM, Hoffman AD, Primrose DA: A neuropsychiatric disorder associated with dense calcification of the external ears and distal muscle wasting: ‘Primrose’ syndrome. Clin Dysmorphol 5:27, 1996. Doerfler W, Wieczorek D, Gillessen-Kaesbach G, et al.: Three brothers with mental and physical retardation, hydrocephalus, microcephaly, internal malformations, speech disorder, and facial anomalies: Mutchinick syndrome. Am J Med Genet 73:210, 1997. Jolly M, Goodburn S, Cox P, et al.: Congenital nephropathy and ventriculomegaly: a report of four cases. Prenat Diagn 23:48, 2003. Palm L, Hagerstrand I, Kristofferson U, et al.: Nephrosis and disturbances of neuronal migration in male siblings—a new hereditary disorder? Arch Dis Child 61:545, 1986. DeDavid M, Orlow SJ, Provost N, et al.: Neurocutaneous melanosis: Clinical features of large congenital melanocytic nevi in patients with manifest central nervous system melanosis. J Am Acad Dermatol 35:529, 1996. Riccardi VM, Eichner JE: Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Johns Hopkins University Press, Baltimore, 1986, p 136. Fryns JP: Progressive hydrocephalus in Noonan syndrome. Clin Dysmorphol 6:379, 1997. Teebi AS, Hassoon MM: Urofacial syndrome associated with hydrocephalus due to aqueductal stenosis. Am J Med Genet 40:199, 1991. Giorgi PL, Gabrielli O, Catassi C, et al.: Oculo-cerebrocutaneoous syndrome: description of a new case. Eur J Pediatr 148:325, 1989. Ohdo S, Sonoda T, Ohba K: Natural history and postmortem anatomy of a patient with tetra-amelia, ectodermal dysplasia, peculiar face, and developmental retardation. J Med Genet 31:980, 1994. Odent S, Le Marec B, Toutain A, et al.: Central nervous system malformations and early end-stage renal disease in Oro-facio-digital syndrome type 1: a review. Am J Med Genet 75:389, 1998. Balci S, Guler G, Kale G, et al.: Mohr syndrome in two sisters: prenatal diagnosis in a 22-week-old fetus with post-mortem findings in both. Prenat Diagn 19:827, 1999. Gabrielli O, Ficcadenti A, Fabrizzi G, et al.: Child with oral, facial, digital, and skeletal anomalies and psychomotor delay: a new OFDS form? Am J Med Genet 53:290, 1994.

634

Neuromuscular Systems

176. Orstavik KH, Stromme P, Spetalen S, et al.: Aplasia cutis congenita associated with limb, eye, and brain anomalies in sibs: a variant of the Adams-Oliver syndrome? Am J Med Genet 59:92, 1995. 177. Knisely AS, Prates RE, Ambler WM, et al.: Hydrocephalus of intrauterine onset in perinatally lethal osteogenesis imperfecta: clinical, sonographic, and pathologic correlations. Pediatr Pathol 8:367, 1988. 178. al Gazali LI, Sabrinathan K, Nair KG: A syndrome of osteogenesis imperfecta, optic atrophy, retinopathy and severe developmental delay in two sibs of consanguineous parents. Clin Dysmorphol 3:55, 1994. 179. Sklower Brooks S, Kassner G, Qazi Q, et al.: Osteoglophonic dysplasia: review and further delineation of the syndrome. Am J Med Genet 66:154, 1996. 180. Stratton RF, Bluestone DL: Oto-palatal-digital syndrome type II with Xlinked cerebellar hypoplasia/hydrocephalus. Am J Med Genet 41:169, 1991. 181. Palmer SE, Pagon RA: Familial hydrocephalus with a low-insertion umbilicus. Clin Dysmorphol 2:351, 1993. 182. Lammer El, Donnelly S, Holmes LB: Pena-Shokeir phenotype in sibs with macrocephaly but without growth retardation. Am J Med Genet 32:478, 1989. 183. Rodriguez JI, Palacios J, Omenaca F, et al.: Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am J Med Genet. 38: 99, 1991. 184. Pavone L, Rizzo R, Pavone P, et al.: Diffuse polymicrogyria associated with congenital hydrocephalus, craniosynostosis, severe mental retardation, and minor facial and genital anomalies. J Child Neurol 15:493, 2000. 185. Bonnemann CG, Meinecke P: Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 63:428, 1996. 186. Nova HR: Familial communicating hydrocephalus, posterior cerebellar agenesis, mega cisterna magna, and port-wine nevi. J Neurosurg 51: 862, 1979. 187. Norman MG, McGillivray B: Fetal neuropathology of proliferative vasculopathy and hydranencephaly-hydrocephaly with multiple limb pterygia. Pediatr Neurosci 14:301, 1988. 188. Biesecker LG, Happle R, Mulliken JB, et al.: Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84:389, 1999. 189. Dinno ND, Shearer L, Weisskopf B: Familial pseudomarfanism, a new syndrome? Birth Defects Orig Artic Ser XV(5B):179, 1979. 190. Reuss A, den Hollander JC, Niermeijer MF: Prenatal diagnosis of cystic kidney disease with ventriculomegaly: a report of six cases in two related siblings. Am J Med Genet 33:383, 1989. 191. Romanengo M, Tortori-Donati P, Di Rocco M: Rhombencephalosynapsis with facial anomalies and probable autosomal recessive inheritance: a case report. Clin Genet 52:184, 1997. 192. Riccardi VM, Marcus ES: Congenital hydrocephalus and cerebellar agenesis. Clin Genet 13:443, 1978. 193. Rogers RC: Unknown case-SCB (GGC-10079) 11 month old white male. Proc Greenwood Genet Center 7:57, 1988. 194. Rosenak D, Ariel I, Arnon J, et al.: Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs. Am J Med Genet 38:25, 1991. 195. Braddock SR, Jones KL, Superneau DW, et al.: Sagittal craniosynostosis, Dandy-Walker malformation, and hydrocephalus: a unique multiple malformation syndrome. Am J Med Genet 47:640, 1993. 196. Maclennan AC, Doyle D, Simpson RM: Neurosonography and pathology in the Schinzel-Giedion syndrome. J Med Genet 28:547, 1991. 197. Sengers RCA, Hamel BCJ, Otten BJ, et al.: Congenital hydrocephalus, oligophrenie, dwerggroei, centrepetale adipositas en hypogenitalisme: een X-gebonden receddief overerevende ziekte? Tijdschr Kindergeneeskd 53:31, 1985. 198. Pfeiffer RA, Kapferer L: Sensorineural deafness, hypospadias and synostosis of metacarpals and metatarsals 4 and 5: a previously apparently undescribed MCA/MR syndrome. Am J Med Genet 31:5, 1988. 199. Saal HM, Bulas DI, Allen JF, et al.: Patient with craniosynostosis and marfanoid phenotype (Shprintzen-Goldberg syndrome) and cloverleaf skull. Am J Med Genet 57:573, 1995.

200. Siber M: X-linked recessive microencephaly, microphthalmia with corneal opacities, spastic quadriplegia, hypospadias and cryptorchidism. Clin Genet 26:453, 1984. 201. Slee J, Knowles S, Goldblatt J: Siblings with a syndrome of hydrocephalus with patent aqueduct, growth retardation and associated anomalies. Clin Dysmorphol 8:11, 1999. ¨ nay B, Ulucan H, et al.: Unilateral split foot, torticollis, 202. Gu¨l D, U congenital heart defect and hydrocephaly: a new syndrome? Clin Dysmorphol 11:141, 2002. 203. Chan AKJ, Levin AV, Teebi AS: Craniofacial dysmorphism, agenesis of the corpus callosum and ocular colobomas: Temtamy syndrome? Clin Dysmorphol 9:223, 2000. 204. Lammer EJ, Scholes T, Abrams L: Autosomal recessive tetralogy of Fallot, unusual facies, communicating hydrocephalus, and delayed language development: a new syndrome? Clin Dysmorphol 10:9, 2001. 205. Thakker Y, Donnai D: A new recessive syndrome of unusual facies and multiple structural abnormalities. J Med Genet 28:633, 1991. 206. Chow CW, McKelvie PA, Anderson RM, et al.: Autosomal recessive hydrocephalus with third ventricle obstruction. Am J Med Genet 35:310, 1990. 207. Govaert P, Bridger J, Wigglesworth J: Nature of the brain lesion in fetal allo-immune thrombocytopenia. Dev Med Child Neurol 37:485, 1995. 208. Pas B, Whelan D, Modi A: Tibial-ectrodactyly with twinning and hydrocephalus. Dysmorphol Clin Genet 3:28, 1989. 209. Slavotinek A, Clayton-Smith J, Kerr B: Unilateral tibial aplasia, preaxial polysyndactyly, vertebral anomalies and imperforate anus. Clin Dysmorphol 8:223, 1999. 210. Holmes LB, Redline RW, Brown DL, et al.: Absence/hypoplasia of tibia, polydactyly, retrocerebellar arachnoid cyst, and other anomalies: an autosomal recessive disorder. J Med Genet 32:896, 1995. 211. Tranebjaerg L, Lou H, Andresen J: New X-linked syndrome with apraxia, ataxia, and mental deficiency: clinical, cytogenetic and neuropsychological studies in two Danish families. Am J Med Genet 43: 498, 1992. 212. Mizoguchi K, Nishimura Y, Honda N: A family of communicating hydrocephalus with trigonocephaly. Brain Nerve 38:917, 1986. 213. Tollner U, Horst J, Manzke E, et al.: Heptacarpo-octatarso-dactyly combined with multiple malformations. Eur J Pediatr 136:207, 1981. 214. Wegner KJ, Hersh JA: Toriello-Carey syndrome: an additional case and summary of previously reported cases. Clin Dysmorphol 10:145, 2001. 215. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 681. 216. Briard ML, Le Merrer M, Plauchu H, et al.: VACTERL association and hydrocephaly: a new familial entity. Ann Genet 27:220, 1984. 217. Van Biervliet JP, Hendrickx G, van Ertbruggen I: Intrauterine growth retardation with craniofacial and brain anomalies and arthrogryposis. A new syndrome? Acta Paediatr Belg 30:97, 1977. 218. Mazzella M, Arioni C, Bellini C, et al.: Severe hydrocephalus associated with congenital varicella syndrome. Can Med Assoc J 168:561, 2003. 219. Kova´cs T, Cse´csei K, Szabo´ M, et al.: Ventriculomegaly with radial and renal defects: Prenatal diagnosis in two consecutive sibs. Am J Med Genet 73:259, 1997. 220. De Wals P: Surveillance of retinoic acid embryopathy. Teratology 40:274, 1989. 221. Waaler PE, Aarskog D: Syndrome of hydrocephalus, costovertebral dysplasia and Sprengel anomaly with autosomal dominant inheritance. Neuropediatrics 11:291, 1980. 222. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al.: Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 71:1033, 2002. 223. Wallace DC, Exton LA, Pritchard DA, et al.: Severe achondroplasia— demonstration of probable heterogeneity within this clinical syndrome. J Med Genet 7:22, 1970. 224. Weaver DD, Johnson JA: Cranial bone deficiency, craniosynostosis and facial and limb defects. Dysmorphol Clin Genet 1:67, 1987. 225. Winter RM, Shortland D, Collins AL, et al.: Extreme intrauterine growth retardation, hydrocephalus, and aged facial appearance:

Brain

226.

227. 228.

229.

230.

231. 232. 233. 234.

235.

236.

237.

238.

239. 240. 241.

242.

243. 244.

245.

246.

247.

248.

a previously unrecognized autosomal recessive disorder? Clin Dysmorphol 5:313, 1996. Winter RM, Campbell S, Wigglesworth JS, et al.: A previously undescribed syndrome of thoracic dysplasia and communicating hydrocephalus in two sibs, one diagnosed prenatally by ultrasound. J Med Genet 24:204, 1987. Winter RM, Wigglesworth JS: Unusual association of cerebral and renal abnormalities. Clin Dysmorphol 2:71, 1993. Mathias RS, Lacro RV, Jones KL: X-linked laterality sequence: situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:111, 1987. Kang WM, Huang CC, Lin SJ: X-linked recessive inheritance of dysgenesis of corpus callosum in a Chinese family. Am J Med Genet. 44:619, 1992. Joseph M, Shashidhar P, Kenton R, et al.: X-linked myotubular myopathy: clinical observations in ten additional cases. Am J Med Genet 59:168, 1995. Zaglul HF, Odita JC: Multiple herniae: a defect in the celomic mesoderm? Am J Med Genet 57:537, 1995. Zimmer EZ, Taub E, Sova Y, et al.: Tetra-amelia with multiple malformations in six male fetuses of one kindred. Eur J Pediatr 144:412, 1985. Zolotukhina T, Kuznetov M, Lurie I, et al.: Unusual complex of congenital malformations. Am J Med Genet 46:728, 1993. Stein SC, Feldman JG, Stewart A, et al.: The epidemiology of congenital hydrocephalus: a study in Brooklyn, N.Y. 1958–1976. Child Brain 8:253, 1981. Kelly EN, Allen VM, Seaward AG, et al.: Mild ventriculomegaly in the fetus, natural history, associated findings and outcome of isolated mild ventriculomegaly: a literature review. Prenat Diagn 21:697, 2001. Kinzler WL, Smulian JC, McLean DA, et al.: Outcome of prenatally diagnosed mild unilateral cerebral ventriculomegaly. J Ultrasound Med 20:179, 2001. Martinovic J, Sibalic D, Djordjovic M, et al.: Frequency of toxoplasmosis in the appearance of congenital hydrocephalus. J Neurosurg 56:830, 1982. Hagberg C, Femell E, von Wendt: Epidemiology of infantile hydrocephalus in Sweden: reduced optimality in prepartum, partum and postpartum conditions. A case control study. Neuropediatrics 19:16, 1988. Burton BK: Recurrence risks for congenital hydrocephalus. Clin Genet 16:47, 1979. Renier D, Sainte-Rose C, Pierre-Kahn A, et al.: Prenatal hydrocephalus: outcome and prognosis. Child Nerv Syst 4:213, 1988. Kume T, Deng KY, Winfrey V, et al.: The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell 93:985, 1998. Hong HK, Lass JH, Chakravarti A: Pleiotropic skeletal and ocular phenotypes of the mouse mutation congenital hydrocephalus (ch/Mf1) arise from a winged helix/forkhead transcription factor gene. Hum Mol Genet 8:625, 1999. Makiyama Y, Shoji S, Mizusawa H: Hydrocephalus in the Otx þ/– mutant mouse. Exp Neurol 148:215, 1997. Bucher K, Sofroniew MV, Pannell R, et al.: The T cell oncogene Tal2 is necessary for normal development of the mouse brain. Dev Biol 227:533, 2000. Davy BE, Robinson ML: Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Hum Mol Genet 12:1163, 2003. Wagner C, Batiz LF, Rodriguez S, et al.: Cellular mechanisms involved in the stenosis and obliteration of the cerebral aqueduct of hyh mutant mice developing congenital hydrocephalus. J Neuropathol Exp Neurol 62:1019, 2003. das Neves L, Duchala CS, Tolentino-Silva F, et al.: Disruption of the murine nuclear factor I-A (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proc Natl Acad Sci USA 96:11946, 1999. Pilu G, Falco P, Gabrielli S, et al.: The clinical significance of fetal isolated cerebral borderline ventriculomegaly: report of 31 cases and review of the literature. Ultrasound Obstet Gynecol 14:320, 1999.

635 249. Garel C, Luton D, Oury J-F, et al.: Ventricular dilatations. Child Nerv Syst 19:517, 2003. 250. Graham E, Duhl A, Ural S, et al.: The degree of antenatal ventriculomegaly is related to pediatric neurological morbidity. J Matern Fetal Med 10:258, 2001. 251. Bromley B, Frigoletto FD, Benacerraf B: Mild fetal lateral cerebral ventriculomegaly: clinical course and outcome. Am J Obstet Gynecol 164:863, 1991. 252. Greco P, Vimercati A, De Cosmo L, et al.: Mild ventriculomegaly as a counselling challenge. Fetal Diagn Ther 16:398, 2001. 253. Mercier A, Eurin D, Mercier PY, et al.: Isolated mild fetal cerebral ventriculomegaly: a retrospective analysis of 26 cases. Prenat Diagn 21:589, 2001. 254. Monteagudo A, Timor-Trisch IE, Moomjy M: In utero detection of ventriculomegaly during the second and third trimesters by transvaginal sonography. Ultrasound Obstet Gynecol 4:193, 1994. 255. Launay S, Robert Y, Valat AS, et al.: IRM ce´re´brale foetale et ventriculome´galie. J Radiol 83:723, 2002. 256. Bannister CM, Russel SA, Rimmer S, et al.: Pre-natal ventriculomegaly and hydrocephalus. Neurol Res 22:37, 2000. 257. Greco P, Vimercati A, Selvaggi L: Isolated mild fetal cerebral ventriculomegaly. Prenat Diagn 22:158, 2002. 258. Gilmore JH, van Tol JJ, Lewis Streicher H, et al.: Outcome in children with fetal mild ventriculomegaly: a case series. Schizophr Res 48:219, 2001. 259. Bloom SL, Bloom DD, Dellanebbia C, et al.: The developmental outcome of children with antenatal mild isolated ventriculomegaly. Obstet Gynecol 90:93, 1997 260. Von Koch CS, Gupta N, Sutton LN, et al.: In utero surgery for hydrocephalus. Child Nerv Syst 19:574, 2003. 261. Del Bigio MR: Future directions for therapy of childhood hydrocephalus: a view from the laboratory. Pediatr Neurosurg 34:172, 2001. 262. Jones HC, Harris NG, Rocca JR, et al.: Progressive changes in cortical metabolites at three stages of infantile hydrocephalus studied by in vitro NMR spectroscopy. J Neurotrauma 14:587, 1997. 263. Pinckert TL, Golbus MS: Fetal surgery. Clin Perinatol 15:943, 1988. 264. Fernell E, Uvebrant P, von Wendt L: Overt hydrocephalus at birthorigin and outcome. Child Nerv Syst 3:350, 1987. 265. Donders J, Canady AI, Rourke BP: Psychometric intelligence after infantile hydrocephalus: a critical review and reinterpretation. Child Nerv Syst 6:148, 1990. 266. Young HF, Nulsen FE, Weiss MH, et al.: The relationship of intelligence and cerebral mantle in treated infantile hydrocephalus. Pediatrics 52:38, 1973. 267. Macnab GH: Hydrocephalus in infancy. In: Surgical Progress, vol 2. ER Carling, JP Ross, eds. Butterworths, London, 1961, p 98. 268. Hommet C, Billard C, Gillet P, et al.: Neuropsychologic and adaptive functioning in adolescents and young adults shunted for congenital hydrocephalus. J Child Neurol 14:144, 1999. 269. Harmadek MCS, Rourke BP: Principal identifying features of the syndrome of nonverbal learning disabilities in children. J Learning Disab 27:144, 1994. 270. Czepko R, Danilewicz B, Orlowiejska, et al.: The influence of shunt surgery on the improvement of cognitive disorders in hydrocephalic patients. (Abstract) Przegl Lek 56:489, 1999. 271. Castro-Gago M, Rodriguez IN, Rodriguez-Nufiez A, et al.: Therapeutic criteria in hydrocephalic children. Child Nerv Syst 5:361, 1989. 272. Cinalli G: Alternatives to shunting. Child Nerv Syst 15:718, 1999. 273. Torres Lanzas J, Rı´os Zambudio A, Martı´nez Lage JF, et al.: Tratamiento de la hidrocefalia mediante la derivacio´n ventriculopleural Arch Bronconeumol 38:511, 2002. 274. Vinchon M, Fichen A, Delestret I, et al.: Shunt revision for asymptomatic failure: surgical and clinical results. Neurosurgery 52:347, 2003. 275. Mottolese C, Grando J, Convert J, et al.: Zero rate of shunt infection in the first postoperative year in children—dream or reality? Child Nerv Syst 16:210, 2000. 276. Camboulives J, Meyrieux V, Le´na G: Infections des de´rivations du liquide ce´phalorachidien chez l’enfant: pre´vention et traitment. Ann Fr Anesth Re´anim 21:84, 2002.

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Neuromuscular Systems

277. Choux M, Genitori L, Lang D, et al.: Shunt implantation: reducing the incidence of shunt infection. J Neurosurg 77:875, 1992. 278. Govender ST, Nathoo N, van Dellen JR: Evaluation of an antibioticimpregnated shunt system for the treatment of hydrocephalus. J Neurosurg 99:831, 2003. 279. Bruinsma N, Stobberingh EE, Herpers MJ, et al.: Subcutaneous ventricular catheter reservoir and ventriculoperitoneal drain-related infections in preterm infants and young children. Clin Microbiol Infect 6:202, 2000. 280. Takahashi Y: Withdrawal of shunt systems—clinical use of the programmable shunt system and its effect on hydrocephalus in children. Child Nerv Syst 17:472, 2001. 281. Brockmeyer D, Abtin K, Carey L, et al.: Endoscopic third ventriculostomy: an outcome analysis. Pediatr Neurosurg 28:236, 1998. 282. Belloti A, Rapana A, Iaccarino C, et al.: Intracranial pressure monitoring after endoscopic third ventriculostomy: an effective method to manage the ‘adaptation period’. Clin Neurol Neurosurg 103:223, 2001. 283. Sainte-Rose C, Chumas P: Endoscopic third ventriculostomy: Techn Neurosurg 1:176, 1996. 284. Bruce DA, Weprin B: The slit ventricle syndrome. Neurosurg Clin N Am 12:709, 2001. 285. Epstein F, Lapras C, Wisoff JH: ‘‘Slit ventricle syndrome’’: etiology and treatment. Pediatr Neurosci 14:5, 1988. 286. Whitelaw A: Postnatal phenobarbitone for the prevention of intraventricular hemorrhage in preterm infants. Cochrane Database Syst Rev CD001691, 2001. 287. Whitelaw A: Intraventricular streptokinase after intraventricular hemorrhage in newborn infants. Cochrane Database Syst Rev CD000498, 2000. 288. Whitelaw A, Pople I, Cherian S, et al.: Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy. Pediatrics 111:759, 2003. 289. Sharif U, Kuban K: Prenatal intracranial hemorrhage and neurologic complications in alloimmune thrombocytopenia. J Child Neurol 16: 838, 2001. 290. Howard FM, Till K, Carter CO: A family study of hydrocephalus resulting from aqueduct stenosis. J Med Genet 18:252, 1981. 291. Va´radi V, To´th A, To¨ro¨k O: Heterogeneity and recurrence risk for congenital hydrocephalus (ventriculomegaly): a prospective study. Am J Med Genet 29:305, 1988. 292. Haverkamp F, Wo¨lfle J, Aretz M, et al.: Congenital hydrocephalus internus and aqueductal stenosis: aetiology and implications for genetic counselling. Eur J Pediatr 158:474, 1999.

Fig. 15-49. Sagittal ultrasound section typical of colpocephaly, taken at 6 days of age in an infant diagnosed prenatally as hydrocephalic. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario, Ottawa.)

293. Adams C, Johnson WP, Nevin NC: Family study of congenital hydrocephalus. Dev Med Child Neurol 24:493, 1982. 294. Joumel H, Parent P, Roussey M, et al.: ‘‘Isolated’’ hydrocephalus in families of spina bifida and anencephaly: a coincidence? Neuropediatrics 20:220, 1989. 295. Friedman, JM, Santos-Ramos R: Natural history of X-linked aqueductal stenosis in the second and third trimester of pregnancy. Am J Obstet Gynecol 150:104, 1984. 296. Cohen MM, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003.

15.9 Colpocephaly Definition

Colpocephaly is an enlargement of the occipital horns of the ventricular system due to an underdevelopment of the white matter in the posterior cerebrum. The appearance is of an apparent hydrocephalus of the occipital horns, while the frontal portions are relatively normal (Figs. 15-49, 15-50). Diagnosis

There are no specific extracranial or surface clues to the presence of colpocephaly. The condition is a marker of disturbed brain development that may have a variety of clinical presentations and associated intracranial and extracranial anomalies. The condition is usually recognized when a cranial neuroimaging technique is applied to the diagnosis of a patient with developmental delay, seizures, or related neurologic problems. Colpocephaly is a marker of underlying maldevelopment of the brain, and the clinical presentation will be influenced by the underlying pathology. Bodensteiner and Gay1 have stressed the importance of separating colpocephaly from hydrocephalus ex vacuo of the posterior horns. Their patient had a stomy perinatal course, and the CT was interpreted as showing colpocephaly. Later MRI demonstrated acquired cystic changes in the white matter of the posterior centrum semiovale that were responsible for the enlarged posterior horns

Brain

637

those had colpocephaly.11 Table 15-13 lists several syndromes that have been associated with colpocephaly. It does not include the many syndromes with absent corpus callosum and/or malformations of cortical development that are included in their own section and which might be expected to sometimes show colpocephaly. Etiology and Distribution

Fig. 15-50. Axial CT scan at 1 week of age showing narrow anterior ventricle and dilated occipital horns characteristic of colpocephaly. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario.)

and the appearance of colpocephaly. They emphasized that colpocephaly is most often associated with normal reflexes, hypotonia, moderate to severe developmental delay, and other CNS anomalies. Hydrocephalus ex vacuo is acquired and is more likely to be seen with an at risk medical history, spasticity, and more variability in intellect. However, there is significant clinical overlap, and movement abnormalities with choreoathetosis or spasticity may also be seen in colpocephaly, and reliable distinction requires careful neuroimaging. Examples of the milder clinical spectrum of colpocephaly include affected monozygotic twins with above-normal intelligence and brief tonic seizures,2 and a 30-year-old, intellectually normal man with a structurally normal cortex and a right temporal lobe focus of complex-partial seizures.3 Visual impairment, including abnormal fixation, nystagmus, and/or optic atrophy, is a common associated finding. Bittar et al.4 used functional MRI in a patient with normal visual acuity and visual fields, and showed major reorganization of the visual cortex and reduced activation foci in the occipital lobes. Partial or complete absence of the corpus callosum is the most commonly associated intracerebral malformation, and it is logical to assume that in these cases the colpocephaly and the callosal agenesis both reflect a primary abnormality of neuronal development. In one series of 23 patients with callosal abnormalities varying from hypoplasia to complete agenesis, 16 had colpocephaly.5 Porencephaly and hydrocephaly are also reported,6,7 and the ventricular system often has the appearance of colpocephaly in lissencephaly. The diagnosis of colpocephaly has been made in patients with a wide array of conditions, including neurofibromatosis, Pierre Robin anomaly, Tourette syndrome, Leigh disease, schizophrenia, and a variety of seizure disorders.6,8–10 MR imaging in a series of 23 patients with caudal spinal dysraphism showed that seven had an absence of the posterior third of the corpus callosum and that six of

Although with greater application of neuroimaging numbers are increasing, relatively few cases of colpocephaly have been reported since its original description as ‘‘vesiculocephaly’’ by Bendas in 1940.26 The term colpocephaly was coined by Yakovlev and Wadsworth7 who reported further on the first patient of Benda. They noted that the cortical gray matter was two to three times normal thickness and that the thin, poorly myelinated white matter contained heterotopic islands of gray matter. Benda’s second patient had a history and pathologic findings compatible with a perinatal encephalopathy and hydrocephalus ex vacuo. Given the broad range of clinical presentation and associated findings in colpocephaly, it is likely that many cases are undiagnosed or simply unreported. The 1988 paper of Noorani et al.,6 which described 14 cases among a review of 3411 consecutive cranial CT scans, doubled the cases reported to that time. Initially, the lateral ventricles are the simple outpouching of the telencephalon. With forward growth of the temporal lobes they then form a ‘‘U’’ shape; the occipital projection rapidly follows. At first this system is relatively large but becomes reduced in size following development of the foramina, and with ventricular and related interhemispheric growth. It is considered that an insult to the developing brain, at a variable time between the first and fourth months, leads to a reduction in white matter development in the region of the posterior pole. Hence, there is a failure of reduction in the size of the occipital horns and maintenance of the fetal appearance.6,27 Clearly colpocephaly is a nonspecific response to a variety of etiologic insults, including metabolic (Leigh), chromosomal (mosaic 8), and multifactorial (meningomyelocele). Maternal diabetes, valproic acid, and alcoholism have been reported as possible causative teratogens.8,11,27,28 Chen at al.29 reported a case of vanishing twin in a monochorionic-diamnionic pregnancy in which the surviving cotwin was noted by 28 weeks gestation to be microcephalic. A postnatal MRI revealed dysgenesis of the posterior corpus callosum, a thin occipital cortex, and colpocephaly. It has been proposed that early loss of a co-twin can cause major abnormalities of the CNS.30 The surviving monozygotic twins reported by Tanaka et al.31 are interesting in that one expressed incontinentia pigmenti and the other had colpocephaly but no skin disease. Familial recurrence of colpocephaly is infrequently reported but could occur on the basis of a syndrome with a significant recurrence risk and reasonable frequency of associated colpocephaly. For example, the two brothers with posterior agyria-pachygyria reported by Ferrie et al.32 both had colpocephaly. Nigro et al.2 argue that the concurrence of colpocephaly in monozygotic twins is evidence for a genetic cause in some cases. Prognosis, Treatment, and Prevention

The ages of patients who have been reported range from 1 week to 30 years, and the prognosis for survival and intellectual development undoubtedly reflects the impact of any associated condition and the severity of the concurrent maldevelopment of the brain. The patient with colpocephaly and mosaic trisomy 8 reported by Herskowitz et al.8 showed only mild developmental delay. There is a spectrum of increasingly significant signs, and several patients have been severely retarded, with seizures, abnormalities of tone, and visual impairment.

Table 15-13. Syndromes with colpocephaly Syndrome

Prominent Features

Causation Gene/Locus

Chudley-McCullough: hydrocephalus-deafness12

Normal intellect, non-dysmorphic, obstruction at foramen of Monro, severe bilateral sensorineural hearing loss; 8/8 with colpocephaly, recent reports with ACC suggest it is same as Hendriks syndrome (Table 15-11137)

AR (604213)

Colpocephaly-recurrent13

Male and female maternal half sibs; girl had unilateral micophthalmia with coloboma, male had mild developmental delay and seizures

Uncertain

Congenital fibrosis extrocular muscles14

Dysfunction of cranial nerves III and IV, or the muscles served by those nerves; CNS infrequent and includes cerebellar vermis hypoplasia, callosal agenesis, pachygyria, hydranencephaly, colpocephaly

AR (135700) (602078) ARIX, 11q13.3-q13.4 AD (607034) KIF21AI, 12p11.2-q12 AD (600638) 16q24.2-q24.3

Cutis verticus gyrata-mental retardation15

Severe mental retardation, microcephaly, vertical furrows on scalp, seizures, optic atrophy, thick calvarium; case with atrophic occipito-parietal cortex, hypoplastic splenium, colpocephaly

Unknown (219300)

Femoral deficiency-facial16

Short anteverted nose, long philtrum, thin upper lip, micrognathia, cleft palate, proximal focal femoral deficiency, pre-axial toe polydactyly; CNS includes agenesis posterior corpus callosum, brain atrophy, absent septum pellucidum, dilated lateral ventricles, heterotopias, colpocephaly

Associated with maternal diabetes (134780)

Grubben: short-dentaleczema17

Pre- and postnatal growth and developmental delay, hypotonia; small, widely spaced or missing teeth, eczematous skin rash; small, puffy hands and feet with tapering digits; partial agenesis of the corpus callosum or ventriculomegaly; selective IgG2 subclass deficiency a possible marker

AR (233810)

Hemimegalencephaly18

Isolated and syndromic forms show abnormal gyration, displacement of the occipital lobe across the midline, ventriculomegaly or colpocephaly

Unknown, heterogeneous

Linear nevus sebaceous19

Papular/verrucous lesions with atrophic scars over craniofacial area, pigment changes, ipsilateral brain anomalies; case report with left megalencephaly, lissencephaly, schizencephaly, excess and heterotopic gray matter and colpocephaly

Unknown (163200)

Marden-Walker20

Motor delay, blepharophimosis, low-set and malformed ears, cleft palate, micrognathia, renal microcysts/cystic dysplasia, arachnodactyly, camptodactyly, joint contractures, congenital heart defect; case with brain stem and cerebellar hypoplasia, callosal agenesis, colpocephaly; likely heterogeneous

AR (248700)

Microphthalmia-linear skin defects21

Male lethal; linear, erythematous skin defects; variable microphthalmia, anterior chamber defects, sclerocornea; short stature; congenital heart defects, CNS includes hydrocephalus, colpocephaly, cavum septum pellucidum, variable corpus callosum defect

del Xp22.31 (309801) male lethality due to loss of holocytochrome c-type synthase

Mosaic trisomy 88

Scaphocephaly, prominent forehead, broad nose, small mandible, contractures of digits, scoliosis, rib and vertebral anomalies, deep creases on soles, mental deficiency

Chromosome imbalance

Muscle-eye-brain22

Early severe hypotonia, delayed development, anterior chamber defects, glaucoma, preretinal glial membrane, ERG becomes abnormal, cataracts, myopathy, predominant frontal pachygyria, agenesis of corpus callosum, hypoplasia of pons and cerebellar vermis, white matter abnormalities patchy or absent, sibs with colpocephaly; common in Finland

AR (253280) POMGnT1, 1p32-p34.1

Nijmegen breakage23

Growth and variable intellectual impairment, sloping forehead, prominent mid-face and long nose, large and abnormal pinnae, upslanting palpebrae, cafe´-au-lait spots, immunodeficiency, chromosome breakage and rearrangements of 7/14; 4/10 cases had posterior callosal agenesis and colpocephaly

AR (251260) NBS1, 8q21

Peroxisome-deficient disorders24,25

Includes Zellweger and isolated peroxisomal b-oxidation defects; developmental delay, hypotonia, hepatic and visual dysfunction, multifoca spikes on EEG; thick cortex with colpocephaly, some with partial callosal agenesis

AR (214100) PEX1, 7q21-q22 PEX2, 8q21.1 PEX3, 6q23-q24 PEX5, 12p13.3 PEX6, 6p Others, 1p22-p21, 1q22, 2p15

638

Brain

Treatment is generally supportive and should be appropriate for the management of the specific associated problems of the patient. Concurrent hydrocephalus may occasionally require treatment.8 There is no primary prevention, other than the recognition of specific syndromes with established recurrence risks. The abnormality may be detected during routine prenatal ultrasound but is likely to be diagnosed as hydrocephalus, as was the case with the patient whose cranial CT scan is shown in Figure 15-50. The investigations outlined for evaluation of fetal ventriculomegaly (Section 15.8) would appear to be appropriate in this situation. Levine et al.33 provided evidence that fetal MRI is superior to ultrasound in detecting subtle differences in the proportions of the ventricles. References (Colpocephaly) 1. Bodensteiner J, Gay CT: Colpocephaly: pitfalls in the diagnosis of a pathologic entity utilizing neuroimaging techniques. J Child Neurol 5:166, 1990. 2. Nigro MA, Wishnow R, Maher L: Colpocephaly in identical twins. Brain Dev 13:187, 1991. 3. Wunderlich G, Schlaug G, Jancke L, et al.: Adult-onset complex partial seizures as the presenting sign in colpocephaly: MRI and PET correlates. J Neuroimaging 6:192, 1996. 4. Bittar RG, Ptito A, Dumoulin SA, et al.: Reorganization of the visual cortex in callosal agenesis and colpocephaly. J Clin Neursci 7:13, 2000. 5. Utsunomiya H, Ogasawara T, Hayashi T, et al.: Dysgenesis of the corpus callosum and associated telencephalic anomalies: MRI. Neuroradiology 39:302, 1997. 6. Noorani PA, Bodenstiener JB, Barnes PD: Colpocephaly: frequency and associated findings. J Child Neurol 3:100, 1988. 7. Yakovlev PI, Wadsworth RC: Schizencephaly: a study of the congenital clefts in the cerebral mantle: II. Clefts with hydrocephalus and lips separated. J Neuropathol Exp Neurol 5:169, 1946. 8. Herskowitz J, Rosman P, Wheeler CB: Colpocephaly: clinical, radiologic, and pathogenetic aspects. Neurology 35:1594, 1985. 9. Shaenboen MJ, Nigro MA, Martocci RJ: Colpocephaly and Gilles de la Tourette’s syndrome. Arch Neurol 41:1023, 1984. 10. Pe´rez Castrillo´n JL, Duen˜as Laita A, Ruiz Mambrilla M, et al.: Ausencia del cuerpo calloso, colpocefalia y esquizofrenia. Rev Neurol 33:995, 2001. 11. Kawamura T, Nisho S, Morioka T, et al.: Callosal anomalies in patients with spinal dysraphism: correlation of clinical and neuroimaging features with hemispheric abnormalities. Neurol Res 24:463, 2002. 12. Ostergaard E, Pedersen VF, Skriver EB, et al.: Brothers with ChudleyMcCullough syndrome: sensorineural deafness, agenesis of the corpus callosum, and other structural brain abnormalities. Am J Med Genet 124A:74, 2004. 13. Cerullo A, Marini C, Cevoli S, et al.: Colpocephaly in two siblings: further evidence of a genetic transmission. Dev Med Child Neurol 42:280, 2000. 14. Pieh C, Goebel HH, Engle EC, et al.: Congenital fibrosis syndrome associated with central nervous system abnormalities. Graefes Arch Clin Exp Ophthalmol 241:546, 2003. 15. Farah S, Farag T, Sabry MA, et al.: Cutis verticis gyrata-mental deficiency syndrome: report of a case with unusual neuroradiological findings. Clin Dysmorphol 7:131, 1998. 16. Leal E, Macias-Gomez N, Rodriguez L, et al.: Femoral-facial syndrome with malformations in the central nervous system. Clin Imaging 27:23, 2003. 17. Ainsworth SB, Baraitser M, Mueller RF, et al.: Selective IgG2 subclass deficiency - a marker for the syndrome of pre/postnatal growth retardation, developmental delay, hypotrophy of distal extremities, dental anomalies and eczema. Clin Dysmorphol 6:139, 1997. 18. Flores-Sarnat L: Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol 17:373, 2002. 19. Hager BC, Dyme IZ, Guertin SR, et al.: Linear nevus sebaceous syndrome: megalencephaly and heterotopic gray matter. Pediatr Neurol 7:45, 1991. 20. Garcı´a-Alix A, Blanco D, Caban˜as F, et al.: Early neurological manifestations and brain anomalies in Marden-Walker syndrome. Am J Med Genet 44:41, 1992.

639 21. Paulger BR, Kraus EW, Pulitzer DR, et al.: Xp microdeletion syndrome characterized by pathognomonic linear skin defects on the head and neck. Pediatr Dermatol 14:26, 1997. 22. Zervos A, Hunt KE, Tong HQ, et al.: Clinical, genetic and histopathological findings in two siblings with muscle-eye-brain disease. Eur J Ophthalmol 12:253, 2002. 23. Bekiesinska-Figatowska M, Chrzanowska KH, Sikorska J, et al.: Cranial MRI in the Nijmegen breakage syndrome. Neuroradiology 42:43, 2000. 24. Suzuki Y, Shimozawa N, Takahashi Y, et al.: Peroxisomal disorders: clinical aspects. Ann NY Acad Sci 804:442, 1996. 25. Nakai A, Shigematsu Y, Nishida K, et al.: MRI findings of Zellweger syndrome. Pediatr Neurol 13:346, 1995. 26. Benda CE: Microcephaly. Am J Psychiatr 97:1135, 1940. 27. Garg BP: Colpocephaly an error of morphogenesis? Arch Neurol 39:243, 1982. 28. Bermejo E, Garcia-Alix A, Martinez S, et al.: Brain anomalies in infants exposed to valproic acid (VPA) monotherapy during the first trimester of gestation. Proc Greenwood Genet Center 10:115, 1991. 29. Chen C-P, Lin S-P, Chiu N-C: Microcephaly with dysgenesis of corpus callosum and colpocephaly in the survivor after the first-trimester death of a monochorionic co-twin. Prenat Diagn 22:633, 2002. 30. Sebire N, Taylor M, Fisk NM: Consequences of in utero death in a twin pregnancy. Lancet 356:1108, 2000. 31. Tanaka K, Kambe N, Fujita M, et al.: Incontinentia pigmenti in identical twins with separate skin and neurological disorders. Acta Derm Venereol 70:267, 1990. 32. Ferrie CD, Jackson GD, Giannakodimos S, et al.: Posterior agyriapachygyria with polymicrogyria: evidence for an inherited neuronal migration disorder. Neurology 45:150, 1995. 33. Levine D, Trop I, Mehta TS, et al.: MR imaging appearance of fetal cerebral ventricular morphology. Radiology 223:652, 2002.

15.10 Hydranencephaly Definition

Hydranencephaly is a condition in which the cerebral hemispheres are virtually absent and have been replaced by fluid-filled sacs, lined by leptomeninges, and contained within a normal skull and brain compartment. Cortical remnants are generally confined to the temporal lobe and the tentorial parts of the occipital lobes.1 Typically the brain stem and cerebellum are normal; the falx is usually present but may be partially or completely absent. Among the basal ganglia, the thalamus and corpus striatum are usually normal. Hydranencephaly is an encephaloclastic abnormality and must be distinguished from maximal hydrocephalus (Section 15.8), which results from an excess of cerebrospinal fluid production over absorption, and from developmental porencephaly (schizencephaly) (Section 15.11), in which clefts or cavities within the cerebral cortex result from a primary abnormality of neurocellular development. The relationship between hydranencephaly and congenital encephaloclastic porencephaly and multicystic encephalomalacia (MCE) (Section 15.11) is essentially one of timing and degree of involvement. Diagnosis

The neonate with hydranencephaly is usually macrocephalic, with frequent seizures, irritability, and hyperreflexia. Elevated intracranial pressure and an expanding head circumference can occur. In the absence of hypothalamic involvement the infant will often survive and show relatively normal behavior until profound developmental delay becomes apparent in the early months.1,2 Hakamada et al.3 have suggested that observation of body movements during sleep may aid the diagnosis. They observed periodic alteration between active and

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quiet sleep and reported that muscle activity, ocular movement, and respiration rates were similar to those in control neonates. However, generalized body movement showed a bilateral synchrony rather than the normal asymmetric pattern. In addition, there was significant increase in symmetric synchronized contraction of two or four limbs and a decrease in brief, isolated movement of a single limb. It is important to distinguish early between hydranencephaly and ‘‘maximal hydrocephalus,’’ because the latter carries a significantly better prognosis and requires ventricular shunt therapy. Transillumination of the skull (Fig.15-51) may occur in both conditions (less commonly in hydrocephalus), but bright light shining out through the pupils appears unique to hydranencephaly. In severe hydrocephalus, in contrast to hydranencephaly, neuroimaging shows maximal preservation of cortex in the frontal region, and the cerebral vascular architecture is normal, albeit attenuated.4 An indentation at the site of division of the frontal lobes may be seen, and, with shunting, the cortical mantle may sometimes show improvement with time.2 Electrophysiological studies, specifically the EEG and various evoked responses, may aid in making the distinction. Patients with maximal hydrocephalus show cortical EEG activity and normal visual and auditory evoked potentials. The EEG in hydranencephaly has been described as flat, but it can show low isoelectric waves in bipolar derivation, with a similar referential derivation from most electrodes.5 Some cases may show independent, irregular spikes and slow waves, reflecting underlying cortical remnants.5 Studies in a child with hydranencephaly and seizures of the Lennox-Gastaut syndrome (LGS)– type showed that the electroencephalographic signatures of the apneic and tonic seizures were similar to children with idiopathic LGS.6 The quantitative disturbances in duration and latency, and the number of sleep cycles, were also similar to the other LGS patients but the patient lacked vertex waves and had abnormal sleep spindles.

Visual, auditory, and somatosensory evoked potentials (SSEP) confirm the absence of cortical response and the preservation of brain stem function.4,7–9 Auditory evoked potentials show an absent middle latency response, and somatic evoked potentials show absent cortical response.7 Kaga et al.10 obtained auditory brain stem responses and wave patterns compatible with age, and reaction to loud noise on behavioral auditory testing that they attributed to brain stem auditory motor reflexes. Tayama et al.9 performed short latency SSEP on two affected children and confirmed absent cortical responses and preservation of brain stem responses. They were also able to correlate an absent No wave in one child with absence of the thalamus. MRI is well suited to showing absence of cortical, and preservation of midbrain and hindbrain, structures.7 Two-dimensional color Doppler has been used successfully to demonstrate absence of the secondary and tertiary branches of the internal carotid arteries in order to distinguish hydranencephaly from maximal hydrocephalus.11 Hydranencephaly is considered by most authors to be the extreme of the enclastic form of porencephaly, and one would not therefore expect this malformation to be a component of many syndromes. Indeed the pathologic findings of ‘‘syndromic’’ hydranencephaly often show variation from the typical isolated cases (Table 15-14). The majority of patients have an abnormal ophthalmologic examination, and findings include microphthalmia, strabismus, nystagmus, chorioretinitis, small retinal vessels, optic nerve hypoplasia, and incomplete cleavage of the anterior chamber.4 Unilateral hydranencephaly, with characteristic clinical, physical, neuroradiologic, and neurophysiologic findings confined to one hemisphere, is occasionally seen and may carry a surprisingly good prognosis (Figs. 15-52, 15-53).28 These patients present with hemiparesis, are less likely to have seizures, and may develop hydrocephalus due to aqueductal stenosis. Etiology and Distribution

Fig. 15-51. Transillumination of an infant with hydranencephaly.

That hydranencephaly usually occurs within a normal cranial cavity is strong evidence that it is the result of an enclastic process rather than a primary malformation. A number of clinical observations and experimental studies support this hypothesis. Prevalent today is the theory that hydranencephaly derives from compromise of carotid artery supply, which provides an explanation for the relative sparing of the inferior temporal and occipital regions. Carotid occlusion using paraffin balls in puppies and ligation of the carotid arteries and jugular veins in monkeys produce massive liquefaction necrosis of the brain and a condition equivalent to hydranencephaly.29,30 Unilateral ligation causes unilateral involvement. However, in contrast to typical hydranencephaly this experimental model has been associated with a degree of cranial collapse and microcephaly and more closely resembles the patients reported by Moore et al.,31 one of whom did, however, have classic hydranencephaly. Other differences from the experimental model include preservation of the lenticulostriatum and patency of the carotid vessels in patients with hydranencephaly.1,32 This may relate to involvement of more distal carotid tributaries in many cases of spontaneous hydranencephaly,11,33 or perhaps to a matter of timing. More recently an ovine model, in which the internal carotid arteries were ligated at day 100 (human weeks 26–27), has produced hydranencephaly, but with evidence of cerebellar involvement.34 There is clinical evidence in support of a vascular disruptive pathogenesis. Hydranencephaly has been reported in surviving monozygotic twins.35–37 It has been hypothesized that fetus to fetus transfer of thromboplastins from the dead twin results in cerebral infarction in the surviving twin. An alternative, and perhaps now

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Table 15-14. Syndromes with hydranencephaly as a feature Syndrome

Prominent Features

Causation Gene/Locus

Agnathia malformation complex12

An association of holoprosencephaly and agnathia is well established; a fetus had agnathia, hydranencephaly, bilobed lungs, situs inversus, polysplenia, duodenal atresia, and a cystic dilation of the oropharynx

Unknown (202650) 6pter-6p24 18pter-18p11

Cerebro-oculo-genital13

Microphthalmia, corneal opacity, severe developmental delay, small phallus, hypospadias, marked microcephaly or hydranencephaly, absent corpus callosum

XLR (309800)

Craniosynostosishumeroradial-aplastic thumbs14

IUGR, marked microcephaly, ridged sutures, prominent eyes with short palpebrae, micrognathia, elbow and knee flexion contractures, absent thumbs, bilateral humeroradial synostosis, hydranencephaly

Unknown

Deletion (13)(q22)15

Transposition of the penis and scrotum, anal atresia, syndactyly of toes 2-3, hypoplasia of optic nerve

Chromosome imbalance

Familial hydranencephaly16

Small for gestational age, microcephaly, microphthalmia, multiple joint contractures, wide-spaced first and second toes, absent olfactory and optic nerves, cerebellum only a remnant

AR

Herpes, prenatal17

About 5% of neonatal herpes is acquired in utero; variable clinical spectrum may include cutaneous, ocular, and CNS lesions; about 1⁄2 have an encephalitis that can cause microcephaly or hydranencephaly

Prenatal infection with herpes virus

Hydranencephalyhydrocephalusmitochondrial18

May represent maximal hydrocephalus; abnormal muscle biopsy included ragged red fibers, abnormal mitochondria; low levels of complexes III and IV enzymes; some evidence of glomeruloid vessels (see ref. 23)

AR?

Hydranencephalyhypoplastic thumbs19

Collapsed skull vault, absent left and proximal right thumb, campto/ clinodactyly of 5th finger, talipes equinovarus, reported as hydranencephaly but closer to aprosencephaly and XK-aprosencephaly spectrum

Unknown

Mbakop: lethal multiple pterygium20

Hydramnios, cystic hygroma, fetal edema, cervicoaxillary pterygia, joint contractures, camptodactyly, cleft lip/palate, abnormal placenta. One case

Unknown (253290)

Microhydranencephaly21

Microhydranencephaly, severe growth and developmental delay, sloping forehead, exophthalmia, micrognathia, spastic quadriplegia, joint contractures, athetosis, respiratory and skin infections

AR (605013) 16p13.3-12.1

PEHO-like22

Progressive encephalopathy, edema, hypsarrhythmia, optic atrophy by age 2 years; hypotonia, hyperreflexia, infantile spasms after 2 weeks; narrow forehead, puffy cheeks; mild supratentoral atrophy and no cerebellar atrophy differ from PEHO. One case hydranencephaly

AR (260565)

Proliferative vasculopathyhydranen/hydrocephaly23

Ventriculomegaly/hydranencephaly; proliferative glomeruloid blood vessels in spinal cord, brain stem, retina, and cerebral mantle; decreased number of primitive neuroectodermal cells, maturing neurons and glia; no gyral pattern; hypoplastic muscles, joint contractures, pterygia; possibly a destructive vascular process; cerebro-oculo-muscular spectrum? (see ref. 18)

AR (225790)

Renal adysplasia24

Renal remnants with primitive tubules and concentric fibrous tissue, 2-3 toe syndactyly, no normal cortical layering in cortical remnant, abnormal multinucleated neurons; sib had ‘‘rudimentary brain at base of skull.’’ Similar case had multicystic dysplastic kidneys

AR (236500)

Trisomy 1325

Scalp defect, holoprosencephaly spectrum (including facies), postaxial polydactyly hands/feet, overlapping fingers, various internal malformations

Chromosome imbalance

Valproate, prenatal26

Brachycephaly, high forehead, prominent eyes, crease of skin below eye, thin and long upper lip, prominent lower lip, long philtrum, metopic ridge, lumbosacral NTD. Case with partial hydranencephaly

In utero exposure

X-linked-abnormal genitalia (XLAG)27

Lissencephaly with posterior-to-anterior gradient, neonatal onset of seizures, hypothalamic dysfuction, ambiguous male genitalia (see Table 15-5); termination mutations in exons 1 to 4 can cause hydranencephaly

XLR (300382, 300215) ARX, Xp22.13

more favored, mechanism is that of an acute hemorrhage from the surviving twin into the dead twin at the time of fetal death, resulting in an acute hypoperfusion/hypoxic insult.37,38 Case reports do associate hypoxia with anomalies along the hydranencephaly spectrum.39,40 Hemorrhagic states such as familial factor XIII deficiency have also been associated with hydranencephaly.41 There are a number of cases where the evolution of the typical picture of

hydranencephaly has been followed on prenatal sonography.1,37,42 In the case of a prenatal intracranial bleed, the echogenic hemorrhage gradually gives way over a period of weeks to anechoic cranial contents that match CSF, and the head size usually increases.1,42 Although most such cases relate to the late second and early third trimester, Tang43 observed abnormal cranial and intracranial findings starting at 11 weeks gestation.

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Neuromuscular Systems

Fig. 15-52. Superior and lateral views of an infant brain with hemihydranencephaly. Histology showed a thin layer of glial tissue lining the inner surface of the hydranencephalic membrane (arrows). A, anterior; P, posterior; LC, left cerebral hemisphere; E, right ear. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Fig. 15-53. Axial and coronal MRI scans of a 3-year-old girl with hemihydranencephaly. She had hemiparesis and unilateral facial paresis. She sat alone at 12 months and walked at 31 months. (Courtesy of Dr. R. C. M. Hennekam, Institute for Human Genetics and Department of Paediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam.)

Brain

There are also cases that suggest localized vascular anomalies may cause hydranencephaly. Stevenson et al.44 reported a patient with hydranencephaly and multiple vascular anomalies that included extensive port wine stains, nevus flammeus, abnormal retinal vessels, and absent internal carotid artery blood flow. Absent right middle cerebral artery with a right hemihydranencephaly,33 and multicystic encephalomalacia (MCE) in association with intraluminal webs of the right common carotid and left subclavian arteries,45 have been reported. Reduced maternal age (MA), which has been associated with other malformations thought to have a vascular basis, has been noted in hydranencephaly. Lubinsky et al.46 found that a MA of < 20 years was five times, and a MA of < 18 years was ten times more frequent in mothers of infants with hydranencephaly than in the general population. An odds ratio of 56 (95% CI; 7.41–427) for maternal smoking in mothers of infants with hydranencephaly compared with mothers of children with other CNS anomalies, and of 179 (95% CI; 18.6–1719) compared with mothers in the general population has been reported.47 Prenatal infections, including toxoplasmosis, herpes simplex, and cytomegalovirus (CMV), have also been associated with hydranencephaly.48–50 A case of prenatal CMV infection with hydranencephaly reported by Kubo et al.50 raises the possibility of a vascular mechanism in prenatal infection. Their patient had narrow carotids and an atheromatous plaque between the right brachiocephalic and left common carotid artery. Experience with natural and experimental animal systems raises the potential that a viral cause of hydranencephaly may be more common than is generally believed. However, it is of note that the viral animal models tend to show cerebellar hypoplasia or agenesis. Administration of live parvovirus vaccine to a pregnant cat resulted in three dead and two living kittens that both had hydranencephaly and cerebellar hypo/aplasia.51 Natural and vaccine-related transplacental transmission of bovine-virus diarrhea virus (BVDV) resulted in 33 neurologically damaged cattle of which 25 had cerebellar hypoplasia in association with one or more of hydranencephaly, obstructive hydrocephalus, porencephaly, or microcephaly.52 The hydranencephalic cases lacked any ependymal lining to the cerebral sac, which contained glial fibrillary acid-protein– positive cells and a dense layer of immunoreactive cell processes. There were small areas of heterotopias. Viral pathogenesis also seems likely as the cause of a 6-month outbreak in Miyazaki, Japan that affected 62 calves, of which 47 had cerebellar hypoplasia and hydranencephaly, eight had isolated hydranencephaly, and seven had ventriculomegaly.53 Inflammatory/reactive changes, heterotopias, loss of lamination, and neuronal degeneration were observed. Hydranencephaly and cerebellar hypoplasia have also been produced by Aino virus infections in chick embryos,54 and it is of note that while viral antigen is detectable early in the infection, it is not found at 13 days, perhaps reflecting the loss of Aino virus–susceptible cells. Finally, there is an interesting and unique report of hydranencephaly in association with a congenital rhabdoid tumor.55 This neoplastic hydranencephaly is distinguished by the highly proteinaceous content within the sac, unlike the CSF characteristics seen in standard hydranencephaly. Thus, hydranencephaly appears to represent the endpoint of massive brain necrosis, which may have different causes, several of which operate through the common mechanism of vascular/oxygenation compromise. Dixon25 states the prevalence of hydranencephaly to be between 1/4000 and 1/10,000 births. Prognosis, Treatment, and Prevention

The outlook for children with complete hydranencephaly is universally poor, although diagnosis may be delayed for several months

643

because of relatively appropriate early behavior. As time passes profound delay, deafness, blindness, and spastic quadriparesis become apparent. There is no primary treatment, and active medical intervention is not indicated. Almost one-half of infants with hydranencephaly die within 1 month, and less than 15% survive 1 year.25 However, long-term survival, up to 20 years, does occur56 and medical and surgical complications can be seen. Patients who do survive do not display meaningful development, have cortical blindness, spastic tetraplegia seizures, and dysphagia. Autonomic57 and hypothalamic dysfunction and chronic hypernatremia have been reported.58,59 Kobayashi et al.59 demonstrated in their patient, who had hypothalamic dysplasia, that the hypernatremia was due to both a disturbed thirst center and abnormal secretion of ADH. In a study of three affected children, Hashimoto et al.60 showed preservation of an active sleep cycle, but with decreased quiet, and increased indeterminate, sleep. The sleep-circadian rhythm was disturbed, and in the two patients who underwent endocrine testing, abnormal cortisol peaks were seen and one child lacked an increase in growth hormone secretion with sleep. Abnormalities were also noted in the establishment and maintenance of the normal circadian rhythm of body temperature. Although it is unlikely that patients with hydranencephaly perceive their situation,61 some long-term survivors do orient to sound, and may react differently to different individuals and to pleasant versus painful stimuli.56 Increased intracranial pressure may complicate hydranencephaly and require treatment because of increasing head size and/or the potential for discomfort. Standard shunt procedures in hydranencephaly have a high rate of complications including blockage, infection and, because of a lack of the sealing effect of normal surrounding cortex, a tendency to leak fluid along the shunt track.58 Wellons et al.58 compared the outcome in 13 patients, nine of whom had undergone standard shunt procedures and four of whom had a choroid plexectomy (removal of the choroid plexus). The latter procedure had been attempted for the treatment of hydrocephalus in the early 20th century, and largely abandoned because of morbidity, mortality, and the development of shunt systems. Seven of the nine patients who received a shunt had complications, six shunts required revision, five on multiple occasions. These patients required an average of two operations, 1.5 readmissions, and 43.5 hospital days for neurosurgical reasons. In contrast, none of the four plexectomy patients had a surgical complication, none required a repeat operation or readmission, and they had fewer day-clinic visits and follow-up neuroimaging tests than the shunt cohort. Care is required at surgery to prevent inward collapse of the hydranencephalic sac.58 As was mention previously, the outlook for patients with hemihydranencephaly is substantially better, although all have a contralateral hemiparesis, which can involve the face mildly.33 Four of five patients who underwent psychomotor assessment had mild to moderate delay, and the one patient with severe mental retardation had multiple congenital anomalies including a median cleft lip and anophthalmia.28 There is evidence for what has been called neuronal plasticity in that patients with both right and left hydranencephaly have developed speech,28 and Porro et al.33 reported a 12-year-old girl with an IQ of 60 whose right visual hemifields had expanded above the middle line. She had an amblyopic left eye that did not respond to patching but photopic visual evoked potentials were the same from both eyes. In addition, she had developed a torticollis, left-sided head tilt, and rotation of the eyes, presumably to aid her visual fixation. Although most patients do not develop hydrocephalus, shunting is indicated when there is danger of compromise to the uninvolved side.

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There is no primary method of preventing hydranencephaly. Familial cases are rare and, as discussed, tend to show anatomic variation from the usual case. Such families should be offered prenatal monitoring by ultrasound. Most cases of hydranencephaly that have been detected by routine prenatal ultrasound have been during the second half of pregnancy,1,37,42,62 although some cases may begin in the first trimester.43 The location of any remaining cortex may help to distinguish hydranencephaly from hydrocephaly, but in light of the difficulty in distinguishing these abnormalities, a cautious approach to intervention is indicated. MRI and/or color Doppler ultrasound may aid in the specific diagnosis.11,63

References (Hydranencephaly) 1. Greene MF, Benacerraf B, Crawford JM: Hydranencephaly: US appearance during in utero evolution. Radiology 156:779, 1985. 2. Sutton LN, Bruce DA, Schut L: Hydranencephaly versus maximal hydrocephalus: an important clinical distinction. Neurosurgery 6:35, 1980. 3. Hakamada S, Watanabe K, Hara K, et al.: Hydranencephaly: sleep and movement characteristics. Brain Dev 4:45, 1982. 4. Herman DC, Bartley GB, Bullock JD: Ophthalmic findings of hydrancephaly. J Pediatr Ophthalmol Strabismus 25:106, 1988. 5. Iinuma K, Handa I, Kojima A, et al.: Hydranencephaly and maximal hydrocephalus: usefulness of electrophysiological studies for their differentiation. J Child Neurol 4:114, 1989. 6. Velasco M, Velasco F, Gardea G, et al.: Polygraphic characterization of the sleep-epilepsy patterns in a hydranencephalic child with severe generalized seizures of the Lennox-Gastaut syndrome. Arch Med Res 28:297, 1997. 7. Hanigan WC, Aldrich WM: MRI and evoked potentials in a child with hydranencephaly. Pediatr Neurol 4:185, 1988. 8. Yuge T, Kaga K: Brain functions of an infant with hydranencephaly revealed by auditory evoked potentials. Int J Pediatr Otorhinolaryngol 45:91, 1998. 9. Tayama M, Hashimoto T, Mori K, et al.: Electrophysiological study on hydranencephaly. Brain Dev 14:185, 1992. 10. Kaga K, Yasui T, Yuge T: Auditory behaviors and auditory brainstem responses of infants with hypogenesis of cerebral ventricles. Acta Otolaryngol 122:16, 2002. 11. Doi H, Tatsuno M, Mizushima H, et al.: The use of two-dimensional Doppler sonography (color Doppler) in the diagnosis of hydranencephaly. Child Nerv Syst 6:456, 1990. 12. Persutte WH, Yeasting RA, Kurczynski TW, et al.: Agnathia malformation complex associated with a cystic distension of the oral cavity and hydranencephaly. J Cranio Gen Dev Bio 10:391, 1990. 13. Siber M: X-linked recessive microcephaly, microphthalmia with corneal opacities, spastic quadriplegia, hypospadias and cryptorchidism. Clin Genet 26:453, 1984. 14. Samson G, Gardner JC: Craniosynostosis, microcephaly, hydrancephaly, humero-radial synostosis, and thumb aplasia: a new syndrome? Am J Med Genet 61:174, 1996. 15. Gershoni-Baruch R, Zekaria D: Deletion (13)(q22) with multiple congenital anomalies, hydranencephaly and penoscrotal transposition. Clin Dysmorphol 5:289, 1996. 16. Najafzadeh TM, Reinisch L, Dumars KW: Etiologic heterogeneity in hydranencephaly. Birth Defects Orig Artic Ser XVIII(3B):229, 1982. 17. Parish WR: Intrauterine herpes simplex virus infection: hydranencephaly and a nonvesicular rash in an infant. Int J Dermatol 28:397, 1989. 18. Castro-Gago M, Pintos-Martı´nez E, Forteza-Vila J, et al.: Congenital hydranencephalic-hydrocephalic syndrome with proliferative vasculopathy: a possible relation with mitochondrial dysfunction. J Child Neurol 16:858, 2001. 19. Norman AM, Donnai D: Hypoplastic thumbs and hydranencephaly: a new syndrome? Clin Dysmorphol 1:121, 1992. 20. Mbakop A, Cox IN, Stormann C, et al.: Lethal multiple pterygium syndrome: report of a new case with hydranencephaly. Am J Med Genet 25:575, 1986.

21. Kavaslar GN, Onengut S, Derman O, et al.: The novel genetic disorder microhydranencephaly maps to chromosome 16p13.3-12.1. Am J Hum Genet 66:1705, 2000. 22. Goizet C, Espil-Taris C, Husson M, et al.: A patient with hydranencephaly and PEHO-like dysmorphic features. Ann Genet 46:25, 2003. 23. Laurichesse-Delmas H, Beaufre`re AM, Martin A, et al.: First trimester features of Fowler syndrome (hydrocephaly-hydranencephaly proliferative vasculopathy). Ultrasound Obstet Gynecol 20:612, 2002. 24. Gschwendtner A, Mairinger T, Soelder E, et al.: Hydranencephaly with renal dysgenesis: a coincidental finding? Gynecol Obstet Invest 44:206, 1997. 25. Dixon A: Hydranencephaly. Radiography 54:12, 1988. 26. Barrera MN, Campos MR, Ribed MLS: Partial hydranencephaly in a child coincidental with intrauterine exposure to sodium valproate. Neuropediatrics 25:334, 1994. 27. Kato M, Das S, Petras K, et al.: Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 23:147, 2004. 28. Greco F, Finocchiaro M, Pavone P, et al.: Hemihydranencephaly: case report and literature review. J Child Neurol 16:218, 2001. 29. Becker H: Uber Himgefassausschaltungen. II. Intrakranielle Gefassverschlusse. Uber experimentalle Hydranencephalie (Blasenhim). Dtsch Z Nervenheilkd 161:446, 1949. 30. Myers RE: Brain pathology following fetal vascular occlusion: an experimental study. Invest Ophthalmol 8:41, 1969. 31. Moore CA, Weaver DD, Bull MJ: The fetal brain disruption sequence. J Pediatr 116:383, 1990. 32. Freide RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 109. 33. Porro G, Wittebol-Post D, de Graff M, et al.: Development of visual function in hemihydranencephaly. Dev Med Child Neurol 40:563, 1998. 34. Wintour EM, Lewitt M, McFarlane A, et al.: Experimental hydranencephaly in the ovine fetus. Acta Neuropathol (Berl) 91:537, 1996. 35. Hoyme HE, Higginbottom MC, Jones KL: Vascular etiology of disruptive structural defects in monozygotic twins. Pediatrics 67:228, 1981. 36. David TJ: Vascular basis for malformations in a twin. Arch Dis Child 60:166, 1985. 37. Hahn JS, Lewis AJ, Barnes P: Hydranencephaly owing to twin-twin transfusion: serial fetal ultrasonography and magnetic resonance imaging findings. J Child Neurol 18:367, 2003. 38. Sebire N, Taylor M, Fisk NM: Consequences of in-utero death in twin pregnancy. Lancet 356:1108, 2000. 39. Iannetti P, Galletti F, Emanuelli O, et al.: Severe outcome of brain perfusion failure: a pre-hydrancephalic state? Brain Dev 13:447, 1991. 40. Ferna`ndez F, Pe`rez-Higuerez A, Herna`ndez R: Hydranencephaly after maternal butane-gas intoxication during pregnancy. Dev Med Child Neurol 28:355, 1986. 41. Takada K, Shiota M, Ando M, et al.: Porencephaly and hydranencephaly: a neuropathological study of four autopsy cases. Brain Dev 11:51, 1989. 42. Edmundson SR, Hallak M, Carpenter RJ Jr, et al.: Evolution of hydranencephaly following intracerebral hemorrhage. Obstet Gynecol 79:870, 1992. 43. Lam YH, Tang MH: Serial sonographic features of a fetus with hydranencephaly from 11 weeks to term. Ultrasound Obstet Gynecol 16:77, 2000. 44. Stevenson DA, Hart BL, Clericuzio CL: Hydranencephaly in an infant with vascular malformations. Am J Med Genet 104:295, 2001. 45. Sandelbach KM, Gujrati M, Husain AN: Web-like malformation of the carotid artery and multicystic encephalomalacia. Pediatr Pathol 12:701, 1992. 46. Lubinsky MS, Adkins W, Kaveggia EG: Decreased maternal age with hydranencephaly. Am J Med Genet 69:232, 1997. 47. To WW, Tang MH: The association between maternal smoking and fetal hydranencephaly. J Obstet Gynaecol Res 25:39, 1999. 48. Plantaz D, Joannard A, Pasquier B, et al.: Hydranence´phalie et toxoplasmose conge´nitale. A propos de quatre observations. Pediatrie 42:161, 1987.

Brain 49. Christie JD, Rakusan TA, Martinez MS, et al.: Hydranencephaly caused by congenital infection with herpes simplex virus. Pediatr Infect Dis 5:473, 1986. 50. Kubo S, Kishino T, Satake N, et al.: A neonatal case of hydranencephaly caused by atheromatous plaque obstruction of aortic arch: possible association with a congenital cytomegalovirus infection? J Perinatol 14:483, 1994. 51. Sharp NJ, Davis BJ, Guy JS, et al.: Hydranencephaly and cerebellar hypoplasia in two kittens attributed to intrauterine parvovirus infection. J Comp Pathol 121:39, 1999. 52. Hewicker-Trautwein M, Liess B, Trautwein G: Brain lesions following transplacental infection with bovine-virus diarrhea virus. Zentralbl Veterinarmed B 42:65, 1995. 53. Tateyama S, Yamaguchi R, Uchida K, et al.: An outbreak of congenital hydranencephaly and cerebellar hypoplasia among calves in South Kyushu, Japan: a pathological study. Res Vet Sci 49:127, 1990. 54. Kitano Y, Ohzono H, Yasuda N, et al.: Hydranencephaly, cerebellar hypoplasia, and myopathy in chick embryos infected with aino virus. Vet Pathol 33:672, 1996. 55. Velasco ME, Brown JA, Kini J, et al.: Primary congenital rhabdoid tumor of the brain with neoplastic hydranencephaly. Child Nerv Syst 9:185, 1993. 56. Covington C, Taylor H, Gill C, et al.: Prolonged survival in hydranencephaly: a case report. Tenn Med 96:423, 2003. 57. Appenzeller O, Snyder R, Kornfeld M: Autonomic failure in hydranencephaly. J Neurol Neurosurg Psychiatry 33:532, 1970. 58. Wellons JC III, Tubbs RS, Leveque J-CA, et al.: Choroid plexectomy reduces neurosurgical interventions in patients with hydranencephaly. Pediatr Neurosurg 36:148, 2002. 59. Endo H, Kobayashi S, Nakamigawa, et al.: Endocrinological analysis of chronic hypernatremia in two cases of hydranencephaly. No To Hattatsu 22:3, 1990. 60. Hashimoto T, Fukuda K, Endo S, et al.: Circadian rhythm in patients with hydranencephaly. J Child Neurol 7:188, 1992. 61. Morgan H: Hydranencephalic children and the ability to suffer. J Clin Ethics 1:325, 1990. 62. Hadi HA, Mashini IS, Devoe LD, et al.: Ultrasonographic prenatal diagnosis of hydranencephaly: a case report. J Reprod Med 31:254, 1986. 63. Vila-Coro AA, Dominquez R: Intrauterine diagnosis of hydranencephaly by magnetic resonance. Magnetic Res Imag 7:105, 1989.

15.11 Porencephaly Definition

The term porencephaly was first used by Heschl1 to include any cavity or cleft of the cerebral cortex. He described a variety of lesions, some of which communicated with both the ventricular and the subarachnoid systems, others that only connected with the ventricles, and some that were enclosed within the cortex. These abnormalities are clinically, pathologically, and etiologically diverse. Most authors recognize two major subgroups, based on both pathologic findings and etiologic hypotheses: type 1 or encephaloclastic porencephaly (EP), and type 2 or developmental porencephaly (DP), with the latter being subdivided into schizencephaly and simple porencephaly (SP). There has been a proliferation of confusing terminology in the literature, and this, along with the nosology used in this section, is shown in Figure 15-54. What has been called congenital midline porencephaly is considered to be a variant of the dorsal cyst seen in holoprosencephaly (Section 15.4 ).2 Encephaloclastic porencephaly is presumed to arise from secondary cortical destruction in an otherwise normal brain, whereas the developmental porencephalies are thought to be due to defective embryogenesis. Schizencephaly is generally accepted as a disorder of

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Fig. 15-54. The terminology used in this section is underlined and in standard script. Type 1 (for encephaloclastic) and type 2 (for developmental) are in common use today. Terms in small italics have been used but should be abandoned.

formation of the germinal matrix or migration of neuroblasts. Thus, it might seem logical to place schizencephaly in the section on malformations of cortical development (Section 15.5), especially as it occurs commonly in association with cortical dysplasia, gyral anomalies, and heterotopias. However, there is a tradition of treating these abnormalities under the heading of porencephaly and, perhaps more important, there is evidence that sometimes these pathological and histological distinctions are more a matter of timing and severity than fundamental differences in underlying etiology. Several examples illustrate this latter point. Cerebral hemorrhage is a welldocumented cause of EP, but schizencephaly has been reported after in utero exposure to warfarin,3 and as a consequence of alloimmune thrombocytopenia with intracranial bleeding prior to 20 weeks, as compared to bleeding after 26 weeks in the equivalent cases with EP.4 Debus et al.5 have provided very suggestive evidence of an association between inherited thrombophilia variants and EP. Therefore, it is of interest that an inherited thrombophilia variant was found in three of four members of a family with incomplete penetrance of an autosomal dominant form of SP.6 Maternal abdominal trauma is thought to result in malformations through hemorrhage or hypoperfusion, and a case of EP with limb reduction defects following serious maternal abdominal trauma has been reported.7 Schizencephaly with limb reduction has also been reported (Table 15-15). In utero cytomegalovirus (CMV) infection has been associated with hydranencephaly and EP, probably as a result of a vasculitis, and schizencephaly has also been reported following CMV infection,8 including a case with a coexisting area of encephalomalacia.9 Schizencephaly has also been reported after probable twin-twin transfusion associated with a genetic amniocentesis.10 In a report of 10 pregnancies with CNS anomalies associated with in utero exposure to vasoactive drugs (predominantly cocaine),11 there was one child with hydranencephaly, three with typical EP, two with schizencephaly, one with a severe SP, one with cortical infarcts, and two with absent corpus callosum and colpocephaly, thus covering the whole spectrum of porencephaly and beyond. Finally, some of the most provocative findings are those of Marin-Padilla et al.12 who reported on the evolution of typical encephaloclastic lesions in the postnatal shaken-baby syndrome. By 6 months of age, the cortex had developed microgyria, abnormal lamination, and cortical dysplasia; changes that might readily be attributed to early prenatal damage. If the possibility of shared etiology is kept in mind it remains reasonable to consider the major groups and subgroups of porencephaly separately because they do tend to differ in their clinical

Table 15-15. Syndromes with porencephaly/schizencephaly Syndrome

Prominent Features

Causation Gene/Locus

Anophthalmiahypopituitarism-renal60

Micro/anophthalmia, cleft lip/palate, absent pituitary, nephronopthisis, delayed development, reduced cerebral white matter, multiple small porencephalic cysts; father had large head

Unknown

Anterior chamberhydrocephalus-heart defect61

Peters anomaly, persistent hyaloid artery, unilateral absent lens, obstructed aqueduct of Sylvius, enlargement of the lateral and 4th ventricles, cerebellar, pontine, and medullary atrophy, porencephaly, tricuspid valve dilation, atrial septal defect, lethal

Unknown

Beckwith-Wiedemann62

Usually prenatal onset overgrowth, macroglossia, omphalocele, visceromegaly, ear creases/pits at the front or back of the lobes or helices, nevus flammeus, midfacial hypoplasia; association with embryonal malignancies; hemihypertrophy a risk factor for malignancy; case report with schizencephaly

AD (130650) imprinting and gene dosage effects 11p15.5

Cerebro-oculo-skeletalrenal63

Optic atrophy, absence of retinal vessels, seizures, growth and developmental delay, elongated clavicles, cupped ribs, mild platyspondyly, rhizomelia, schizencephaly, nephritis/nephrosis

Unknown

Cocaine, prenatal exposure64

Debatable if recognizable facial appearance, limb reduction, genitourinary anomalies; CNS has included porencephaly, septo-optic dysplasia, schizencephaly, midline cysts, and callosal agenesis

In utero exposure

DK-phocomelia65

Occipital encephalocele, absent corpus callosum, variable upper limb and digital absence anomalies, hypoplastic thumbs; case with bilateral upper limb amelia, right parieto-occipital porencephalic cyst, severely retarded, gingival hyperplasia

Unknown (223340)

Encephalocraniocutaneous lipomatosis66

Unilateral cerebral anomalies include hemiatrophy and defective operculization of insula, ipsilateral protuberant soft scalp masses with overlying alopecia, papular skin lesions on face and eyes, pterygium-like scleral lesions that may lead to scarring, and progressive intracranial calcifications associated with vascular malformations; a few cases with porencephaly

Unknown (176920)

Linear nevus sebaceous67,68

Various skin lesions include nevus unius lateris, icthyosis histrix, acanthosis nigricans, nevus sebaceous of Jadasshon; cortical atrophy, intracranial aneurysms; various neurologic sequelae in 50% of patients; brain tumor in 2/64; cases with porencephaly/schizencephaly

Unknown (163200)

Generalized fibromatosiscutis marmorata69

Fibrous nodules of various organs may compromise vital organs. Only one case with associated cutis marmorata telangiectasia, hemiatrophy, porencephaly

Unknown, some familial (228550)

Glass: ear anomalies-limb reduction70

Findings variable: macrocephaly, over-folded helices, preauricular tags, external meatal stenosis, narrow palpebrae, cleft palate, agenesis of the corpus callosum, multilocular porencephaly; sister lacked brain abnormalities, had absent right arm, absent proximal left humerus, humero-radio-ulnar synostosis

AR

Hypocalvaria-heartcamptomelia71

IUGR, microcephaly, wide sutures, areas of absent calvarial bones, prominent eyes, low-set and anomalous pinnae, anteverted nares, bowing greatest in tibia, bilateral cleft-like cysts in front of anterior horns

Uncertain

L’Hermitte: oxycephaly72

Oxycephaly with open sutures, absent frontal sinuses, flat face, shallow orbits, absence of the corpus callosum, hypoplastic vermis

AR

Merlob: morning gloryporencephaly73

Macrodolichocephaly, long palpebrae, epicanthus, absent eye movements, central retinal colobomas, anteverted nares, tented lips, high palate, hydronephrosis, unilateral porencephaly and atrophy, parasagittal arachnoid cyst.

Unknown

Microgastria-upper limb reduction74

Microgastria, variable upper limb defects, asplenia/splenogonadal fusion; case reports in association with iris coloboma, orbital cyst, fused thalami, arhinencephaly, agenesis of corpus callosum, several internal anomalies, hypothalamic hamartoma; anophthalmia, porencephalic cyst, and hydrocephalus

Unknown (156810)

Nephrotic syndromeinfantile spasms-GallowayMowat75

Developmental delay, early nephrotic signs due to focal glomerulosclerosis that may show IgM, IgG, and/or C3 deposits, areas of microgyria, cortical layer fusion. Single incompletely documented case with ‘‘diffuse encephalomalacia’’

AR (251300)

Neurocutaneous melanosis76

Classical and variant forms of cutaneous pigmented nevi and leptomeningeal melanosis with malignant change, intracranial anomalies and cysts, arachnoid villi infiltration in some. Report of a case with porencephaly

Unknown (249400)

Oculocerebrocutaneous77

Orbital cysts, microphthalmia, lid coloboma, periorbital skin appendages, areas of skin hypoplasia/aplasia, skeletal anomalies, agenesis of the corpus callosum, multiple brain cysts of undetermined type

Unknown (164180)

Oral-facial-digital type I78

Midline cleft/notched upper lip, multiple oral frenulae, lobulated tongue with hamartomas, asymmetric brachysyndactyly; CNS includes hydrocephaly, porencephaly, cerebellar vermis hypoplasia, Dandy-Walker cysts, neuronal migration defects, and agenesis of the corpus callosum

XLD (311200) male lethal CXORF5, Xp22.3-p22.2 (continued)

646

Brain

647

Table 15-15. Syndromes with porencephaly/schizencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Oral-facial-digital type II

Short stature, hypertelorism, low nasal bridge, broad and bifid nasal tip, hypertropied oral frenula, cleft and lobulate tongue, cleft palate; brachysyndactyly, preaxial and postaxial polydactyly of hands; preaxial foot polydactyly; usually normal intelligence; CNS includes porencephaly, hydrocephaly, callosal agenesis

AR (252100)

Porencephaly-cerebellar hypoplasia-heart defect80

Prominent metopic suture, bilateral epicanthus, high arched palate, absent septum pellucidum, hydrocephalus, bilateral cortical defects, dilated 4th ventricle, absent vermis, cerebellar hypoplasia, probable porencephaly in one sib, congenital heart defects

AR (601322)

Porencephaly/ schizencephaly-septum pellucidum81

Absent septum pellucidum, porencephaly/schizencephaly, mental retardation, neurologic dysfunction including paraplegia; this is basically a developmental association (see text)

Unknown, case in utero benzol exposure

Porphyria-acute intermittent, homozygote82

Optic nerve changes, cataracts, ataxia, developmental delay, skin photosensitivity; microcephaly, porencephaly, vermis hypoplasia, anterior encephalocele

AD (176000) porphobilinogen deaminase, 11q23.3

Progressive hemifacial microsomia-tumors83

Progressive postnatal hemifacial atrophy with ipsilateral cerebral calcification, mild learning difficulties, orbital neuroma, oral odontogenous fibroma, lower limb cartilaginous hamartomas, porencephaly; same as encephalocraniocutaneous lipomatosis?

Unknown

Proud: XLMR-seizurescallosal agenesis84

Microcephaly, severe mental retardation, seizures, spasticity, coarse face, nystagmus, joint contractures, tapering fingers, porencephaly, agenesis of the corpus callosum; conservative substitution in homeodomain

XLD (300004) ARX, Xp22.13

Pycnodysostosis85

Osteosclerosis, short stature, open fontanels, wide cranial sutures, wormian bones, prominent nose, dental anomalies, abnormal clavicles, acro-osteolysis, fractures, variable mental retardation

AR (265800) cathepsin K, 1q21

Schizencephalyectrodactyly86

Two unrelated children with unilateral schizencephaly associated with an ipsilateral ectrodactyly in one, and a contralateral lobster claw deformity in the other

Unknown

Septo-optic dysplasia87

Septum pellucidum agenesis, optic nerve hypoplasia, hypothalamic/pituitary dysfunction; variable growth hormone deficiency, diabetes insipidus, trophic hormone deficiencies; seizures and developmental delay common; brain anomalies include agenesis of the corpus callosum, hydrocephalus, cerebral atrophy, porencephaly, schizencephaly. May be a component of other syndromes or occur occasionally in established syndromes (see this text and Section 15.7).

Heterogeneity (182230) some due to HESX1, 3p21.2-p21.1

Triophthalmia-facial clefting88

Dolichocephaly, cleft lip/palate, asymmetric face, micrognathia, ventricular septal defect; dilated ventricles, brain atrophy and ‘‘porencephaly’’

Unknown

Triple-X89

Tall stature, disproportionately long limbs, lowered mean OFC, mean IQ 85-90; commonly poor coordination, delayed motor milestones, poor verbal learning and expressive language. Case with right closed-lip schizencephaly, arachnoid cyst, abnormal left gyri.

Chromosome imbalance

Vitamin A embryopathy90

Microtia/anotia, asymmetric second arch anomalies, flat nose, hypertelorism, micrognathia, limb and heart defects. CNS includes hydrocephalus, microcephaly, porencephaly, focal agyria, heterotopias, vermis hypoplasia, Dandy-Walker

In utero exposure

79

presentation, management, and prognosis. Also some etiologies may be limited to a specific type of porencephaly. 15.11.1 Encephaloclastic Porencephaly Definition

Congenital encephaloclastic porencephaly is a cavity in the brain resulting from destruction of normal tissue. It may be single or multiple and may be self-contained within the cerebral hemisphere or connect with the lateral ventricles and/or subarachnoid space. As such it forms part of the spectrum of hydranencephaly (Section 15.10). Congenital EP usually originates from a hemorrhage anterior to the subependymal germinal matrix at 24 to 32 weeks gestation, which tends to show centripetal growth with relative sparing of the medial structures.13 The in utero sonographic evolution of several cases of EP, often with earlier documented normal ultrasounds, has been reported. The initial hemorrhage appears as a hyperechoic area,

and over a period of up to several weeks it presents an anechoic center with an echogenic border, eventually developing anechoic properties characteristic of CSF. Angiography, and presumably in utero color-Doppler ultrasound, typically shows normal preexisting blood vessels crossing the cavity. With maturation the cavity is lined by gliosis, and the degree of glial scarring varies with the timing of the insult. Unlike the situation with DP, clefts are not lined by gray matter, and MRI can be useful in clarifying this detail. There is often asymmetric dilation of the lateral ventricles with a midline shift.13 Etiology and Distribution

The major causes of EP relate to hemorrhage/infarction, infection, and trauma, and it is likely that the latter two have an underlying vascular hypoxic basis. The distribution of EP is often seen to fall within the distribution of a specific cerebral artery, of which the middle cerebral is the most common.14 Debus et al.5 reported that 13 of 24 infants and children with EP had a single, and three others had two, inherited risk factors for thrombophilia. Two children

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Neuromuscular Systems

with microcephaly, cerebral atrophy, cerebral cystic lesions, and factor V Leiden mutations were reported by Voudris et al.15 Several additional cases have been reported with alloimmune thrombocytopenia,4,8 and it is generally accepted that hemorrhage is the mechanism of damage with warfarin exposure.3 Prenatal sonography has documented the development of EP following in utero CMV infection7,16 and herpes zoster infection at 25 weeks gestation.17 Cases have also been reported following penetration of the skull by an amniocentesis needle,18 and after early (9 weeks) chorionic villus sampling (CVS).19 It is of note that early CVS has also been related to limb reduction defects, and that the combination of limb reduction and EP has followed maternal abdominal trauma.7 Cases segregating with COL4A1 mutations have been reported in mice and humans.112 There are no good estimates of the incidence of EP. Porencephaly was noted in 2.5% of pediatric autopsies with known CNS anomalies, of which 2.2% were considered to be DP.20 Congenital cases appear to be uncommon, and the prevalence will be higher if peri- and postnatally acquired cases are included. Premature infants (24–32 weeks) are clearly susceptible to major intracranial bleeding, which may be observed to evolve, both by neuroimaging and pathological examination, into a full thickness necrosis of the cerebral cortex.21 Another picture typical for EP can be seen following postnatal head trauma,22 including the shaken baby syndrome.12 Initial concerns that perinatal chest physiotherapy in very premature infants might cause EP appear to have been unfounded.23 Prognosis, Treatment, and Prevention

The outcome for children with EP will largely depend on the timing, extent, and location of the lesion, and may range from asymptomatic, to later-onset seizures, to motor and/or variable intellectual disability and medication-resistant seizures. Seizures can be an important complication, and in some cases originate directly from the EP and are often of the Lennox-Gastaux type. A good response to ‘‘decapping’’ a large cyst has been reported, and in a series of 37 children with relatively smaller lesions, 62% became seizure free after fenestration of the cyst into the lateral ventricle.24 In addition, it appears that there is an over 30% associated occurrence of mesial temporal sclerosis with EP. Ho et al.14 reported 14 patients with EP and seizures; 12 had congenital hemiparesis, and the MRI showed the porencephaly to be in the distribution of the middle cerebral artery in eight, the posterior in three, the internal carotid in one, and multiple arteries in three. Thirteen had demonstrable hippocampal, and 10 amygdalar atrophy, and the seizures showed a temporal origin in nine. Two patients were surgically treated and became seizure free. Burneo et al.25 reported 24 patients with EP and seizures. In nine patients the seizures were drug resistant, and in six of these there was an extratemporal porencephaly with a temporal sclerosis and focus of the seizures. Five patients had surgical removal of the temporal focus and were seizure free at an average follow-up of 47 months. In five of the six cases, the temporal sclerosis was ipsilateral to the porencephaly, and the authors hypothesized a common ischemic pathogenic event. For the contralateral lesion they raise the possibility of diaschisis, where an insult at one site causes changes at a distant contralateral region of the brain. Prevention of EP would largely depend on removing the causes of brain hemorrhage/ischemia, infections, and trauma. Specific treatment of alloimmune thrombocytopenia can reduce the risk of fetal intracerebral hemorrhage26; amniocentesis should be performed under direct ultrasound guidance, and CVS should not be performed below 11 weeks gestation. The risk of EP in the fetus of a mother carrying a single inherited risk factor for thrombophilia is clearly low, and there is no indication for the treatment of such

women in pregnancy. However, a woman with two such risk factors, who already had an affected child would present difficult management choices, for which there are no informing data. 15.11.2 Developmental Porencephaly

15.11.2.1 Schizencephaly Definition

The term schizencephaly was first used by Yakovlev and Wadsworth27 to refer to clefts found in the region of the primary fissures and is characterized by an infolding of the cerebral cortex into the cleft and continuity of a pia-ependymal seam. The lesion can be bilateral or unilateral, and contralateral gyral anomalies or heterotopias often accompany the latter (Figs. 15-55 and 15-56). Yakovlev and Wadsworth27 subdivided schizencephaly according to whether the sides of the clefts are closely apposed or lie completely open and allow the ventricles to connect to the subarachnoid space (Fig. 15-57). Today the former, which usually lacks hydrocephalus, is called closed-lip, and the latter, in which hydrocephalus is the norm, is called open-lip schizencephaly. This distinction has no pathogenic basis, indeed 12 of 15 patients with bilateral schizencephaly reported by Denis et al.28 had one open and one closed cleft, but it is useful as a measure of severity. In utero progression from closed to open-lip has been observed.29 Diagnosis

The clefts most often involve the parasylvian fissure and region of the central sulcus. Patients typically present with developmental delay, asymmetric muscle tone, seizures, and hemiparesis or quadriparesis. Patients with the closed-lip form more often present with motor delay and hemiparesis; those with the open-lip type more often present with hydrocephalus and seizures.30 The seizures may be of a variety of types, including tonic-clonic, partial motor, sensory, and infantile spasms.31 Mental retardation is variable but is usually toward the Fig. 15-55. Axial CT scan showing bilateral schizencephaly with the margins of the cleft closely apposed on the right. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario, Ottawa.)

Brain

Fig. 15-56. Axial MRI scan of a 26-year-old woman who presented with hemiparesis and onset of seizures, showing unilateral left-sided cleft and contralateral gyral anomalies. (Courtesy of Dr. S. Grahovac, Ottawa Hospital, Ottawa.)

Fig. 15-57. Axial CT scan showing bilateral schizencephaly and wide separation of the cleft margins. (Courtesy of Dr. C. Greenberg, Winnipeg.)

649

severe end of the spectrum in individuals with bilateral openlip schizencephaly,28,30 and microcephaly is a poor prognostic sign.32 Motor deficits are more common with frontal than non-frontal lesions.33 Patients with large clefts may show increased transillumination over the affected area, but this is a nonspecific finding, and the diagnosis is confirmed with appropriate imaging techniques. It is the continuity of the cerebral gray matter into and along the walls of the cleft and of the pia-ependymal connection that provides the distinctive findings on neuroimaging (Fig. 15-56). Although angiography has been superceded by noninvasive approaches, it does show a characteristic incurving of the cortical vessels at the border of the cleft and their continuity with the subependymal veins, as well as reticular masses of small vessels in the areas of accompanying microgyria.34 Sonographic diagnosis of open-lip schizencephaly is made by demonstrating dilated ventricles that connect directly with the subarachnoid space, and in closed lip by detecting a funnel-shaped, cortically lined, indentation of the cortex.29,35 The diagnosis is not always apparent on prenatal sonography and is more likely to be perceived as hydrocephalus, with or without visualization of the associated cortical abnormalities. For example, Denis et al.36 reported three cases where ultrasound detected ventriculomegaly and cortical anomalies, but where prenatal fast MRI images were required to make the diagnosis of schizencephaly. The specific neuroimaging findings will vary with the size and precise location of the cleft(s). Typically, the cleft is seen to arise vertically from the area of the midsylvian fissure and may be presylvian or suprasylvian; the length and orientation of the fissure may be altered.31 The cleft itself extends through the entire cortical mantle and is lined by cortex of normal density, but often increased thickness.32 There may be a triangular indentation (dimple) at the ventricular end of the cleft, with gray matter extending a short distance along the ventricle. Choroid plexus may extend into larger open-lip clefts. MRI appears to be the procedure of choice to best define the cleft and its associated anomalies. There have been several reports where CT has either failed to detect or has imprecisely defined schizencephaly.28,33,37 Pathologic examination of the cleft demonstrates the piaependymal lining along the seam, and true micropolygyria and heterotopias, both at the site and often at more distant locations. Functional imaging with positron emission tomography and single photon emission CT have shown that the gray matter lining the cleft has equivalent perfusion and glucose metabolism to that of normal cortex.38 Absence of the septum pellucidum occurs in association with schizencephaly often enough that the finding of either of these lesions should trigger a search for the second.31,37,39,40 Some have argued that this is a distinct neuropathological syndrome,37,39,40 but there is nothing distinctive about the clinical, etiologic, or pathologic nature of schizencephaly with or without absence of the septum pellucidum. This author agrees with Osborn41 that the single name schizencephaly should be used whether or not the septum pellucidum is present. Furthermore, there is evidence that the difference simply reflects the site and timing of the initial embryologic insult. Raybaud et al.42 hypothesized that the septum pellucidum is part of a medial medullary velum that represents the frontal lobe, and that the psalterium corresponds to the parietooccipital, and the fimbria to the temporal, lobes. They found that in all cases where the septum pellucidum was absent, the clefts were in the frontal lobe; whereas if the septum pellucidum was present, the clefts were occipital, parietal, or temporal. In three

650

Neuromuscular Systems

central clefts there were overlapping findings, but in these cases the actual lobar location of the cleft could not be determined. These results support a segmental organization of septal and cortical development and indicate that the presence or absence of the septum pellucidum depends on the precise location of the developmental disturbance. Kuban et al.43 highlighted that schizencephaly may be present in septo-optic dysplasia (SOD), which includes absent septum pellucidum, optic nerve hypoplasia, and pituitary hypofunction. They argued, from a review of the literature, that either optic nerve hypoplasia or absence of the septum pellucidum alone is also associated with neuroendocrine dysfunction, and they proposed that this represented a spectrum of neurodevelopment malformations. The concept of a spectrum is further supported by reports of patients with SOD and polymicrogyria.44,45 Etiology and Distribution

The facts that the clefts in schizencephaly are lined by cortex, there is continuity between the ependyma and pia, a dimple of the ventricle is often seen at the point of entry, blood vessels are often seen extending between the cortical surfaces, and associated brain anomalies such as absence of the septum pellucidum, heterotopias, and microgyria are present, argue strongly for a developmental rather than a destructive basis for schizencephaly.32 The timing and nature of the underlying insult remain matters for debate. Yakovlev and Wadsworth27 argued for an origin during the first 2 months of gestation, while Dekaban,46 noting the common location in the distribution of the middle cerebral circulation, has argued in favor of a somewhat later vascular basis. The frequent bilateral involvement, including microgyria, supports a timing before division of the cerebral hemispheres, and this is further supported by the strong association with optic nerve hypoplasia and absence of the septum pellucidum that relate to development of the lamina terminalis.43 The ultimate gross pathologic lesion can be explained as the result of a local failure of neuroblast migration from the germinal matrix. The pia and ependyma become apposed at this site of failure and cause the surrounding, normally developing cortex, as well as the ventricular wall, to be drawn into the cleft, producing both the cortical lining and the ventricular dimple characteristic of schizencephaly. Arachnoid cysts have been reported a number of times in association with schizencephaly. Sener47 reported two patients with large schizencephalic clefts and large temporal arachnoid cysts, and argued that the cyst originated from splitting of the leptomeninges caused by the cortical infolding into the cleft. However, the report of monozygotic twins, one with unilateral schizencephaly and the other with a temporal arachnoid cyst,48 and a patient with schizencephaly and dilated subarachnoid space whose brother had a typical arachnoid cyst,28 rather favor a shared, and possibly familial, underlying pathogenesis. The distinction between open-lip and closed-lip schizencephaly may reflect the size of the initial lesion rather than be a consequence of obstructive hydrocephalus, because many patients with open-lip schizencephaly are microcephalic.32 The discovery that mutations in EMX2, a homeobox gene specifically expressed in proliferating cells of the ventricular zone and considered to play an important roll in the proliferation and possible migration of neuroblasts, are present in a substantial portion of cases of sporadic schizencephaly49,50 supports an early origin involving cells of the germinal matrix as a cause for this disorder. In the two small series reported to date, sequence changes have been reported in 13 of 18 patients. While there is an early suggestion of some

genotype-phenotype correlation, the pathogenicity of some of the mutations is uncertain at this time, and more information is required before the true importance of this gene can be assessed. However, the fact that not all cases studied have had mutations in EMX2, together with evidence from certain case reports, suggests that other etiologies, and perhaps later timing, may also come into play. Hamsters infected with Kilham strain mumps virus during the time of neuronal migration show antigen on neuroepithelial cells in the ventricular zone and in vimentin immunoreactive radial glial fibres.51 There is pathologic evidence of hemorrhage, neuronal necrosis, and a picture compatible with schizencephaly, which raises the potential of a direct viral cause for schizencephaly. Examples of schizencephaly associated with alloimmune thrombocytopenia,4 fetal bradycardia following genetic amniocentesis in a twin pregnancy,10 and in utero exposure to vasoactive drugs11,52 have already been mentioned. One of those patients reported by Souchet52 had occlusion of the right middle cerebral artery, which the author speculated might have recanalized in the other two cases; middle cerebral artery stenosis was also noted in the CMV-associated cases of Tonas-Vila et al.9 Landrieu and Lacroix53 reported a 3-month-old girl with bilateral schizencephalic clefts lined by microgyric cortex without evidence of arrested neuronal migration. Distant areas had subependymal heterotopias, and there was evidence of later cortical ischemic events and atypical vessels in the cleft, a hemorrhage from which led to her death. Thus, there is substantive support for a vascular origin for some cases of schizencephaly, and for the suggestion by Landrieu and Lacroix53 that a malacic process, at a time when the entire cortical mantle can be destroyed (< 20 weeks), can cause this malformation. Chromosome imbalance is not a significant cause of schizencephaly. A number of familial cases of non-syndromic schizencephaly, typified by the families reported by Haverkamp et al.,54 Ueda et al.,55 Hillberger et al.,56 Robinson,57 and the brothers with identical EMX2 mutations reported by Granata et al.,58 have all involved affected siblings with normal parents. All the familial cases have been bilateral, although the severity has varied, and both males and females have been affected. Senol et al.59 did report a pair of dizygotic twins with absent septum pellucidum in which one member had bilateral closed-lip schizencephaly and the other had unilateral cortical dysplasia in the same area as the sibling’s cleft. On the surface the pattern is most suggestive of autosomal recessive inheritance. However, the mutation reported in the two brothers reported by Granata et al.58 was not found in either parent. The likely explanation is that of germline mosaicism and this, together with the relatively high rate of EMX2 mutations in sporadic schizencephaly,49,50 raises the question as to whether these ‘‘autosomal recessive’’ families are in fact further examples of germline mosaicism for heterozygous genetic lethal mutations. Alternatively, some sibling recurrences of milder schizencephaly could be expected to occur due to non-penetrance of less severe mutations in a carrier parent. Four patients with mild unilateral sporadic schizencephaly have been found to have the same synonymous C ! A substitution at position 7 in EMX2 (not seen in 1500 controls), and in one case the unaffected mother, carried the same muation.50 The true incidence of schizencephaly is unknown. There does not appear to be any significant difference in sex ratio. Considering that patients are selected for neuroimaging study because of suspicion of an intracranial lesion, it must be a rare malformation. Rates of 1 in 625 and 1 in 1650 have been reported from large series of consecutive CT examinations.31,32 Table 15-15

Brain

lists a number of syndromes in which porencephaly has been reported, but the specific type has not always been made clear. Prognosis, Treatment, and Prevention

The prognosis in schizencephaly is correlated with the extent and type of the malformation, and can be affected by the presence and medical responsiveness of any accompanying seizure disorder. Packard et al.30 reported 12 cases of bilateral and 17 unilateral openlip, and 6 cases of bilateral and 12 unilateral closed-lip schizencephaly. The majority of clefts were anterior. Among the total group, 57% had seizures and a third of these were medically unresponsive. Fifty-one percent were severely, 32% moderately, and 17% mildly or not at all mentally retarded. Patients with a closed-lip malformation were more likely to show mild to moderate delay than were those with open-lip schizencephaly (78% vs. 31%), as were those with unilateral as compared to those with bilateral involvement (62% vs. 28%). Normal language development was noted in 48% of those with a unilateral cleft compared with only 6% of those with bilateral clefts, and children who had a single lobe involved made up 88% of those with mild, and 58% of those with moderate delay. Eleven of 12 patients with bilateral, open-lip schizencephaly had severe mental retardation. Denis et al.28 reported 15 patients with bilateral and 15 patients with unilateral schizencephaly. Mental retardation was noted in 57% of the cases. Of the unilateral cases, 53% had presented by 1 year of age with asymmetric muscle tone (8), seizures (2), developmental delay (2), locomotor delay (2), and nystagmus (1). Twelve of the 15 children had a mild hemiparesis, which was contralateral in 11, and one had no motor deficiency. Intelligence was considered normal in 10, although seven exhibited language delay. Seven children had seizures, with a mean age of onset of 4 years, and although there were a variety of seizure types, most children expressed a single form, and only one case was refractory to drug treatment. Of the bilateral cases, 47% were diagnosed by 1 year of age with the presenting signs including developmental delay and asymmetric tone (5), language abnormality (1), and microcephaly (1). Nine patients had tetraparesis, and five had hemiparesis; 12 were considered to have mental retardation and all showed language delay, with four exhibiting a bucco-lingual apraxia equivalent to that seen in bilateral perisylvian cortical malformation (Section 15.5). Only four of the 15 had a seizure disorder and all were drug responsive. Similar results were obtained in the smaller series reported by Granata et al.,91 and it can be concluded that patients with bilateral, open-lip defects have the poorest developmental and motor prognosis, while those with unilateral, closed schizencephaly have the most favorable outlook, and may indeed show very little impact.31,32,92 In contrast, the occurrence of seizures does not correlate as well with the type of lesion,8,28,91 although they may be determined by the presence of associated areas of cortical dysplasia. There is no specific treatment for schizencephaly. If the site of origin of medically resistant seizures can be localized, patients may benefit from surgery, which may involve dysplasia in the wall of the cleft itself,93 or a more distant focus, such as the temporal lobe.94 Other complications that may respond to intervention include hydrocephalus, which may be associated with a mass effect and midline shift in unilateral cases. Alexander et al.95 described two patients with schizencephaly and a schizoaffective disorder, and Relan et al.96added another with bipolar affective disorder. At this time there are insufficient data by which to determine whether these cases represent chance concurrence or an increased risk for psychosis in schizencephaly.

651

As is the case in hemihydranencephaly, there is evidence that the unaffected cortex may undergo some functional compensatory reorganization (plasticity), notably in the case of unilateral disease,97–99 although Denis et al.28 discuss the concern that such reorganization, in order to preserve one function, may compromise other specific functions through a crowding effect. There are no direct preventive measures, although the steps mentioned under EP might be expected to have some small impact. Testing for mutations in EMX2 should be considered especially in typical cases where no other etiology is apparent. If a mutation is found, prenatal diagnosis should be offered in subsequent pregnancies, even if parental evaluations are negative because of the, as yet undefined, risk of germline mosaicism. In the absence of a mutation or additional cases in the family, patients can be counseled that the recurrence risk is low. Targeted prenatal ultrasound may be provided in subsequent pregnancies, with the understanding that all cases will not be detected, and that other neuroimaging approaches, such as fetal MRI, may be required in order to clarify suspicious signs. 15.11.2.2 Simple Porencephaly Definition

Simple porencephalies appear as unilateral or bilateral outpouchings or diverticuli of the lateral ventricle(s). These lesions are lined by ependyma and are to be distinguished from encephaloclastic or destructive lesions that develop after the adult brain shape has been achieved. Again, it should be kept in mind that at least in some cases it may be the gestational timing and not the underlying pathogenesis that differs between the two, and that the distinction is often not clear from the available neuroimaging in clinical reports. Also, as already discussed, it is not certain that schizencephaly is fundamentally different from what is herein called simple porencephaly.100 However, differences in clinical presentation, prognosis, and treatment make the distinction useful. Diagnosis

Most infants are symptomatic shortly after birth, and, with increased use of noninvasive neuroradiographic techniques, the diagnosis is usually made before age 1 year. Presenting signs include delayed growth and development, spastic paresis, hypotonia, seizures that are often infantile spasms, and macrocephaly or microcephaly.101,102 The presentation of unilateral lesions may be more distinctive because of contralateral hemiparesis and ipsilateral cranial bulging. Porencephaly is a diagnostic consideration in any child with unexplained hemiparesis.103 Transillumination of the skull is positive in the presence of large cysts and shows good correlation with their location. Routine skull radiographs may show local bulging and thinning on the side of unilateral cysts and a shift in the attachment of the falx.101,102 The EEG is frequently abnormal and may show local changes over the site of the cysts.102 CT or MRI readily shows the cyst and its communication to the lateral ventricles, which may show hydrocephalus.100 In unilateral cases there is frequently a marked thinning of the cortex over the lesion and a shift toward the contralateral normal side that becomes compressed. The porencephaly usually involves more than one lobe. The frequency of associated extracranial malformations does not appear increased above normal, but associated cerebral pathology such as heterotopias, microgyria, and absence of the corpus callosum or septum pellucidum are not uncommon and

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help to distinguish this malformation from later in utero acquired encephaloclastic lesions, which may on occasion communicate with the ventricles.101,102,104,105 Blood vessels crossing the cyst and ipsilateral atrophy both suggest the latter etiology, but in some cases the distinction may be difficult. Simple porencephaly is not a common component of syndromes (Table 15-15). Although absence of the septum pellucidum occurs with SP, it is more characteristic of schizencephaly. Etiology and Distribution

The pathogenesis of this form of porencephaly remains a matter of debate, with the weight of evidence favoring a disturbance in vascular supply leading to the cerebral dysgenesis. The nature of associated malformations would place the event before 12 weeks gestation. Several studies have found an apparent association between porencephaly and adoption and/or fostering or unwed mothers.102,106 There is currently no evidence as to whether this may represent an effect of reduced maternal age, poor prenatal care, attempted abortion, in utero drug exposure, or some unexplained bias of ascertainment. The majority of cases of SP have been sporadic, but there have been several reports of familial occurrence.6,107–110 These families are generally characterized by a pattern consistent with autosomal dominant inheritance with variable expression and lack of penetrance, and are clinically indistinguishable from sporadic cases. The reported neuroimaging findings are compatible with both simple and encephaloclastic porencephaly. None of these dominant families have displayed schizencephaly, none have yet been reported with EMX2 mutations and, as discussed previously, it is possible that inherited thrombophilic variants may play a role in some cases.6 A careful family history is always indicated, and to date neuroimaging studies have not detected asymptomatic obligate carriers.6,108 The cases reported by Smit et al.111 with apparent autosomal dominant inheritance of porencephalies within the white matter that bordered on a normal cortical ribbon may be different. The authors interpreted areas of hypodensity in the remaining periventricular white matter as evidence of a possible disease of myelinization. Simple developmental porencephaly is far less common than both the prenatal and perinatal encephaloclastic types and has been estimated to have a prevalence of 1 in 9000.111 The true rates as revealed by modern neuroimaging techniques may be higher. Prognosis, Treatment, and Prevention

Simple porencephaly in general presents with early neurologic signs and carries a poor prognosis. However, the degree of impairment reflects the variability in the size and location(s) of the lesion and any associated cerebral pathology. It is thus quite variable, with some patients showing only mild to borderline impairment.101,102 Of major importance is the fact that a significant proportion of patients with unilateral lesions have evidence of compression of the cerebral mantle next to the porencephaly, an increasing size of the cyst over time, and a shift of the midline toward the contralateral normal side. Such patients may show progression of their impairment. In some cases shunting, which allows collapse of the cyst, is followed by an increased thickness of the cerebral mantle neighboring the cyst, a return of the midline, and an improvement in neurologic signs.103 Any ipsilateral cranial bulge returns to normal, and ultimately the side can become relatively microcephalic. Tardieu et al.101 have advocated shunting of children under age 2 years who have, in the absence of concurrent significant cerebral lesions, a large cyst, macrocephaly, marked motor signs, and developmental delay. They speculate that

early treatment might have prevented some of the neurologic impairment seen in their patients. Older and/or microcephalic patients should be followed closely for evidence of progression of clinical signs. Patients who have had appropriate studies do not show evidence of impaired CSF circulation, and the hydrocephalus is of a normal pressure type, perhaps reflecting the effect of the increased ventricular surface area due to the porencephaly. The underlying cause of SP has not been determined. Prevention is therefore limited to recognition of genetic cases, the true incidence of which is unknown, and to the provision of appropriate counseling. The majority, if not all, of familial cases of simple porencephaly have shown dominant inheritance, and the affected parent is by necessity mildly affected. Therefore, it is reasonable to have a high index of suspicion when deciding whether to investigate a parent or sibling of an affected individual. References (Porencephaly) 1. Heschl R: Gehimdefekt und Hydrocephalus. Prager Vierteljahrsch Prakt Heilkunde 61:59, 1859. 2. Vintzileos AM, Hovick TJ, Escoto DT, et al.: Congenital midline porencephaly: prenatal sonographic findings and a review of the literature. Am J Perinatol 4:125, 1987. 3. Pati S, Helmbrecht GD: Congenital schizencephaly associated with inutero warfarin exposure. Reprod Toxicol 8:115, 1994. 4. Dale ST, Coleman LT: Neonatal alloimmune thrombocytopenia: antenatal and postnatal imaging findings in the pediatric brain. AJNR Am J Neuroradiol 23:1457, 2002. 5. Debus O, Koch HG, Kurlemann G, et al.: Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly. Arch Dis Child Fetal Neonatal Ed 78:F121, 1998. 6. Vilain C, Van Regemortar N, Verloes A, et al.: Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Am J Med Genet 112:198, 2002. 7. Viljoen DL: Porencephaly and transverse limb defects following severe maternal trauma in early pregnancy. Clin Dysmorphol 4:75, 1995. 8. LiangJS,LeeWT,PengSS,etal.:Schizencephaly:correlationbetweenclinical and neuroimaging features. Acta Paediatr Taiwan 43:208, 2002. 9. Tomas-Vila M, Garcia-Tamarit P, Garcia-Colino A, et al.: Schizencephaly associated with congenital cytomegalovirus infection. Rev Neurol 31:952, 2000. 10. Sherer DM, Salafia CM: Midtrimester amniocentesis of a twin gestation complicated by immediate severe fetal bradycardia with subsequent associated fetal anomalies. Am J Perinatol 13:347, 1996. 11. Dominguez R, Vila-Coro AA, Slopis JM, et al.: Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs. Am J Dis Child 145:688, 1991. 12. Marin-Padilla M, Parisi JE, Armstrong DL, et al.: Shaken infant syndrome: developmental neuropathology, progressive cortical dysplasia, and epilepsy. Acta Neurol (Berl) 103:321, 2001. 13. Eller KM, Kuller JA: Fetal porencephaly: a review of etiology, diagnosis, and prognosis. Obstet Gynecol Surv 50:684, 1995. 14. Ho SS, Kuzniecky RI, Gilliam F, et al.: Congenital porencephaly and hippocampal sclerosis. Clinical features and epileptic spectrum. Neurology 49:1382, 1997. 15. Voudris KA, Skardoutsou A, Vagiakou EA: Congenital microcephaly in two infants with the factor V Leiden mutation. J Child Neurol 17:905, 2002. 16. Moinuddin A, McKinstry RC, Martin KA, et al.: Intracranial hemorrhage progressing to porencephaly as a result of congenitally acquired cytomegalovirus infection—an illustrative report. Prenat Diagn 23:797, 2003. 17. Ong C-L, Daniel ML: Antenatal diagnosis of a porencephalic cyst in congenital varicella-zoster virus infection. Pediatr Radiol 28:94, 1998. 18. Eller KM, Kuller JA: Porencephaly secondary to fetal trauma during amniocentesis. Obstet Gynecol 85:865, 1995. 19. Sharma AK, Phadke SR: CVS and porencephaly. Prenat Diagn 13:1077, 1993.

Brain 20. Gross H, Simanyi M: Porencephaly. In: Handbook of Clinical Neurology. Vinken PJ, Bruyn GW, eds. Elsevier/North Holland Biomedical Press, Amsterdam, 1977, p 479. 21. Cross JH, Harrison CJ, Preston PR, et al.: Postnatal encephaloclastic porencephaly—a new lesion? Arch Dis Child 67:307, 1992. 22. Yang DN, Townsend JC, Ilsen PF, et al.: Traumatic porencephalic cyst of the brain. J Am Optom Assoc 68:519, 1997. 23. Knight DB, Bevan JE, Harding JE, et al.: Chest physiotherapy and porencephalic brain lesions in very preterm infants. J Paediatr Child Health 37:554, 2001. 24. Koch CA: How should patients with porencephaly and generalized seizures such as West syndrome be treated? Brain Dev 21:566, 1999. 25. Burneo JG, Faught E, Knowlton RC, et al.: Temporal lobectomy in congenital porencephaly associated with hippocampal sclerosis. Arch Neurol 60:830, 2003. 26. Sharif U, Kuban K: Prenatal intracranial hemorrhage and neurologic complications in alloimmune thrombocytopenia. J Child Neurol 16:838, 2001. 27. Yakovlev PI, Wadsworth RC: Schizencephalies: a study of the congenital clefts in the cerebral mantle. I. Clefts with fused lips. J Neuropathol Exp Med 5:116, 1946. 28. Denis D, Chateil J-F, Brun M, et al.: Schizencephaly: clinical and imaging features in 30 infantile cases. Brain Dev 22:475, 2000. 29. Klingensmith WC III, Cioffi-Raggan DT: Schizencephaly: diagnosis and progression in utero. Radiology 159:617, 1986. 30. Packard AM, Miller VS, Delgado MR: Schizencephaly: correlations of clinical and radiologic features. Neurology 48:1427, 1997. 31. Miller GM, Stears JC, Guggenheim MA, et al.: Schizencephaly: a clinical CT study. Neurology 34:997, 1984. 32. Bird CR, Gilles FH: Type I Schizencephaly: CT and neuropathologic findings. AJNR Am J Neuroradiol 8:451, 1987. 33. Barkovich AJ, Norman D: MR imaging of schizencephaly. AJR Am J Roentgenol 150:1391, 1988. 34. Braun JP, Toumade A: Porencephaly. J Neuroradiol 9:161, 1982. 35. Di Pietro MA, Brody BA, Kuban K, et al.: Schizencephaly: rare cerebral malformation demonstrated by sonography. AJNR Am J Neuroradiol 5:196, 1984. 36. Denis D, Maugney-Laulom B, Carles D, et al.: Prenatal diagnosis of schizencephaly by fetal magnetic resonance imaging. Fetal Diagn Ther 16:354, 2001. 37. Menezes L, Aicardi J, Goutieres F: Absence of the septum pellucidum with porencephalia: a neuroradiologic syndrome with variable clinical expression. Arch Neurol 45:542, 1988. 38. Morioka T, Nishio S, Sasaki M, et al.: Functional imaging in schizencephaly using [18F]fluro-2-deoxy-D-glucose positron emission tomography (FDGPET) and single photon emission computed tomography with technetium99m-hexamethyl-propyleneamine oxime (HMPAO-SPECT). Neurosurg Rev 22:99, 1999. 39. Shimozawa N, Ohno K, Takashima S, et al.: The syndrome of the absence of a septum pellucidum with porencephaly. Brain Dev 8:632, 1986. 40. Aicardi J, Goutieres F: The syndrome of absence of the septum pellucidum with porencephalies and other developmental defects. Neuropediatrics 12:319, 1981. 41. Osborne RE: Schizencephaly: the true name for the syndrome of absence of the septum pellucidum with porenecephalies. Clin Neuropathol 10:107, 1991. 42. Raybaud C, Girard N, Levrier O, et al.: Schizencephaly: correlation between the lobar topography of the cleft(s) and absence of the septum pellucidum. Child Nerv Syst 17:217, 2001. 43. Kuban KCK, Teele RL, Wallman J: Septo-optic-dysplasia schizencephaly. Pediatr Radiol 19:145, 1989. 44. Siejka S, Strefling AM, Urich H: Absence of septum pellucidum and polymicrogyria: a form fruste of the porencephalic syndrome. Clin Neuropathol 8:174, 1989. 45. Miller SP, Shevell MI, Patenaude Y, et al.: Septo-optic dysplasia plus: a spectrum of malformations of cortical development. Neurology 54: 1701, 2000.

653 46. Dekaban A: Large defects in cerebral hemispheres associated with cortical dysgenesis. J Neuropathol Exp Neurol 24:512, 1965. 47. Sener RN: Coexistence of schizencephaly and middle cranial fossa arachnoid cyst: a report of two patients. Eur Radiol 7:409, 1997. 48. Briellmann RS, Jackson GD, Torn-Broers Y, et al.: Twins with different temporal lobe malformations: schizencephaly and arachnoid cyst. Neuropediatrics 29:284, 1998. 49. Capra V, De Marco P, Moroni A, et al.: Schizencephaly: surgical features and new molecular genetic results. Eur J Pediatr Surg 6(Supp 1):27, 1996. 50. Faiella A, Brunelli S, Granata, et al.: A number of schizencephaly patients including two brothers are heterozygous for germline mutations in the homeobox gene EMX2. Eur J Hum Genet 5:186, 1997. 51. Takano T, Takikita S, Shimada M: Experimental schizencephaly induced by Kilham strain of mumps virus: pathogenesis of cleft formation. Neuroreport 10:3149, 1999. 52. Suchet IB: Schizencephaly: antenatal and postnatal assessment with color-flow Doppler imaging. Can Assoc Radiol J 45:193, 2000. 53. Landrieu P, Lacroix C: Schizencephaly, consequence of a developmental vasculopathy? A clinicopathological report. Clin Neuropathol 13:192, 1994. 54. Haverkamp F, Zerres K, Ostertun B, et al.: Familial schizencephaly: further deliniation of a rare disorder. J Med Genet 32:242, 1995. 55. Ueda M, Kamiya T, Ohyama M, et al.: Two siblings with familial schizencephaly—report of a family and review in relation to clinical features and neuroradiological findings. Rinsho Shinkeigaku 36:774, 1996. 56. Hillberger AC, Willis JK, Bouldin E, et al.: Familial schizencephaly. Brain Dev 15:234, 1993. 57. Robinson RO: Familial schizencephaly. Dev Med child Neurol 33:1010, 1991. 58. Granata T, Farina L, Faiella A, et al.: Familial schizencephaly associated with EMX2 mutation. Neurology 48:1403, 1997. 59. Senol U, Karaali K, Aktekin B, et al.: Dizygotic twins with schizencephaly and focal cortical dysplasia. AJNR Am J Neuroradiol 21:1520, 2000. 60. Rauchman M, Hoffman WH, Hanna J, et al.: Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure. Am J Med Genet 104:31, 2001. 61. Gunderson CA, Stone R, Peiffer R, et al.: Corneal coloboma, aphakia and retinal neovascularization with anterior segment dysgenesis (Peters’ anomaly). Ophthalmologia 210:361, 1996. 62. Worth LL, Slopis JM, Herzog CE: Congenital hepatoblastoma and schizencephaly in an infant with Beckwith-Wiedemann syndrome. Med Pediatr Oncol 33:591, 1999. 63. Silengo MC, Lerone M, Pelizza A, et al.: A new syndrome with cerebrooculo-skeletal-renal involvement. Pediatr Radiol 20:612, 1990. 64. Gieron-Korthals MA, Helal A, Martinez CR: Expanding spectrum of cocaine induced central nervous system malformations (Case report). Brain Dev 16:253, 1994. 65. Urioste M, Paisan L, Martinez-Frias ML: DK-phocomelia syndrome in a child with a long follow-up. Am J Med Genet 52:269, 1994. 66. Fishman MA: Encephalocraniocutaneous lipomatosis. J Child Neurol 2:186, 1987. 67. Baker RS, Ross PA, Baumann RJ: Neurologic complications of the epidermal nevus syndrome. Arch Neurol 44:227, 1987. 68. Hager BC, Dyme IZ, Guertin SR, et al.: Linear nevus sebaceous syndrome: megalencephaly and heterotopic gray matter. Pediatr Neurol 7:45, 1991. 69. Spraker MK, Stack C, Esterly NB: Congenital generalized fibromatosis: a review of the literature and a report of a case associated with porencephaly, hemiatrophy, and cutis marmorata telangiectasia congenita. J Am Acad Dermatol 10:365, 1981. 70. Glass IA, Walford-Moore J, Chapman S, et al.: Ear anomalies, clefting and limb reduction defects: a new autosomal recessive condition? Clin Dysmorphol 3:150, 1994. 71. al-Gazali LI, Bakalinova D, Aziz, S, et al.: Hypocalvaria associated with intrauterine growth retardation, facial dysmorphism, congenital heart disease and camptomelia. Clin Dysmorphol 8:129, 1999.

654

Neuromuscular Systems

72. L ’Hermitte MMS, Ajuriaguerra J de, Trotot RP: Oxycephalie avec age´nesie de la commissure calleuse et du vermis inferieur. Rev Neurol (Paris) 76:146, 1944. 73. Merlob P, Horev G, Kremer I, et al.: Morning Glory fundus anomaly, coloboma of the optic nerve, porencephaly and hydronephrosis in a newborn infant: MCPH entity. Clin Dysmorphol 4:313, 1995. 74. al-Gazali LI, Bakir M, Dawodu A, et al.: Recurrence of the severe form of microgastria-limb reduction defect in a consanguineous family. Clin Dysmorph 8:253, 1999. 75. Hou JW, Wang TR: Galloway-Mowat syndrome in Taiwan. Am J Med Genet 58:245, 1995. 76. Martinez-Granero MA, Pascual-Castroviejo I, Roche Herroer MC, et al.: Melanosis neurocuta´nea y nevus melanocı´tico conge´nito: presentacio´n de 6 casos. Neurologia 12:287, 1997. 77. Giorgi PL, Gabrielli O, Catassi C, et al.: Oculo-cerebro cutaneous syndrome: description of a new case. Eur J Pediatr 148:325, 1989. 78. Odent S, Le Marec B, Toutain A, et al.: Central nervous system malformations and early end-stage renal disease in Oro-facio-digital syndrome type 1: a review. Am J Med Genet 75:389, 1998. 79. Balci S, Guler G, Kale G, et al.: Mohr syndrome in two sisters: prenatal diagnosis in a 22-week-old fetus with post-mortem findings in both. Prenat Diagn 19:827, 1999. 80. Bonnemann CG, Meinecke P: Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 63:428, 1996. 81. Hosley MA, Abroms IF, Ragland RL: Schizencephaly: case report of familial incidence. Pediatr Neurol 8:148, 1992. 82. Beukeveld GJJ, Wolthers BG, Nordman, et al.: A retrospective study of a patient with homozygous form of acute intermittent porphyria. J Inherit Metab Dis 13:673, 1990. 83. Derex L, Isnard H, Revol M: Progressive facial hemiatrophy with multiple benign tumors and hamartomas. Neuropediatrics 26:306, 1995. 84. Kato M, Das S, Petras K, et al.: Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 23:147, 2004. 85. Figueiredo J, Reis A, Vaz R, et al.: Porencephalic cyst in pycnodysostosis. J Med Genet 26:782, 1989. 86. Humbertclaude V, Pedespan JM, Azaı¨s M, et al.: Schizence´phalie et malformation du membre supe´rieur. Arch Pediatr 3:357, 1996. 87. Burke JP, O’Keefe M, Bowell R: Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol 75:236, 1991. 88. Tayel SM, Sabry MA, Kader NA, et al.: Triophthalmia and facial clefting: a case report. J Med Genet 35:875, 1998. 89. Ehara H, Eda I: Schizencephaly in triple-X syndrome. Pediatr Int 43:296, 2001. 90. De Wals P: Surveillance of retinoic acid embryopathy. Teratology 40:274, 1989. 91. Granata T, Battaglia G, D’Incerti L, et al.: Schizencephaly: neuroradiologic and epileptologic findings. Epilepsia 37:1185, 1996. 92. Cho WH, Seidenwurm D, Barkovich AJ: Adult-onset neurologic dysfunction associated with cortical malformations. AJNR Am J Neuroradiol 20:1037, 1999. 93. Maehara T, Shimizu H, Nakayama H, et al.: Surgical treatment of epilepsy from schizencephaly with fused lips. Surg Neurol 48:507, 1997. 94. Landy HJ, Ramsay RE, Ajmone-Marsan C, et al.: Temporal lobectomy for seizures associated with unilateral schizencephaly. Surg Neurol 37:477, 1992. 95. Alexander RC, Patkar AA, Lapointe JS, et al.: Schizencephaly associated with psychosis. J Neurol Neurosurg Psychiatry 63:373, 1997. 96. Relan P, Chaturvedi SK, Shetty B: Schizencephaly associated with bipolar affective disorder. Neurol India 50:194, 2002. 97. Lee HK, Kim JS, Hwang YM, et al.: Location of motor cortex in schizencephaly. AJNR Am J Neuroradiol 20:163, 1999. 98. Takajo I, Ohi T, Shiomi K, et al.: A case with symptomatic epilepsy and mirror movements due to unilateral schizencephaly. No To Shinkei 52:617, 2000. 99. Vandermeeren Y, De Volder A, Bastings E, et al.: Functional relevance of abnormal fMRI activation after unilateral schizencephaly. Neuroreport 13:1821, 2002.

100. Friede RL: Developmental Neuropathology. Springer—Verlag, New York, 1975, p 1055. 101. Tardieu M, Evrard P, Lyon G: Progressive expanding congenital porencephalies: a treatable cause of progressive encephalopathy. Pediatrics 68: 198, 1981. 102. Nixon GW, Johns RE, Myers GO: Congenital porencephaly. Pediatrics 54:198, 1981. 103. Claeys V, Deonna T, Chrzanowski R: Congenital hemiparesis: the spectrum of lesions. A clinical and computerized tomographic study of 37 cases. Helv Paediatr Acta 38:439, 1983. 104. Suarez JC, Sfaello ZM, Albarenque M, et al.: Porencephalic congenital cysts with hydrocephalus. Child Brain 11:77, 1984. 105. Kolawole TM, Patel PJ, Mahdi AH: Porencephaly: computed tomography (CT) scan findings. Comput Radiol 11:53, 1987. 106. Barth PO, Gerver J, Mahdi AH: Porencephaly and schizencephaly in adopted infants: frequency ascertainment in a risk group. Clin Neurol Neurosurg 89:17, 1987. 107. Berg RA, Aleck KA, Kaplan AM: Familial porencephaly. Arch Neurol 40:567, 1983. 108. Zonana J, Adomato BJ, Glass ST, et al.: Familial porencephaly and congenital hemiplegia. J Pediatr 109:671, 1986. 109. Haar L, Dyken P: Hereditary nonprogressive athetotic hemiplegia: a new syndrome. Neurology 27:849, 1977. 110. Sensi A, Cerruti S, Calzorari E, et al.: Familial porencephaly. Clin Genet 38:396, 1990. 111. Smit LME, Barth PG, Valk J, et al.: Familial porencephalic white matter disease in two generations. Brain Dev 6:54, 1984. 112. Gould DB, Phalan FC, Breedveld GJ, et al.: Mutations in COL4A1 cause perinatal cerebral hemorrhage and porencephaly. Science 308: 1167, 2005.

15.12 Cerebellar Anomalies Definition

Cerebellar abnormalities include agenesis/hypoplasia of all or individual parts, dysplasias that may be focal or diffuse, disruptions of normal embryologic processes, and atrophy of a normally formed(ing) cerebellum. Advances in the molecular biology and embryology of the cerebellum, together with a quantum leap in the ability to visualize its abnormalities with MRI and renewed evidence of the role of the cerebellum in higher cognitive functions and language, have kindled a remarkable upsurge of interest in this organ. Unfortunately, at this time there is not a standard use of terminology or an agreed-upon classification of anomalies that meets the needs of all. Much of the new data are from the field of neuroimaging, but often there is a paucity of clinical and/ or pathologic information to match with the radiologic findings. Agenesis or hypoplasia is the absence of all or part of the cerebellum, which can be isolated or accompany anomalies of other parts of the brain. At neuroimaging, the defining features of hypoplasia are a small vermis and/or hemispheres with small fissures that are of normal width compared to the folia.1,2 In agenesis, there is absence of specific lobules and fissures of the vermis and/or hemispheres. Strictly, dysplasia refers to a disorganization of cells within the cerebellum, and it may be focal or diffuse within the cerebellum and in the latter case is usually associated with a generalized brain dysplasia. However, in the nosology of cerebellar abnormalities, dysplasia has been used at neuroimaging to denote a cerebellum with disorganized/abnormal vermian and/or hemispheric folia, with the assumption that the alterations in the folia reflect underlying disturbances in cell migration and cortical layering. Although there is evidence that the pattern of folia is reproducibly initiated and

Brain

determined by the arrival of migrating neurons,3,4 it is not clear that all MRI-defined folial anomalies are true dysplasias. Furthermore, dysplasia has been stated to accompany ‘‘most if not all’’ cases of partial cerebellar agenesis.2 Some prefer the term dysgenesis for such radiologic anomalies.5 Atrophy represents loss of cerebellar tissue that was present in the cerebellar vermis and/or hemispheres, which is represented on gross examination and at neuroimaging as a reduction in tissue mass and a concomitant increase in fissure width relative to that of the folia. The vermis may take on a ‘‘fern leaf’’ appearance on MRI.2 In practice, it is not always clear whether an apparent atrophy is simply a degenerative condition or whether the atrophy is superimposed on a developmental abnormality.1,6 The cerebellum presents a particular challenge because its development continues well into the second year of life. The one point of agreement with respect to the classification of cerebellar abnormalities is that there is no agreed-upon classification.1,2,5,7,8 As mentioned, the radiologic classifications1,2 have some current disadvantages, and clinicians continue to favor a more anatomic and embryologic approach.7,8 Still others have come from the direction of the clinical presentation of a non-progressive ataxia and emphasize key clinical points. Patients whose cerebellar abnormalities fit different categories of classification may have the same clinical presentation, and the actual malformation may differ between siblings. Patients with no visible cerebellar anomaly may have the identical presentation to those with a visible malformation and, again, there can be discordance within a siblingship.9,10 The approach taken for purposes of this chapter is outlined in Table 15-16 and follows a predominantly anatomic/embryologic approach.

655

Table 15-16. Classification of cerebellar anomalies used in this section A. Vermis and paravermian hemispheric anomalies (mainly paleocerebellum) 1. Dandy-Walker malformation (Section 15.13) 2. Tectocerebellar dysraphia (also Chapter 16) 3. Rhombencephalosynapsis 4. Molar tooth sign complex 5. Isolated vermis hypoplasia/aplasia/dysplasia - syndrome associated (Table 15-17) B. Hemispheres with or without vermis involved (mainly neocerebellar) 1. Complete cerebellar agenesis 2. Unilateral cerebellar agenesis/hypoplasia 3. True cerebellar dysplasia a. with generalized equivalent supratentorial pathology (e.g., lissencephaly, congenital muscular dystrophy; Section 15.5) b. focal to cerebellum—local heterotopia/abnormal cortex layering - hypertrophy 4. Cerebellar hypoplasia/aplasia/dysplasia a. Type I - syndromic (Table 15-17) b. Type II - granule cell aplasia and related - metabolic disorders - syndromic (Table 15-17) C. Pontocerebellar

Diagnosis

1. Pontine agenesis

Except for syndromes with a defined pattern of associated anomalies, or certain cerebellar syndromes like Joubert syndrome that have a diagnostic handle such as hyperpnea, the clinical presentation of young children with cerebellar anomalies is non-specific, and the diagnosis requires a high index of suspicion. The classic signs of ataxia or dysequilibrium do not appear until completion of postnatal cerebellar maturation and the integration of higher cerebellar functions.9 Early infancy is characterized by hypotonia and delayed motor milestones, with extended periods of cruising and delayed walking. The initial hypotonia and common orofacial dysfunction often leads to a tented, open-mouthed appearance and drooling. Refractive errors, strabismus, and other ocular anomalies are common.10 The mean age at walking in the mixed series of patients reported by Esscher et al.10 was 25 months, with 11.5% walking before 18 months, and 14% walking after 7 years or not at all. The patients with idiopathic, pure non-progressive cerebellar ataxia reported by Steinlin9 sat between 2 to 3 years and walked between 3 to 7 years of age. Once walking does occur it tends to be broad-based, clumsy, and ataxic, and with time fine motor problems become apparent. Speech is affected both by dysarthria and cognitive delays, which may affect speech disproportionately. In the series of Esscher at al.,10 25 (32%) of patients had an IQ of < 50 and 28% fell between 50 and 75. Of 31 children in normal school, 14 required help with language. Only 22% were considered completely cognitively normal, and 88% had language delay. Twelve lacked any speech. The IQ of the patients discussed by Steinlin9 ranged from 20 to 90, and one-third had seizures, which were a negative correlate with IQ. In some cases, intellectual delay can be ascribed to an associated supratentorial anomaly, but such cases are the exception and there is a growing consensus that the cerebellum has a, yet to

2. Pontocerebellar hypoplasia (PCH1, 2 and 3) Italicized headings or subheadings are considered in this section.

be fully defined, role in normal cognitive development.11–13 This role may include behavior such as expression of aggression and habituation, anticipatory planning, mental imagery, language processing, abstract thought, and word and pattern recognition.11 Connections to the cerebellum, via the pons, from the cerebral associative and paralimbic areas are well established. The diagnosis and understanding of these pure non-progressive cerebellar ataxias are further complicated by the lack of pathologic data in most cases, and the fact that neuroimaging has frequently been unable to document a cerebellar anomaly. A cerebellar abnormality was demonstrated in half the patients studied by Steinlin,9 who stated that MRI did not detect malformations missed by CT but that it did add useful information in several cases. No data were provided as to the quality of the imaging, and there was an instance of discordance within an affected sibling pair for the presence of a detectable malformation. Neuroimaging failed to detect cerebellar pathology in 43 of 70 (61%) of cases studied by Esscher et al.,10 but only 46 patients had an MRI and in a significant proportion of cases the studies were suboptimal (i.e., adequate or less). MRI did detect two cases considered normal with CT and added useful data to other cases. Notwithstanding less than excellent imaging in some instances, it is likely that the cerebellar ataxia and other clinical signs are related to changes in the cerebellum at the microscopic level. That the clinical spectrum does relate to changes in the cerebellum is suggested by a correlation between the degree of cerebellar involvement and clinical severity.9 Changes in the anterior vermis appear to produce mild signs and

656

Neuromuscular Systems

symptoms; changes in the whole vermis and hemispheres are found with the most severe cerebellar signs. The likelihood that MRI will diagnose a posterior fossa anomaly, either prenatally or postnatally, will vary with the quality of the study, which is often dependent on the patient. The sonographic prenatal diagnosis of posterior fossa anomalies is biased toward the more readily visible cystic lesions. Prenatal diagnosis, primarily as it relates to MRI, has been reviewed by Adamsbaun et al.14 Developmental landmarks include a closed, triangular fourth ventricle covered by the cerebellar vermis by 15 weeks, a vermis length of 15 mm at 28 weeks and 20 mm at 30 weeks, the appearance of the primary fissure by 30 weeks, and greater size of the posterior lobe than the anterior lobe. They also suggest four questions to be addressed with a prenatal posterior fossa scan: 1) whether and where are there any abnormal fluid collections, 2) whether the volume of the posterior fossa is normal, and if it is increased whether this relates to increased fluid pressure, 3) whether or not the fourth ventricle is open and has a membrane, and 4) whether the cerebellar peduncles, vermis, and hemispheres appear normal. This same group has also outlined the planes, cuts, weighting, and appearance to be noted in the postnatal MRI assessment of the posterior fossa, including the component parts of the cerebellum.2 15.12.1 Tectocerebellar Dysraphia

Tectocerebellar dysraphia (TCD) was first described in the literature by Padget and Lindenberg15 as ‘‘inverse cerebellum with occipital encephalocele,’’ and it was Friede, in 1978, who coined the term tectocerebellar dysraphia.16 TCD consists of hypoplasia/aplasia of the vermis, with a marked dorsal deformation of the tectum toward an occipital encephalocele, which contains hypoplastic cerebellar cortex, with traction of the brain stem causing kinking, and positioning of the hypoplastic cerebellum ventrolateral to the brain stem. Associated findings can include subependymal heterotopias, thalamic fusion, hydromyelia, callosal agenesis, absent septum pellucidum, and arhinencephaly.17 The origin of TCD has been hypothesized to result from herniation of the mesencephalon, prior to the appearance of the cerebellum, into an occipital encephalocele.18 There is a significant associated mortality, and surviving children are often microcephalic and require shunting.7 Developmental delay is expected but may not always be severe. 15.12.2 Rhombencephalosynapsis

In rhombencephalosynapsis (RES) the cerebellar vermis is absent, or severely hypoplastic, the hemispheres are fused across the midline, and there is variable underdevelopment of the cerebellar peduncles and quadrigeminal plate. Fusion of the cerebellar peduncles and inferior colliculi give the fourth ventricles a typical ‘‘keyhole’’ appearance.19 The roof nuclei are absent and the dentate nuclei are fused or apposed;1,19 the posterior fossa is small.7 A partial form has been described.245 The typical presentation is with hypotonia and delayed motor milestones. Other neurologic signs have included optokinetic nystagmus,20 clumsiness, drop attacks, and side-to-side head nodding.18 The latter may be the same as the 1–2 Hertz head stereotypy noted by Hottinger-Blanc et al.20 in eight patients with cerebellar anomalies, one of whom had RES. Intellectual and psychological development appears to vary from the normal range to severe impairment, but the latter may sometimes be due to associated supratentorial anomalies, which may include absent septum

pellucidum, cerebral dysplasia, callosal agenesis, and hydrocephalus.1,21 RES is considered rare, and in 2002 Niesen7 was only able to find 20 cases in the literature. However, in that same year, Patel and Barkovich1 reported eight cases among 70 patients with MRI-detected cerebellar malformations; two patients were added by Demaerel et al.18; and there were two single case reports.20,21 Odemis et al. reported a case with pretibial hemangiomas.22 The etiology is unknown; one pregnancy each was reported with in utero exposure to phencyclidine19 and ethosuxamide.18 To date there does not appear to have been a familial recurrence of RES, but the cerebellar vermis defect rat (cvd), which may be a model of this malformation, shows autosomal recessive inheritance.23 The cvd rat has an overall reduction in the size of the cerebellum, not typical of RES, and appears to be due to abnormal migration of external granule cells to a perivascular position, perhaps secondary to abnormal Purkinje cell location, resulting in dysplastic lamination and cell positioning within the cerebellar cortex.23 15.12.3 Molar Tooth Sign Complex

First described in 1997, the molar tooth sign, or MTS (Fig. 15-58), is an appearance on axial view through the isthmus that results from marked hypoplasia/dysplasia of the cerebellar vermis, an unusually profound interpeduncular fossa, and straight and thickened superior cerebellar peduncles.24 Additional findings commonly include a bent or kinked appearance of the vermis on mid-sagittal view, enlargement of the fourth ventricle, whose margin has an umbrella shape, and less often an excess of fluid in the posterior fossa.25 The archetypical disease associated with the MTS is Joubert syndrome, which was first described in 1969 (Table 15-17) and presents with an unusual pattern of alternating hyperpnea and apnea in the newborn period. The breathing pattern usually improves in surviving children, but most suffer moderate developmental delay, ataxia, and may develop seizures and other

Fig. 15-58. Axial view at isthmus showing molar tooth sign (arrow).

Table 15-17. Syndromes with cerebellar hypoplasia Syndrome

Prominent Features

Causation Gene/Locus

3-a hydroxyisobutyric acid

Poor neonatal behavior, triangular face, short and sloping forehead, narrow bitemporal distance, shallow supraorbital ridges, epicanthus, micrognathia, adducted thumbs, clinodactyly of toes 4-5, intracerebral calcification, cerebellar hypoplasia, agenesis of the corpus callosum, lissencephaly, pachygyria

AR (236795)

Acrania67

Absent calvarial bones; CNS includes absent pituitary, hydrocephalus, holoprosencephaly, cerebellar hypoplasia; often misinterpreted prenatally as encephalocele; cleft lip/palate, congenital heart defects, omphalocele, and NTD often concurrent

Unknown

Acrocephalopolysyndactylytype II68

Craniosynostosis, developmental delay is variable, high forehead, midfacial hypoplasia, ptosis, epicanthic folds, anteverted nares, brachysyndactyly of hands, radial deviated thumb, pre-axial polydactyly of feet, hypoplasia of middle phalanges; case with cerebral atrophy and marked cerebellar vermis ‘‘atrophy’’

AR (201000)

Adenylosuccinase deficiency69

Mental retardation, autistic features, muscle wasting, cerebellar hypoplasia; accumulation of succinyladenosine and succinylaminoimidazole

AR (103050) ADSL, 22q13.1

Agonadism-CNS anomalies70

Agonadism with urogenital sinus and 46,XY karyotype, severe mental retardation, absent corpus callosum, cerebellar agenesis, pachygyria. Single case.

Unknown

Aicardi71

Chorioretinal lacunae, infantile spasms, hypsarrhythmia, vertebral segmentation defects, polymicrogyria, periventricular nodules, colpocephaly, hypoplastic cerebellar vermis

XLD (304050) male lethal Xp22

Alcohol, prenatal72

IUGR, microcephaly, psychomotor delay, flat midface, short palpebrae, micrognathia, minor cardiac and vertebral anomalies, various CNS anomalies; cerebellar hemisphere hypoplasia, hypoplastic/malformed vermis

Prenatal alcohol exposure

Amelo-cerebrohypohydrotic73

Can show normal early development, variable regression, and seizures; can have ataxia, amelogenesis imperfecta; cases with broad thumbs and great toes; CNS includes hypoplasia of cerebellar vermis and dilation of the lateral ventricles

AR (226750)

Anterior chamber cleavagecerebellar hypoplasia74

Postnatal microcephaly, dense hair, broad nose with low bridge, wide cupid-bow mouth, shield chest, tracheostenosis, congenital hypothyroidism, cerebellar hypoplasia, anterior chamber eye anomalies

Unknown (601427)

Anterior chamber-cleft lip/ palate-skeletal75

IUGR, anterior chamber abnormalities, clouded cornea, cleft lip and palate, congenital heart disease, radio-ulnar synostosis, bowed forearms and fibulas, arachnodactyly, variable dislocation of interphalangeal joints, fractures, sclerosis of skull base. One case with hypoplastic inferior cerebellar vermis.

AR

Anterior chamberhydrocephalus-heart defect76

Peters anomaly, persistent hyaloid artery, unilateral absent lens, obstructed aqueduct of Sylvius, enlargement of the lateral and 4th ventricles; cerebellar, pontine, and medullary atrophy; porencephaly, tricuspid valve dilation, atrial septal defect, lethal

Unknown

Arena: XLMR-spastic paraplegia77

Severe spastic paraplegia; lower limbs greater than upper; macrogyria, poor myelination, white matter hypoplasia, cerebellar hypoplasia, possible iron deposits in basal ganglia

XLR Xq22-q25

Arima: cerebro-oculohepato-renal78

Telecanthus, ptosis, flat nasal bridge, large mouth, aplasia of the cerebellar vermis, micropolygyria of dentate nuclei, pachygyria of inferior olivary nuclei, anomalous pyramidal tracts, Leber’s amaurosis, nephronophthisis, hepatic fibrosis (see also ref. 26,143,167)

AR (608091)

Arthrogryposis-craniofacialeye anomalies79

Normal intelligence, congenital contractures of small and large joints, pulmonary hypoplasia, nonspecific muscle changes, some denervation, minor skeletal anomalies, abnormal retinal vessels, mild vermis hypoplasia

Unknown

Avegno: mental retardationface dysmorphia80

Severe psychomotor and postnatal growth delay, short stature, microcephaly, cerebral dysgenesis, cerebellar hypoplasia, hypotonia and late hypertonia, marked hypertelorism, downslanting palpebrae, supernumerary teeth, hypospadias, cryptorchidism, overlapping fingers, rocker-bottom feet

AR, product of incest

Bardet-Biedl81

Developmental delay, retinal dystrophy, obesity, variable post-axial polydactyly, hypogenitalism, renal anomalies; reported with cerebellar hypoplasia

AR (209900) BBS1, 11q13 BBS2, 16q21 BBS3, ARL6, 3p13-p12 BBS4, 15q22.3-q23 BBS5, 2q31 BBS6, 20p12 BBS7, 4q27 BBS8, 14q32.1

66

(continued)

657

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Barth: cerebro-cerebellar

Very small brain, extreme neopallial and cerebellar hypoplasia, failure of mesencephalic flexure, absence of rhombic lip and corticospinal structures, type I lissencephaly (one form with type II lissencephaly)

Probable AR

Bertini: myoclonic epilepsymacular degeneration83

Hypotonia, congenital ataxia, mental retardation, progressive encephalopathy, recurrent infections, hypoplasia of corpus callosum and cerebellar vermis, septum pellucidum cyst

XLR Xp22-Xpter

Branchio-oculo-facial84

Variable mental retardation and short stature, ear pits, colobomas, hemangiomatous orbital cysts, hypertrophy of philtral pillars (pseudocleft), lip pits, broad and asymmetric nose with broad tip, lacrimal duct stenosis, sinus or linear skin lesion behind the ear, premature gray hair. A case with agenesis of the cerebellar vermis.

AD (113620)

Congenital disorders of glycosylation85

Dysmorphic signs can include abnormal fat distribution and inverted nipples; various subtypes with postnatal growth failure, psychomotor delay, retinopathy, renal cysts/ tubulopathy; cerebellar hypoplasia most likely in type I

AR (212065) CDIa PMM2, 14q21 CDIb PMI, 16p13

Cerebellar hypoplasia-brain stem calcification86

Sib fetuses with cerebellar aplasia, dilated ventricles, aqueductal stenosis in one, necrosis and calcification in the brain stem and cortex, cortex contained foamy macrophages and prominent vascularity

AR

Cerebellar hypoplasiaendosteal sclerosis87

Developmental delay, oligodontia, small teeth, congenital hip dislocation, sclerosis of long bones and vertebrae, stenosis of medullary space

AR (213002)

Cerebellar hypoplasiahemangioma-coarctation of aorta88

Two unrelated cases with cavernous facial hemangioma, ipsilateral cerebellar hypoplasia with abnormal internal ganglia, coarctation of the aorta

Unknown

Cerebellar hypoplasialymphedema89

Mental retardation, hypotonia, ataxia, clonic/tonic seizures, pale fundi and poor VEP, variable duodenal atresia, cerebellar hemisphere and vermis hypoplasia, poor cerebral white matter, abnormal neuronal migration, pachygyria

AR (600514) RELN, 7q22

Cerebellar hypoplasia-short stature90

Nonprogressive congenital ataxia, truncal ataxia, dysarthria, hypotonia, hyperreflexia, short stature, hypoplasia of cerebellar hemispheres and vermis

AR 9q34-9qter

Cerebellar hypoplasia-short stature, type Kvistad91

Postnatal onset of growth failure between 12 and 18 months, normal intelligence, mild to moderate cerebellar signs, mild spasticity; cerebellum on CT include normal, mostly vermis ‘‘atrophy,’’ one slight hemispheric change

AR

Cerebello-trigeminal-dermal dysplasia92

Parietal alopecia, midface hypoplasia, clouded cornea, low and rotated ears, facial anesthesia, developmental delay, ataxia, fusion of pons and vermis, absent 4th ventricle, hypoplastic cerebellar hemispheres

AR (601853)

Cerebro-oculo-muscular93

Initial hypotonia, infancy-onset cataract, retardation, ataxia, myopathic changes with cavuolar degeneration, cerebellar hypoplasia or atrophy; resembles Marinesco-Sjo¨gren (248810)

AR

Cerebro-oculo-nasal94

Macrobrachycephaly, craniosynostosis, anophthalmia, nares separated by a midline groove, nasal skin appendages, low-set ears, single maxillary central incisor; reported with agenesis of the corpus callosum, hypoplastic vermis; other CNS not well documented but may include hydrocephalus, frontal encephalocele, holoprosencephaly, Dandy-Walker cyst

Unknown (605627)

Cerebro-renal-digitalPiantanida95

Mental retardation, cerebellar vermis agenesis, polydactyly, unusual appearance. Two sibs, one with cystic dysplastic kidney, other a meningocele

AR?

CHARGE96

Choanal atresia, congenital heart defects, growth failure, mental retardation, hypoplastic genitalia, deafness, external ear anomalies; over half with CNS including holoprosencephaly/arhinencephaly, absent corpus callosum, septal agenesis, migrational defects

Most sporadic, AD (214800) CHD7, 8q12

Chondrodysplasia-pseudohermaphroditism97

IUGR, growth retardation, hypoplastic irides, optic disc colobomas, micromelia, narrow chest, hypoplastic scapulae, trapezoid vertebrae, short hand bones. One case a 46,XY female with cerebellar hypoplasia

AR? (600092)

Chondrodysplasia punctatairis coloboma98

Developmental delay, brachycephaly, low-set ears, small nose, anteverted nares, midface hypoplasia, iris coloboma, stippled proximal humeral epiphyses, dysplastic distal phalanges, hepatic fibrosis. Case with partial callosal agenesis, small cerebellar vermis, mild enlargement of anterior horns

AR (215105)

Chromosomal aberrations99,100

Includes trisomy 13, 18, 21; duplications (1)(q25-qter), (2)(pter-p13), (3)(pter-p21), (3)(q21-qter), (4)(p15-pter), (5)(p11-p13.2), (5)(p15.1), (6)(q21-qter), (7)(p11-p12), (7)(pter-p11), (9)(q32-qter), (9p), (13)(q14-qter) (20)(q13.1-qter), der(22) from t(11q;22q); deletions of (4)(pter-p16.1), (9)(pter-p21), (11)q23.3), (14)(q22-q23), (17)(q25-qter)

Chromosome imbalance

82

(continued)

658

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

COACH: cerebello-oculorenal101,102

Developmental delay, molar tooth sign, coloboma; variable occurrence of nephronophthisis, hepatic fibrosis, Dandy-Walker cyst/encephalocele

AR (216360)

Coats disease-hair and nail defects103

Abnormal retinal vessels lead to exudate and detachment, sparse wispy hair, mild finger zygodactyly, dysplastic or deep-set nails; calcification of cerebrum, cerebellum, and basal ganglia; seizures, normal development. Case with marked cerebellar atrophy, but no calcification.

AR

Colobomatous microphthalmia-cerebellar hypoplasia104

Microcephalic at birth, microphthalmia, iris coloboma, cataracts, optic nerve hypoplasia, high palate, cerebellar hypoplasia. Single case, parental consanguinity.

Uncertain

Congenital fibrosis extraocular muscles105

Dysfunction of cranial nerves III and IV, or the muscles served by those nerves; CNS anomalies are occasional findings and include cerebellar vermis hypoplasia, callosal agenesis, pachygyria, hydranencephaly, colpocephaly

AR (135700), (602078) ARIX, 11q13.3-q13.4 AD (607034) KIF21A, 12p11.2-q12 AD (600638) 16q24.2-q24.3

Craniofacial-congenital hypothyroidism-cerebellar hypoplasia106

Postnatal growth and developmental failure, large and anteverted ears, brachycephaly, strabismus, small nose and mouth, pectus carinatum, severe hypoplasia of right cerebellar hemisphere and vermis, brain stem hypoplasia

Unknown

Congenital muscular dystrophy-vermis agenesis107

Congenital myopathy, mild calf hypertrophy, cerebellar ataxia, dysarthria, cerebellar vermis agenesis; several similar reports may or may not reflect the same condition

Uncertain

Congenital mydriasis108

Congenital fixed and dilated pupils; all cases to date are female; patient with developmental delay had enlarged 4th ventricle, a degree of cerebellar vermis hypoplasia

AD (159420)

Crome: cataractsnephropathy109

Congenital cataracts, growth failure, renal tubular necrosis, seizures, lack of development, spongiform changes in gray and white matter, lack of myelination, lack of Purjinke cells. Degenerative disorder?

AR (218900)

Curatolo: white matter hypoplasia-callosal agenesis110

Severe mental retardation, growth failure, downslanting palpebrae, broad nasal root, hypertelorism, synophrys, long eyebrows, micrognathia, severe diffuse cerebral white matter hypoplasia, agenesis/hypoplasia of the corpus callosum, partial agenesis of cerebellar vermis

Uncertain

Cutis aplasia-pulmonic stenosis-vermis aplasia111

Midline scalp defect, valvular pulmonary stenosis, cerebellar hypoplasia with vermis agenesis

Unknown

Cytomegalovirus infection, prenatal112

Microcephaly, intracranial calcification, choreoretinopathy, deafness, mental retardation, general and often asymmetric hemisphere changes, vermis hypoplasia, gliosis (similar to animal models)

Prenatal infection

D-CHRAMPS113

Postnatal growth failure, microcephaly, sparse scalp hair, absent eyebrows, triangular face, developmental delay, hypergonadotrophic hypogonadism, absent pubic and axillary hair, retinitis pigmentosa, pancerebellar hypoplasia

Unknown

Deafness-hypospadiassynostosis114

Developmental delay, sensorineural deafness, anteverted ears, small nose with blunt tip, long chin, fused 4th and 5th metacarpals, mild hypoplasia of occipital lobes and cerebellum

Unknown

De Lange115

IUGR, mental retardation, synophrys, short nose, anteverted nares, prominent philtrum, thin upper lip with downward ‘‘V’’ at midpoint, proximal thumbs, ulnar ray defects, several cases with cerebellar hypoplasia

AD (122470) NIBPL, 5p13.1

Dyskeratosis congenita116

Unusual case of autosomal recessive form with severe microcephaly, mental retardation, and cerebellar hypoplasia, in addition to usual nail dystrophy, mucosal and skin pigment changes, and bone marrow failure

AR (224230)

Dystonia-cataractencephalopathy117

Normal head circumference becomes microcephalic, progressive neurologic deterioration, extrapyramidal signs, cataracts, partial agenesis of vermis, ventricular dilation, loss of central white matter, elevated methylmalonic aciduria but not at usual pathological levels

AR

Egger-Joubert-Boltshauser118

Joubert syndrome with typical hyperpnea, apnea, associated with polydactyly, fleshy nodules under tongue. Dandy-Walker in one sib, and cerebellar hypoplasia in other.

AR (213300) variant

Exomphalos-short limbsmacrogonadism119

Nuchal web, low-set ears, hypertelorism, macrostomia, anteverted nares, long philtrum, micrognathia, wide and irregular metaphyses, coronal cleft vertebrae, thin ribs, adrenal cytomegaly; hypoplastic Leydig cells, ovarian stroma cells and Langherans cells, renal microcysts, microgyria, cerebellar hypoplasia

AR

(continued)

659

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Facial hemangiomacerebrovascular anomalies120

Strawberry nevus, ipsilateral optic atrophy, stenotic and aneurysmal cerebral vascular anomalies, hypoplasia of cerebellar hemisphere

Unknown

Fernhoff; abnormal facies121

IUGR; microcephaly, growth failure, small facies, low-set ears, narrow palpebrae, micrognathia, cleft palate, camptodactyly, absent granular cell layer

Unknown

Fetal phencyclidine19

Rhombencephalosynapsis, hypoplastic commissural systems, septo-optic dysplasia, absent septum pellucidum, absent posterior lobe of hypothalamus, fused cerebellar hemispheres, absent vermis, moderate hydrocephalus, abnormal pulmonary venous return, spinal segmentation defect; mother took phencyclidine in first 6 weeks

In utero exposure

Fragile-X mental retardation122

Tend to be macrocephalic, long face, large and/or prominent ears, prominent jaw, postpubertal macroorchidism, hyperextensible joints, hyperactivity, autistic-like behavior, seizures, decreased cerebellar posterior vermis size, occasional frank cerebellar hypoplasia

XLR (309550) FMR1, Xq27.3

Frontonasal dysplasia123

Occult frontal cranium bifidum, widow’s peak, hypertelorism/telecanthus, broadtipped or bifid nose, cleft mid-lip/palate. One patient with coloboma, small penis, absent corpus callosum, microgyria, hypoplastic cerebellar vermis.

Unknown

Frontonasal dysplasia-like124

Large fontanel, hypertelorism, wide nasal tip with midline groove, notched upper lip, high/cleft palate, short neck, cryptorchidism, pre/postaxial polydactyly of hands and feet, short limbs

Unknown

Fryns: acral-diaphragmatic hernia125

Hydramnios, coarse face, facial hirsutism, cloudy corneae, large nose with broad flat bridge, short upper lip, micrognathia, cleft lip/palate, abnormal pinnae, hypoplastic distal phalanges and nails, diaphragmatic defects, gut anomalies, cardiac defects, bicornuate uterus; CNS includes callosal agenesis, arhinencephaly, heterotopias; probable case with cerebellar hypoplasia

AR (229850)

G126

Dysphagia, stridor, hypertelorism, prominent forehead, laryngotracheal cleft, tracheoesophageal fistula, hypospadias developmental delay, more severe in males

AD (145410) 22q11.2 XLR (300000) Xp22

Gentile: vermis hypoplasialiver fibrosis127,128

Developmental delay, ataxia, no hyperpnea, ocular motor apraxia/amaurosis, hepatic fibrosis, no colobomas, no retinal dysplasia, vermis hypoplasia with ‘‘molar tooth sign’’(see also ref. 26,143)

AR

Gillespie: aniridia-ataxia129

Partial aniridia, ptosis, mild mental retardation, pulmonic stenosis (one case), cerebellar hypoplasia (most marked of vermis)

AR (206700)

Glutaric aciduria type 2130

Macrocephaly, absent cerebellar vermis, cryptorchidism, hypospadias; usually normal early health and development; signs can include respiratory distress, hypoketotic hypoglycaemia, sweaty-foot odor, seizures, dystonic cerebral palsy; aliphatic monoand dicarboxylic acids, sarcosine, glycine conjugates in blood and urine; abnormal electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETFdehydrogenase)

AR (331680) ETF-dehydrogenase, ETFDH, 4q32-qter ETFA, 15q23-25 ETFB, 19q13.3 15q23-25, 19q13.3 4q32-qter

Goldberg-Shprintzen131

Microcephaly, short stature, developmental delay, hypertelorism, submucous cleft palate; diminished white matter, hypo/partial absence of corpus callosum, pachygyria, cerebellar hypoplasia

AR (235730) SMADIP1 2q22

Herrick: multisystem atrophy132

Microcephalic at birth, low forehead, contractures, hypertonia, death, severe cortical atrophy (‘‘walnut brain’’), cerebellum disproportionately small vestige. Combination of hypoplasia and atrophy?

AR

Hingorani: hypothalamic hamartoma-polydactyly133

Hypothalamic hamartoma, preaxial polydactyly of toes, midline cleft lip, oral frenula, notched tongue, short long bones; dilated 4th ventricle, absent inferior vermis; overlap with several syndromes including Pallister-Hall

Unknown

Histidinemia134

Single report of patient with callosal dysgenesis and cerebellar hypoplasia, clinical picture of Joubert syndrome and congenital ocular fibrosis. Association with histidinemia likely fortuitous.

AR (235800) Histidase, 12q22-q23

Holoprosencephaly-fetal hypokinesia135

Extreme IUGR and microcephaly by 2nd trimester, sloped forehead; micrognathia; short neck; flexed elbows, thumbs, hips; extended fingers, knees; severe brain disorganization may include rudimentary cerebellum and brain stem, and cellular architecture

XLR (306990)

Horizontal gaze palsy-scoliosis-brain stem hypoplasia136

Horizontal gaze palsy, progressive scoliosis, significant developmental delay in two of three affected sibs, brain stem hypoplasia likely affecting abducens nucleus and caudal longitudinal fascicle

AR 11q23 (continued)

660

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Hoyeraal-Hreidarsson

Microcephaly, congenital thrombocytopenia, pancytopenia in year 2, postnatal growth failure, immunodeficiency, cerebellar hypoplasia most marked of the vermis; probable heterogeneity

XLR (600545) DKC1, Xq28

Hutterite dysequilibrium138

Moderate to profound mental retardation, nonprogressive truncal ataxia, mild dysmetria; variable short stature, microcephaly, seizures; absent inferior hemispheres and inferior vermis, granular cell ‘‘aplasia’’

AR (224050)

Hydrocephalus-VATERlike139

Bilateral radial aplasia, anal atresia, hypospadias, incomplete lung lobation, hypoplastic adrenals, horseshoe kidneys, accessory spleens, hydrocephalus, hypoplastic cerebellum; three males from consanguineous relationship

AR/XLR? (276950)

Isotretinoin, prenatal140

Microtia, anotia, narrow and sloped forehead, U-shaped cleft palate, conotruncal malformations, microcephaly, hydrocephalus, absent corpus callosum

Prenatal retinoic acid exposure

Jespers: midline defectsHirschsprung141

Excessive nuchal skin, low-set ears, hirsute forehead, unusual eyebrows, hypertelorism, broad nasal bridge, anteverted nares, flat philtrum, micrognathia, cleft palate, heart defect; hypoplastic larynx, vocal cords, and trachea; omphalocele, cryptorchidism, metatarsus adductus, hypoplastic nails, hypoplastic corpus callosum, cerebellar hypoplasia, subcortical atrophy

AR ?

Joubert: cerebello-oculo-renal 1142

Severe developmental delay, aggressivity, hyperactivity, prominent forehead, high and round eyebrows, anteverted nares, open mouth, ocular motor apraxia, rhythmic tongue protrusion, hyperpnea/apnea, molar tooth sign, superior vermis hypoplasia/ aplasia; CORS1 is used by some for patient without renal or eye changes

AR (213300) NPHP1, 2q13 AHI1, 6q23.2-q23.3 9q34.3

Joubert: cerebello-oculo-renal 226,143

As per type 1, CORS2 has addition of cystic renal dysplasia/agenesis and retinal dysplasia/coloboma; significant additional clinical and genetic heterogeneity (see also ref. 78,101,127,167,224)

AR (608091) 11p12-q13.3 Heterogenity

KID (keratitis-ichthyosisdeafness)144

General or patchy ichthyosiform, hyperkeratosis, palmoplantar hyperkeratosis, keratosis impairing vision, nerve deafness, hypoplasia middle and lower cerebellar hemispheres and tonsils

AR (242150)

Leber amaurosis, congenital145

Severe early visual impairment, progressive disc pallor and arteriolar attenuation, polycystic kidneys, variable CNS anomalies, normal to impaired intellect, vermis hypoplasia (see discussion of Joubert syndrome)

AR (204100) Multiple loci: GUCY2D, RPE65, CRX, AIPL1, etc.

Leptomeningeal angiomatosis-cleft lip146

Mild hydrops, small and posteriorly rotated ears, overfolded helices, cleft lip/palate, hypoplastic left heart, leptomeningeal angiomatosis, absent septum pellucidum and olfactory tracts, hypoplastic corpus callosum and inferior vermis. Single case

Unknown

Lethal mesomelic dwarfism147

V-shaped upper lip, micrognathia, cysts of tongue, webbed neck, dislocated femur and radius, four-finger creases; cardiac, lung, renal abnormalities

AR (268670)

Lethal osteopetrosis148

In utero hyperdense bones, fractures, macrocephaly, hydrocephaly, skin edema, absent osteoclasts, loss of neurons, gliosis, ischemia leading to arrest of brain development

AR (259720)

L’Hermitte: oxycephalyretardation149

Macrocephaly, oxycephaly with open sutures, high palate, flat facies, shallow orbits, porencephaly, absent inferior vermis

AR

Lissencephaly-cleft palatecerebellar hypoplasia150

IUGR, cleft palate, ventriculomegaly, long thumbs and halluces, absent distal digital creases, variable brain stem involvement, absent corpus callosum, absent cerebellum, thick and disorganized cortex, no cortical lamination, severe cerebellar hypoplasia

AR?

Majewski: short ribpolydactyly151

Micromelia, hydrops, median cleft, hypoplastic epiglottis, renal anomalies, ambiguous genitalia, hypoplastic cerebellar vermis, pachygyria

AR (263520)

Marden-Walker152

Motor delay, blepharophimosis, low-set and malformed ears, cleft palate, micrognathia, renal microcysts/cystic dysplasia, arachnodactyly, camptodactyly, joint contractures, congenital heart defect; case with brain stem and cerebellar hypoplasia, callosal agenesis, colpocephaly; likely heterogeneous

AR (248700)

Marinesco-Sjogren153

Mental retardation, congenital cataracts, cerebellar ataxia, muscle wasting with neurogenic atrophy and vacuolar degeneration, distal weakness, skeletal anomalies including scoliosis, posterior vertebral scalloping, enlargement of intervertebral foramina, short metatarsals and metacarpals; cerebellar atrophy mostly of vermis; cerebellar dysplasia reported

AR (248800) 5q31

Marshall-Smith154

Initial increased length with postnatal growth failure, dolichocephaly, prominent forehead and eyes, anteverted nares, micrognathia, larygeal anomalies, accelerated bone age, broad proximal and middle phalanges, reported with absent corpus callosum and cerebellar hypoplasia

Unknown (602535)

137

(continued)

661

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Posterior encephalocele, cystic dysplastic kidneys, postaxial polydactyly, cleft palate, microphthalmia, genital anomalies, cerebellar agenesis or hypoplasia

AR (249000) Multiple loci: 8q, 11q13, 17q22-q23

Me´garbane´: joint dislocationabnormal skin156

Microcephaly, delayed growth, severe retardation, ptosis, prominent and low-set ears, beaked nose, joint laxity, dislocations, delayed bone age, abnormal blood vessels in skin; consanguinity, mild vermis hypoplasia

AR or XLR

Melorheostosis-cerebellar hypoplasia157

Bone changes in femoral and humeral diaphyses, pelvis, and lower spine; optic atrophy; hearing loss, mental retardation; small cerebellar hemispheres

AR? (155950) Consanguinity

Microcephalyaminoaciduria158

Postnatal growth failure, marked psychomotor delay, hyperreflexia, optic atrophy, myoclonus becoming opisthotonus, mild aminoaciduria, elevated CSF a-amino nitrogen

XLR (311400)

Microcephaly-cerebral calcificationmicrophthalmia159

Progressive microcephaly, periventricular, basal ganglia and cerebellar calcification, seizures, cataracts, hypermetropia, large ears, laxity at smaller joints; inferior vermis and cerebellar hemisphere hypoplasia

AR

Microcephaly-flexion contractures-ichthyosis160

Progressive microcephaly and postnatal growth failure, sloping forehead, prominent nose, posteriorly rotated ears, limitation at major and small joints, mild lamellar ichthyosis, generalized skin edema, hypertonia, cerebellar hypoplasia, brain atrophy

Uncertain

Mo¨bius161

Usually bilateral sixth and seventh nerve palsy, although other cranial nuclei may be involved; minority with mental retardation, associated hypoglossia, and/or hypodactyly; minor facial anomalies. One case with unilateral cerebellar hypoplasia.

Vascular disruption AD (157900) Multiple loci: 3q21-q22, 10q21.3-q22.1, 13q12.2-q13

Mubashir: situs inversusmental retardation162

Profound mental retardation, growth failure, small head, situs inversus totalis, long face, hypertelorism, ptosis, anteverted nares, long philtrum, large mouth, tented upper lip, goiter, brachydactyly, short 4th and 5th metacarpals, tetraparesis, contractures at ankles, talipes equinovarus; cerebellar/brain stem migration disorder with featureless cerebellar cortex, no folia or vermis

Unknown

Muller: cerebral malformationhypertrichosis163

Hypertelorism, telecanthus, microphthalmos, small and low-set ears, hypertrichosis, camptodactyly, overlapping fingers, absent swallowing and suck; variable CNS in sibs including macrocephaly, absent corpus callosum, septum pellucidum cyst, cerebellar hypoplasia

AR (213820)

Multiple hernia164

Moderate mental retardation, hypotonia, low-set ears, downslanting palpebrae, hypotelorism, ptosis, anteverted nares, retrognathia, high-arched palate; hernias included diaphragmatic, hiatal, lung, and inguinal; bladder diverticulae; hydrocephalus, ‘‘cerebellar atrophy’’

Unknown

Multiple pterygium syndrome-lethal165

IUGR, polyhydramnios, multiple joint contractures, joint pterygia, pulmonary hypoplasia, edema, cystic hygromas, hypertelorism, downslanting palpebrae, cleft palate. Case with cerebellar and pontine hypoplasia

AR (253290)

Muscle-eye-brain166

Early severe hypotonia, delayed development, anterior chamber defects, glaucoma, preretinal glial membrane, ERG becomes abnormal, cataracts, myopathy, predominant frontal pachygyria, agenesis of corpus callosum, hypoplasia of pons and cerebellar vermis, white matter abnormalities patchy or absent, sibs with colpocephaly; common in Finland

AR (253280) POMGnT1, 1p32-p34.1

Nephronophthisis-molar tooth sign26,167

Nephronophthisis, variable ocular motor apraxia, normal eyes; a minority of patients with deletions/mutations of this gene have cerebellar hypoplasia (see Joubert)

AR (607100) NPHP1, 2q13

Neonatal diabetes mellituscerebellar168

Severe IUGR, microcephaly, low-set and dysplastic pinnae, beaked nose, poor subcutaneous fat, joint stiffness, talipes equinovarus, cerebellar aplasia/hypoplasia

AR (609069) PTFIA, 10p13-p12.1

Nephrotic syndromeinfantile spasms-GallowayMowat169

Developmental delay, early nephrotic signs due to focal glomerulosclerosis that may show IgM, IgG, and/or C3 deposits, areas of microgyria, cortical layer fusion. Cases reported with cerebellar atrophy/hypoplasia

AR (251300)

Neu-Laxova170

Sloped forehead, flat nose, abnormal auricles, finger hypoplasia, finger and toe syndactyly, severe microcephaly, IUGR, subcutaneous edema, genital hypoplasia, cerebellar vermis hypoplasia, external granular cell layer hypoplasia

AR (256520)

Neuroepithelial cysts-corpus callosum171

Interhemispheric cysts of glio-ependymal type, absent corpus callosum, neocortical microgyria, abnormal foramen magnum, nodular heterotopias, cerebellar hypoplasia

Unknown

Nievergelt: mesomelic dysplasia172

Severe mesomelia, elbows broad and restricted, talipes ulna/ radius, radioulnar synostosis, rhombdoid shaped tibia and fibula, relatively normal hands. Case with cataracts and agenesis of cerebellar vermis.

AD (163400)

Meckel-Gruber

155

(continued)

662

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Nonketotic hyperglycinemia173

Early-onset myoclonic seizures, progressive encephalopathy, profound mental retardation, absent corpus callosum, gyral anomalies, high mortality

AR (238300) GCSP, 3p21.2-21.1 GCST, 9p22 GCSH, 16q24

Ocular motor apraxianeurologic deficit174

Impaired horizontal voluntary saccadic eye movement in association with jerky head movement; variable absence of fast phase horizontal optokinetic nystagmus, verbal apraxia, dysarthria, ataxia, developmental delay; cases with vermis aplasia; also part of cerebello-oculo-renal

Unknown, AR (257550) 2q13

Oculo-renal-cerebellar175

Progressive mental retardation, spastic diplegia, glomerulopathy, retinopathy, absence of cerebellar granular layer

AR (257970)

Olivopontoneocerebellar hypoplasia-dysmorphia176

Like trisomy 18 with prominent occiput, overlapping fingers, rocker-bottom feet; neurologic signs of spasticity, extra-pyramidal dyskinesia, absent voluntary motor responses, marked pontocerebellar hypoplasia, progressive cerebral atrophy (PCH2)

AR (277470)

Organoid nevus177

Linear nevus sebaceous reported in one girl who was retarded and had mild cataract, cerebellar agenesis with superior vermis remnant

Unknown (165630)

Orofaciodigital-type III178

Lobulated tongue, supernumerary teeth, postaxial polydactyly, metronome eye movements, cleft palate, choanal atresia, cerebellar hypoplasia. Case with Dandy-Walker cyst

AR (258850)

Osteosclerosis-brain anomalies179

Generalized osteosclerosis, wide metaphyses, wide sutures, large anterior fontanel, downslanting palpebrae, depressed nasal bridge, micrognathia, large posterior fossa cyst, cerebellar hypoplasia, agenesis of the corpus callosum, large interhemispheric cyst, hydrocephalus

AR

Osteosclerosis-meningeal abnormalities180

Narrow face, prominent eyes, mandibular and maxillary hypoplasia, osteosclerosis mainly of skull and spine, wide thoracic and lumbar dorsal sac and subarachnoid, hypoplastic vermis with smooth rostral surface

AD (130720)

Oto-palato-digital II181

Mandibular hypoplasia, cleft palate, malar hypoplasia, downslanting palpebrae, narrow ribs, bowed forearms and legs, absent fibulas and carpals, pelvic hypoplasia. Case with cerebellar hypoplasia and hydrocephalus

XLR (304120) FLNA, Xq28

PAX6-related eye-brain anomalies182

Compound heterozygote for PAX6 mutations had microcephaly, anophthalmia, small nares, large pinnae, absent corpus callosum, focal polymicrogyria, hypoplastic pons and cerebellum; heterozygotes had unilateral polymicrogyria and absent pineal

AR (106210) 11p13

Pena-Shokeir phenotype183

IUGR, fetal hypokinesia, polyhydramnios contractures, trismus, retrognathia, hypertelorism, trilobed lungs, hydrocephalus, hypoplastic basal ganglia and cerebellum, lethal

AR (208150)

Periodic alternating nystagmus-microcephaly184

Growth and developmental retardation, congenital periodic alternating nystagmus with decreased visual acuity, prominent ears, cerebellar hypoplasia

Unknown

Periventricular nodular heterotopia-syndactylycerebellar hypoplasia185

Severe mental retardation, seizures, syndactyly; variable cataracts, hypospadias, areas of cortical dysplasia

XLR (300049) possibly FLNA, Xq28

Perrault: deafness-ovarian dysgenesis186

Severe sensorineural hearing loss, ovarian dysgenesis; neurologic signs include variable mental retardation, ataxia, hypotonia, limited extraocular movement; cerebellar hypoplasia noted in one case

AR (233400)

Pfeiffer: oligodactylyabnormal facies187

Absent fibula/ulna, bowed femora, oligodactyly, cleft lip/palate, facial dysmorphia, contractures, Arnold-Chiari type II, absent velum medullare of vermis, focal microgyria, lethal

AR (228930)

Pitt-Hopkins188

Severe developmental delay, voluntary over-breathing, variable microcephaly, prominent nose with wide bridge and flared nares, macrostomia, thick and fleshy lips, finger clubbing, seizures, cerebellar hypoplasia

AR?

Porencephaly-cerebellar hypoplasia-heart defect189

Prominent metopic suture, bilateral epicanthus, high arched palate, absent septum pellucidum, hydrocephalus, bilateral cortical defects, dilated 4th ventricle, absent vermis, cerebellar hypoplasia, probable porencephaly in one sib, congenital heart defects

AR (601322)

Porphyria-acute intermittent, homozygote190

Optic nerve changes, cataracts, ataxia, developmental delay, skin photosensitivity; microcephaly, porencephaly, vermis hypoplasia, anterior encephalocele

AD (176000) homozygote HMBS, 11q23-11qter

Port wine nevus191

Severe port wine nevus, large cisterna magna, communicating hydrocephalus, hypoplasia of posterior vermis

Uncertain (continued)

663

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Pseudo-TORCH

Severe retardation and seizures, extensive and variable deep and superficial supratentorial and basal ganglia calcification, hepatosplenomegaly, petechial rash; may be allelic with Aicardi-Goutieres and Cree encephalitis; 1 of 2 affected brothers had cerebellar hypoplasia

AR (251290)

Refsum, infantile193

Severe psychomotor delay, hypotonia, seizures, retinitis pigmentosa, sensorineural hearing loss, hepatomegaly, similar to but milder than Zellweger, acyl-CoAdihydroxyacetone phosphate acyltransferase deficiency, granular layer hypoplasia

AR (266510) PEX1, 7q21-q22 PEX2, 8q21.1

Retinal coloboma-congenital ataxia194

Bulging fontanels, split sutures, mild hydrocephalus, nystagmus, minor athetosis, hypotonia, abnormal respiration, dilated basal cisterna

AR or XLR

Saldino-Mainzer195

Leber congenital amaurosis, short limbs, small chest, short middle phalanges, coned epiphyses in hands, flat proximal femoral epiphyses, wide femoral neck, sclerotic metaphyses, nephronophthisis; may be same as Senior-Lo¨ken26

AR (266920)

Seller: cerebellar hypoplasiafacial dysmorphism196

Varied intrafamilial spectrum; high and receding forehead, low-set ears, hypertelorism/hypotelorism, absent external nares, thick and overhanging upper lip, small jaw, cardiac defects, dilated ileum, cerebellar hypoplasia

AR

Senior-Lo¨ken: cerebellooculo-renal26

Developmental delay, molar tooth sign, Leber congenital amaurosis, nephronophthisis; variable Dandy-Walker malformation, hepatic fibrosis, coned epiphyses; see also Joubert142

AR (266900)

Siber: microphthalmia197

Microphthalmia, corneal opacities, hypospadias; one sib had callosal agenesis, the second aqueduct stenosis; underdeveloped cerebellum, pons, midbrain, and basal ganglia; absent olfactory, optic, oculomotor nerves, areas of macrogyria

XLR (309800) Xq27-q28

Situs inversus-autosomal recessive198

Midline and lateralization defects including dextrocardia, atrioventricular canal defect, common atrium, lung segmentation defects, polysplenia, hemivertebrae, optic nerve coloboma, chorioretinal atrophy, cleft soft palate, hypoplastic corpus callosum, cerebellar dysgenesis, vermis hypoplasia

AD (601086), AR (605376) EBAF, 1q42.1 CFC1, Chr 2 CRELD1, 3p25.3 ACVR2B, 3p22-p21.3 NKX2-5, 5q34

Slee: hydrocephalus-growth failure-digital199

Severe polyventricular hydrocephalus, patent aqueduct of Sylvius, cleft palate, overlapping fingers; CNS variable and includes partial/complete callosal agenesis, hypoplastic mid- and hindbrain, cerebellar agenesis; lethal

AR/XLR?

Smith-Lemli-Opitz200

Postnatal growth failure, mental retardation, narrow forehead, ptosis, epicanthus, broad anteverted nasal tip, broad alveolar ridges, micrognathia. Severe end of spectrum has more marked genital and internal anomalies, postaxial polydactyly, cerebellar hypoplasia

AR (270400) DHCR7, 11q12-q13

Smith-Magenis201

Short stature, square and broad face, upslanting palpebrae, deep-set eyes, full cheeks, depressed and broad nasal root, marked malar hypoplasia, fleshy and tented upper lip, bulky philtral pillars, characteristic and possibly unique behavior. Two reports with cerebellar anomalies, one with Joubert phenotype

AD (182290) del 17p11.2

Stippled humeral epiphysesiris colobomata202

Developmental delay, brachycephaly, small nose and anteverted nares, low-set ears, midface hypoplasia, iris coloboma, stippled proximal humeral epiphyses, dysplastic distal phalanges, hepatic fibrosis, deep palmar creases, toenail hypoplasia, partial absence of the corpus callosum, small cerebellar vermis

AR (215105)

Stoll: cerebellar hypoplasiaspastic paraplegia203

Mental retardation, spastic paraplegia, hypoplasia of the cerebellar hemispheres, partial agenesis of cerebellar vermis, agenesis of the corpus callosum

AR

Sublobar cortical dysplasia204

Dysplasia of a single hemisphere within a lobe and separated from normal brain, absent or thin corpus callosum, 4 of 5 had hypoplastic cerebellar vermis

Unknown

Syndactyly-cerebellar atrophy-mental retardation205

Developmental delay, axial hypotonia, lower limb hypotonia, lambdoid fusions, large ears, sparse hair, tapered fingers, broad halluces, variable syndactyly

Uncertain

Teebi: Aarskog-like206

Normal intelligence and growth, broad forehead, widow’s peak, hypertelorism, downslanting palpebrae, ptosis, broad nasal bridge, hypoplastic mid-face, long philtrum, thin upper lip, short and broad hands, shawl scrotum. Case with ventricular septal defect, occipital lipoma, hypoplasia of left cerebellar hemisphere

AD (145420)

Thanatophoric dysplasia207

Usually neonatally lethal, short ribbed, micromelic dwarfism, excess skin folds, achondroplasia-like face, H or U-shaped vertebrae on AP, curved femur, metaphyseal changes; cerebellar hypoplasia, inferior vermis aplasia, polymicrogyria, leptomeningeal and periventricular neuronal heterotopias

AD (187600) FGFR3, 4p16

192

(continued)

664

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Thrombocytopenia-absent radius208

Congenital thrombocytopenia, absent radius with preservation of thumbs, variable additional anomalies. Case with cerebellar hypoplasia, callosal hypoplasia, cavum septum pellucidum.

AR (274000)

Thrombocytopenia-Robin sequence209

Mental retardation, pre- and postnatal growth failure, Robin sequence, telecanthus, downslanting palpebrae, short and broad-tipped nose, enamel hypoplasia, camptodactyly, cerebellar vermis hypoplasia

Unknown

Thyrocerebrorenal210

Renal tubular and interstitial nephropathy, thrombocytopenia, thyroid organification defect, late childhood muscle wasting, ataxia, cerebellum with severe demyelination of white matter, neuronal loss

AR (274240)

Trichorrhexis nodosa-lip pits211

Developmental delay, hydrotic ectodermal dysplasia involving hair, nails, and teeth (hypodontia), long narrow face, narrow auditory meati, lip pits, submucous cleft palate, cerebellar hypoplasia

Uncertain

Troost: cerebral calcifications212

Progressive cerebral blindness, tetraplegia, regression; periventricular, ganglial, cerebellar calcification; cerebellar hypoplasia with sparing of paleocerebellum; atrophic granular layer; irregular Purkinje cells

AR

Van Maldergem: blepharonaso-facial213

Moderate to severe mental retardation, small and malformed ears, telecanthus, epicanthus, broad and flat nose, wide mouth, camptodactyly, clinodactyly, mild skin syndactyly. Case with ataxia, hypotonia enlarged lateral ventricles, reduced white matter, absence callosal rostrum, hypoplastic superior vermis and tonsils.

Unknown

Van Staey: facial dysmorphiadeafness214

Developmental delay, overfolded helices, sensorineural deafness, hypertelorism, epicanthus, submucous cleft palate, hydronephrosis, enlarged 4th ventricle, large cisterna magna, and probable vermis hypoplasia

Unknown

Va´radi: OFD-VI215

Severe retardation, postnatal growth failure, median clefts, fatty hamartomas of tongue, pre-axial polydactyly feet, bifid 3rd metacarpal, abnormal cerebellar vermis, high mortality

Uncertain (277170)

Velo-cardio-facial216

Long narrow face, retrognathia, prominent nose with hypoplastic tip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay, congenital heart, microcephaly, hypoplastic pons and vermis lobules VI-VII

AD (192430) del 22q11 del 10p

Vici: immunodeficiencycataracts217

Hair and skin hypopigmentation, combined immunodeficiency, cleft lip/palate, hypertelorism, hypospadias, hypoplastic cerebellar vermis

XLR or AR (242840)

Whistling face-severe form with hearing loss218

Lethal with severe postnatal growth failure, microcephaly, hypertelorism, blepharophimosis, long philtrum, small and puckered mouth, joint stiffness, digital flexion contractures and ulnar deviation, restricted thorax; hypoplastic medulla, pons, midbrain, cerebellar hemispheres and vermis

Unknown

Winter: IUGRhydrocephalus-skeletal219

Severe IUGR, rhizomelia, small face and ears, blue sclerae, beaked and pinched nose, small hands, zygodactyly of toes 4–5, bifid 5th left toenail, small penis, retarded bone age; radiologic changes include metaphyseal flaring, platyspondyly, pelvic anomalies, wormian bones; enlarged 3rd and lateral ventricles, small 4th ventricle, probable cerebellar vermis dysgenesis/agenesis

Unknown, AR?

220

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, poorly formed hemispheres; microscopic renal changes

Unknown

X-linked cerebellar hypoplasia-normal intelligence221

Nonprogressive, ataxia, hyperreflexia, dysarthria, nystagmus, absent upward gaze, hypoplasia of cerebellar hemispheres and vermis

XLR Xp11.21-q24

X-linked laterality defect222

Variable visceral situs inversus, complex congenital heart disease, splenic malformations; CNS anomalies less common and include arhinencephaly, hydrocephalus, meningomyelocele, and cerebellar hypoplasia

XLR (304750) ZIC3, Xq24-q27

XLMR-Christianson223

Mild microcephaly, profound mental retardation, no speech, ophthalmoplegia, truncal ataxia, lowered life expectancy, cerebellar and brain stem ‘‘atrophy’’; females may show delay

XLR (300243) Xq24-q27

XLMR-oligophrenin defect32,33

Moderate to severe mental retardation, myoclonic-astatic epilepsy, ataxia, hypogenitalism, fronto-temporal atrophy, lower vermian agenesis, asymmetric cerebellar hypoplasia; 46,XY sisters deleted for oligophrenin and androgen receptor genes expressed syndrome

XLD (300127) OPHN1, Xq12

Yano: cerebello-oculorenal224

Developmental delay, molar tooth sign, Leber congenital amaurosis, renal hypoplasia/ agenesis (see also Joubert ref. 142)

AR (608091)

Winter-Wigglesworth

(continued)

665

666

Neuromuscular Systems

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Young: agenesis of the corpus callosum225

Relative macrocephaly, prominent forehead, deep-set eyes, thin nose, mental retardation, gut malrotation, asymmetric hypoplasia of cerebellar hemisphere

AR (217990)

Young: X-linked congenital ataxia58

Mild to moderate developmental delay, decreased reflexes, trunk and limb ataxia, intention tremor, nystagmus, broad gait, cerebellar hypoplasia

XLR (302500) Xp11.21-q21.3

Yunis-Varon: cleidocranial dysostosis226

Wide anterior fontanelle, sparse scalp hair, short philtrum, narrow palate, micrognathia, thin lips; absent/hypoplastic thumbs, great toes, clavicles; distal toe/ finger aphalangia. Case with hypoplastic vermis

AR (216340)

behavioral problems.8 Oculomotor apraxia is common. Findings at postmortem examination have included vermis dysplasia, cerebellar cortex heterotopias in the white matter, lack of decussation of the pyramidal tracts, dysplasia of the olivary nuclei, and hypoplasia of the fasciculus solitarius and descending trigeminal tract.7 There can be significant interfamilial and intrafamilial variation in the severity of the neurologic signs and CNS changes seen on MRI. From the original report of Joubert syndrome there followed numerous papers describing patients with additional and varied anomalies of the brain, eyes, kidneys, liver, and digits, and this has led to considerable nosological confusion. The common associated anomalies include Leber congenital amaurosis, later onset retinopathies, colobomas, cystic dysplastic kidneys, nephronophthisis, hepatic fibrosis and cysts, and occasional postaxial polydactyly. Satram et al.26 reviewed 100 patients with cerebellar vermis hypoplasia plus additional ocular and/or renal involvement. They excluded cases of pure Joubert syndrome, which has now been linked to 9q34, from the analysis. The authors were able to show that the specific types of associated anomalies ran true within siblingships, and they tentatively identified six MTS syndromes, all but one of which had at least one case reported with demonstrable MTS. These syndromes were Joubert, Arima, Senior-Lo¨ken, COACH, Gentile, and cerebelloretinal-renal agenesis (Table 15-17). The authors also suggested that MTS with nephronophthisis due to NPHP1 mutations be added to the list,27 and questioned the nosological relationship of the 3C and Va´radi (OFD Type VI) syndromes (Table 15-17). Further clarification awaits progress in uncovering the genes for these conditions. Thus far NPHP1 at 2q13 and AHI1 on 6q23.2 have been associated with Joubert syndrome. Of note, the Dandy-Walker malformation, sometimes with the cyst included in an encephalocele, was an occasional component of several of the syndromes.26 Others have simply separated Joubert syndrome as cerebello-oculo-renal syndrome type 1 (CORS1) and grouped the others as CORS2. 15.12.4 Isolated Vermis Aplasia/ Hypoplasia/Dysplasia

In complete vermis aplasia there is either no tissue or a thin remaining membrane. The cerebellar hemispheres may be normal, hypoplastic, or show abnormal convolutions or dysplasia. The dorsal accessory olives are virtually absent, and variable anomalies may be seen in the dentate, inferior olives, ventral accessory olives, and restiform body.28 Parisi and Dobyns8consider that hypoplasia of the vermis is likely underdiagnosed, and often mislabeled as Dandy-Walker variant. Vermian hypoplasia is distinguished from Dandy-Walker malformation by the normal or minimally upwardly rotated position of the vermis relative to the brain stem, the absence of an elevated tentorium and lateral sinuses, and the smaller retrocerebellar collection of fluid that does connect to the fourth ventricle.8,29 Partial agenesis/

hypoplasia generally involves the later developing caudal parts of the cerebellum (Figs. 15-59, 15-60). Again, this is clearly a heterogeneous disorder, which may occur as an isolated CNS anomaly in patients with CNS signs, or as part of a more generalized syndrome (Table 15-17). In a number of syndromes listed, the cerebellar anomaly has not been well described and some may well have been limited to the vermis. Al Shahwan et al.30 described a family with an autosomal recessive, non-progressive cerebellar hypoplasia involving absence of the caudal vermis and hypoplasia of the remaining vermis and paravermian cerebellar hemispheres. The patients exhibited hyperreflexia and positive Babinski signs, along with other typical cerebellar signs. Families with apparent X-linked recessive inheritance have been reported,31 and vermis hypoplasia, specifically with incomplete sulcation of the anterior and posterior vermis with the prominent defects in lobules VI and VII, is seen in the X-linked oligophrenin-1 (OPHN1) form of mental retardation (Table 15-17).32,33 Steinlin9 found reference to seven families in the literature with autosomal dominant, or in some cases perhaps sex-linked dominant, inheritance of a relatively mild, non-progressive cerebellar ataxia with cerebellar vermis hypoplasia. Cognitive impairment was mild with IQ ranging from 70 to 90 and walking prior to age 2 years. There are no available pathologic data. Fig. 15-59. Sagittal MRI scan showing agenesis of the inferior vermis.

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genu of the corpus callosum, pons, and vermis lobules VI–VII has also been reported in Turner syndrome.43 Autism with agenesis of the vermis in association with elevated succinyl purines has been reported in two patients.44 15.12.5 Complete Cerebellar Agenesis

Total agenesis of the cerebellum is exceedingly rare, and Hamilton and Grafe,45 who added two cases of their own in children with multiple associated anomalies, were only able to find two reports in the literature with convincing evidence for a complete lack of the cerebellum. Thus, the majority of the over 50 cases reported as cerebellar agenesis can be shown to have a small cerebellar remnant,46 perhaps representing the flocculus (Fig. 15-61).28 The cerebellar peduncles, olivary nuclei, and pons may be extremely hypoplastic or even absent.28,45 In cases of true agenesis the posterior fossa is small and may be of an abnormal shape; whereas in cases with a cerebellar remnant, it may be of normal size, thus supporting the view that a destructive process may be involved (see Unilateral cerebellar hypoplasia/agenesis). Significant psychomotor delay with severely delayed speech and walking between 4 and 7 years of age is the rule, and gait tends to be clumsy and speech dysathric.46 Glickstein46 has pointed out that there is no evidence to support a claim of normal motor capacity in a man previously reported to have cerebellar agenesis, and that an MRI of the patient’s brain in fact showed a cerebellar remnant. Fig. 15-60. Axial MRI scan showing agenesis of the inferior vermis.

Cortical dysplasia of the hemispheres may accompany vermis hypoplasia.34 Asymptomatic cases of vermis aplasia/hypoplasia may occur, but most patients are recognized because of early psychomotor delay, and typical cerebellar signs.9 Clinically they are not readily distinguishable from patients with more diffuse cerebellar involvement.35 Harris et al.36 described a family with likely autosomal dominantly inherited vermis hypoplasia in which the presentation was with ocular motor apraxia (saccade initiation failure) and mild learning difficulties. In some cases the neurologic picture may be dominated by supratentorial anomalies, and it is certain that mutations in OPHN1 have an effect beyond that in the cerebellum. Parisi and Dobyns8 stress that the neurologic prognosis is generally worse in patients with cerebellar vermis hypoplasia/aplasia than for those with the more obvious Dandy-Walker malformation. This is of great importance when interpreting anomalies of the posterior fossa detected at prenatal sonography, at which time larger cysts with a statistically better prognosis are more likely to be detected, but it can be difficult to distinguish vermis hypoplasia from a true DandyWalker malformation.37 There is continuing interest in the possible association of minor degrees of vermis hypoplasia, often confined to specific lobules, and certain syndromes or neurologic illnesses. Early MRI studies suggested that otherwise normal persons with autism may be found to have hypoplasia of the declive, folium, and tuber of the posterior vermis.38,39 Kaufmann et al.40 confirmed a reduction in the size of vermis lobules VI–VII in idiopathic autism and showed that lobules VI through X were reduced in Down syndrome and fragile-X syndrome. A smaller cerebellum in Down syndrome has also been confirmed between 13 and 26 weeks gestation on prenatal sonography.41 Hypoplasia of vermis lobules VI–VII and the pons has been proffered as a possible explanation for the neurobehavioral profile of velocardiofacial syndrome,42and a reduction in area of the

15.12.6 Unilateral Hemispheric Agenesis/Hypoplasia

The degree of involvement of the cerebellum in unilateral hemispheric agenesis/hypoplasia (UAH) is quite variable. The ipsilateral vermis may or may not be affected, the involved hemisphere may be completely absent, be represented as a remnant, or simply be small, and in some cases the normal side may also be somewhat smaller than normal. Thus, it is likely that this represents a heterogeneous grouping. Secondary changes occur in the contralateral inferior olivary and pontine nuclei, which are normally connected to the affected hemisphere. UAH should be distinguished from crossed cerebellar diaschisis in which the cerebellar hypoplasia is a Fig. 15-61. Axial CT scan at level of the fourth ventricle showing somewhat enlarged basal cisterns and absence of cerebellar structures.

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secondary degeneration that follows atrophy of the contralateral cortex.47 Significant cerebellar asymmetry may be reflected on routine skull radiographs by ipsilateral hypoplastic development of the posterior fossa, thickening of the skull table, and excess petrous pneumatization.48 In the absence of associated CNS pathology, a significant number of cases have been asymptomatic or have exhibited relatively mild cerebellar signs. This speaks for a significant plasticity in the development of the cerebellum, and makes it difficult to ascribe a patient’s clinical signs to the UAH with any certainty. For example, Boltshauser et al.49 described three children, one with complete and two with a small remnant, with UAH. The patients presented, one each, with delayed motor development and contralateral torticollis, hemiplegia, and an ‘‘unusual head nodding,’’ and the authors concluded that it was doubtful that the UAH accounted for their symptoms. In contrast, Goraya et al.50 argued that the hyperekplexia they observed in a 10-year-old girl could logically be attributed to her vermis and right cerebellar UAH. There were three cases of UAH among the 70 patients described by Patel and Barkovich.1 Two were children with developmental delay and one an adult with headaches. Ramaekers et al.51 ascertained 16 cases of UAH among 78 patients with non-Dandy-Walker cerebellar structural anomalies. In eleven cases, the UAH was extensive, and in five it was minor. Although full details were not provided, it would appear that children with significant medical/developmental findings had either associated physical anomalies or medical histories that would account for developmental problems. Of interest were two unrelated males with UAH, microcephaly, severe mental retardation, and ipsilateral choroidal-retinal coloboma. There is some consensus that UAH is often an acquired lesion, and to date there have been no recurrences within a family. Of the seven patients reported by Ramaekers et al.51 with marked UAH but no associated malformations, six had a history of severe prenatal or perinatal hypoxia. Of the five with mild UAH, one had suffered cerebellitis and two had documented cerebellar strokes. The case reported by Robins et al.52 appears to provide concrete evidence of an acquired vascular cause. At an obstetric ultrasound performed because of non-specific abdominal pain at 24 weeks gestation, a 2cm echogenic mass was noted in the right cerebellar hemisphere. By 29 weeks, this was a 5-cm cystic lesion, and a perinatal MRI showed a right UAH. The child showed normal development at 18 months. Fuwa and Kogo53 presented a 51-year-old woman with progressive cerebellar signs and cranial nerve palsies who was shown to have a porencephalic cavity, lined by nonspecific gliosis, suggesting a similar mechanism can occur later in life. 15.12.7 Cerebellar Hypertrophy

Cerebellar hypertrophy is uncommon and not associated with the classic overgrowth syndromes, although it may be seen in hemimegalencephaly.7 The best known cause of cerebellar hypertrophy is the PTEN-associated L’Hermitte-Duclos hamartoma, which is characterized by 1) partial or complete disassociation of the cerebellar cortex from the underlying atrophic/absent white matter, 2) replacement of Purkinje cells, and less so granule cells, by a layer of dysplastic cells that react immunologically as Purkinje cells, 3) replacement of the molecular layer by thick, horizontal and radial nerve fibers, 4) abnormal lamination, even in normal appearing lobules and folia, 5) macrocephaly, and 6) anomalies of the dentate nuceus.54 De Leo´n et al.54 described massive cerebellar hypertrophy due to a lesion that appeared to derive from the inferior vermis, was attached to the hemispheric folia, and consisted of a completely

disorganized mass of poorly differentiated neuroepithelial cells. This may be more of a benign tumor than a true hypertrophy. Schweitzer et al.55 reported two brothers who both had cerebellar hypertrophy and van den Ende-Gupta syndrome. This autosomal recessive syndrome consists of blepharophimosis, a flat and wide nasal bridge but narrow nose, prominent ears with anomalous pinnae, a high or cleft palate, camptodactyly and other contractures that improve over time, arachnodactyly, and other minor skeletal anomalies. MRI showed generalized cerebellar hypertrophy, which was 130% of normal in the one brother in whom measurements were possible. There is no information about the cerebellum in the six other patients reported with this syndrome. The cerebellum has been noted to be enlarged in Williams syndrome, and in a recent study using radiologists blinded to the diagnosis and hypothesis, the radiologists separated out the Williams syndrome patients because of their large cerebellum.56 Finally, in a study that compared normal children, children with idiopathic autism, and children with Down syndrome and fragileX syndrome, with and without autistic features, an enlargement of lobules VI–VII was found (only) in children with fragile-X syndrome and autistic behavior.43 Nothing is known of the histopathology in these syndromes. 15.12.8 Cerebellar Hypoplasia/Aplasia/Dysplasia

Niesen7 has divided cerebellar hypoplasia into type I with normal folia, usually a normal three-layered cortex, and heterotopias, and type II where the fissures are prominent and there is significant cell loss. The former is considered an abnormality of cell migration and differentiation. The latter, which presents the difficulty of separating hypoplasia from atrophy, is viewed as a disorder of cell proliferation. Again, there is nothing distinctive about the clinical presentation, and the two patients with diffuse involvement in the series of 11 patients with non-syndromic cerebellar hypoplasia reported by Shevell and Majnemer35 were not clinically different from those with isolated vermis hypoplasia. Type I hypoplasia is exemplified by trisomy 13 and 18,7 whereas the prototypic type II disorder is granule cell aplasia (GCA), also called granuloprival hypoplasia. GCA is an autosomal recessively inherited cerebellar hypoplasia that presents with a clinical picture typical for a non-progressive cerebellar ataxia.9,57 PascualCastroviejo et al.57 reported 14 cases and reviewed the literature. They believe that cases can be divided into two groups, based on the presence or absence of a normal head circumference, the likelihood of survival, and of language and intellectual skills that allowed them to maintain social contact and learn simple concepts. The histopathology of GCA shows generalized cerebellar hypoplasia with diminished to absent granule cells. The Purkinje cell layer can appear virtually normal, but usually shows reduced cell numbers, heterotopias, and dendritic abnormalities with resultant asteroid bodies and axonal torpedoes (Fig. 15-62).57,58 There may be defective myelination of the cerebellar white matter and cerebral changes consistent with primary microcephaly. Pascual-Castroviejo et al.57 raised the question as to whether this might be a prenatal onset abiotrophy. Genetic heterogeneity of GCA seems likely. Chou et al.59 described three of five male siblings with virtual absence of granule cells in both the fascia dentata of Ammon’s horns of the hippocampus and the cerebellum. In addition to the typical cerebellar signs of GCA, the siblings had intractable seizures and athetoid movements. There was relative preservation of the Purkinje cells, and this condition could be autosomal or X-linked recessive. One form of mild cerebellar hypoplasia with spinal involvement has been linked to 9p12-q12,60

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Fig. 15-62. Silver stain of cerebellar section showing absence of granule cell layer and disoriented Purkinje cells.

and an X-linked form was reported by Young et al. (Table 15-17).61 Pascual-Castroviejo et al.62 described what is probably an autosomal recessive cerebellar hypoplasia that is clinically indistinguishable from GCA, but is characterized by preservation of the granule cell layers, irregular loss of Purkinje cells, mild Bergman gliosis, and globular thickening and deformities of the Purkinje dendrites. Specific diagnosis requires histologic study of the brain. Type II cerebellar hypoplasia may also be seen in the face of metabolic disease, but here again it may be difficult to separate hypoplasia from atrophy. Niesen7 uses congenital disorders of glycosylation as a prime example of type II hypoplasia, whereas Steilin et al.63 consider CDGS to be the most impressive form of atrophy. Those authors list adenylsuccinase deficiency, pyruvate dehydrogenase deficiency, and L-2-hydroxyglutaric acidemia as causing cerebellar hypoplasia, to which can be added cytochrome c oxidase (complex IV) deficiency.64 In reality, the distinction may not be as clear-cut with metabolic diseases likely having both a negative effect on cerebellar development and maturation as well as causing atrophy. 15.12.9 Pontocerebellar Anomalies

Pontine agenesis is exceedingly rare, and Niesen7 was able to find only three cases with adequate documentation. Clinical presentation is with abnormal respiration, increased tone, and absent oculocephalic, corneal, gag, and sucking reflexes. Death is from respiratory failure, and the pons and midbrain are a thin ribbon of tissue, with the cerebellum being small and displaced rostrally. The cause is unknown. The pontocerebellar hypoplasias are not discussed in this chapter because they are progressive abiotrophies. There are three subtypes: one with spinal muscular atrophy (PCH1); one with microcephaly, epilepsy, and chorea (PCH2); and the last similar to PCH2 but without dyskinesia (PCH3), which has been mapped to 7q11-q21.65 Table 15-17 summarizes a number of syndromes in which cerebellar abnormalities have been reported. An effort has been made to identify the specific nature of the cerebellar abnormality, although in some cases it has not been clearly stated, and in most cases pathologic confirmation is not available. Etiology and Distribution

At this time one can do little more than guess the prevalence of cerebellar malformations. Certainly the availability of noninvasive

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CT and MRI has led to an increased awareness and detection of these abnormalities. Still, mild malformations may be hard to detect and require good quality studies,2,5 which are not always possible to obtain, especially where a patient is unable to cooperate.9 The picture is further clouded by the fact that children who have nonprogressive cerebellar ataxia (NPCA) and a detectable cerebellar anomaly do not differ clinically from those with NPCA and no detectable lesion; furthermore, there can be discordance within a siblingship.9,10 Esscher et al.10 found 78 cases of NPCA among a population of 595,688 persons for a prevalence of 0.13/1000. There was no sex difference in prevalence. Fewer cases in earlier years suggest there was some underascertainment. Shevell and Majnemer35 found 11 cases of non-familial, isolated cerebellar hypoplasia (mostly vermian) among 2500 consecutive referrals to a pediatric neurologist. Patel and Brakovich1 gathered 70 cases of cerebellar malformation over 15 years of practice, but the population denominator is not available. However, they had 19 patients with a Dandy-Walker malformation, which has a prevalence as high as 1/5000.8 If one assumes no bias in the referral of cases by type of malformation, then their 12 cases of Joubert syndrome, eight of rhombencephalosynapsis, and six of cerebellar hypoplasia would give rates of 0.13/1000, 0.08/1000, and 0.06/1000, respectively. This is an order of magnitude higher than a survey estimate of the prevalence of Joubert syndrome.227 Of the 78 patients without trapped fourth ventricle, DandyWalker malformation, or Dandy-Walker variant reported by Ramaekers et al.,51 16 had unilateral and 62 bilateral lesions, and of the latter, 15 were primarily vermian, 9 pontocerebellar, and 38 hemispheric. However, 28 of the latter were judged to be progressive and progressive abiotophies were included in the pontocerebellar group. The cerebellum accounts for only 10% of intracranial volume but it contains 50% of neurons in the adult, and until recently knowledge of its development lagged behind that of other parts of the brain. However, recent developments in embryology and molecular biology have added much, and will continue to contribute, to an increased understanding of the pathogenesis of cerebellar abnormalities. The cerebellar origins are defined early in embryogenesis but its maturation continues well into postnatal life and makes it susceptible to malformation, disruption, and dysplasia over a prolonged period. By the week 3 of gestation, the prosencephalon, mesencephalon, and rhombencephalon are apparent, and during the subsequent 2 weeks the neural tube develops the cranial and cervical flexions and the eight transient hindbrain rhombomeres.7 This is followed in the fifth week by the pontine retroflexion, which results in the fourth ventricle and its triangular rhombic roof-plate. Physical evidence of the future cerebellum is present by 5 weeks in the form of the rhombic lips, which develop as a proliferation of cells in the bilateral alar plates at the junction of the roof-plate and neural tube, anterior to the choroid plexus. The bilateral elements come to fuse in the midline. This rhombic lip development is intimately related to the isthmus organizer (IO), a narrowing that originates near the mesencephalic–metencephalic border. It was thought that location of the organizer evidenced both mesencephalic and metencephalic origin of the cerebellum, but more recent work has shown that the isthmus moves rostrally during development to the actual mesencephalic/metencephalic boundary.228,229 An important initial step in defining the rostral limit of the cerebellum and the IO is a reciprocal repression between the expression of Otx2 in the anterior CNS and the posterior CNS expression of Gbx2, with the interface being at the mesencephalic–metencephalic boundary.229,230

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Mutations in these genes have a major effect on the developing CNS and the integrity of the IO.230 The caudal limit of the cerebellum is defined by the rostral limit of Hoxa2 expression, which defines the rh1/rh2 border.231 Mice with mutations in Hoxa2 have enlarged cerebellums, and retinoic acid is important in the function of these genes. Thus, the cerebellum and some pontine neurons derive solely from rhombomere 1. The genes involved in maintaining the integrity of the IO and the pathways emanating from there that control cerebellar development continue to be studied, but do include Wnt1, Fgf8, Pax2/5, En1/2.7,229 Mutations, both natural and knockout, together with transgenic expression studies, result in a variety of midbrain–hindbrain and cerebellar abnormalities, which may vary with strain and/or level of background sensitization.228–230,232 Two sources provide the neurons of the cerebellum. The Purkinje cells, and all other non-granule cells, derive from the subventricular zone in the floor of the fourth ventricle, 233 and the first cells to migrate from this area at about 8 weeks gestation become the deep cerebellar nuclei.233 In the human, from about 9 to 13 weeks, Purkinje cells migrate in the usual radial fashion along the reelin (RELN)-dependent radial fibers of the Bergmann glial cells.1,229 Differentiation and survival of Purkinje cells is dependent on Wnt3 expression.234 Although granule cells are not required during the migration and initial maturation of Purkinje cells, they do play an important interactive role in their final maturation229 and in determining the stop signal for migration.235 The granule cells begin to develop at about 11 weeks and continue their proliferation as external granule cells until about 3 months after birth, with final migration and loss of the external layer ending at about 15 months postnatally.7 The granule cells are unique both in their derivation from a separate germinal matrix in the rhombic lip, and in that they migrate tangentially to form the external granule cell layer before undergoing their final mitosis and migrating inward, between the Purkinje cells, to form the inner granule cell layer. Math-1 has a critical role in granule cell production.7 Additional genes and factors that appear to play a role in the initial migration and differentiation of these cells include nectin, N-methyl-d-aspartate receptor, Zic1/3, and Zipro1.7,229 Markers and genes involved in the development of the internal granule cell layer may include Pax6, Tag1, Tuj1, the Dcc/ netrin pathway, and Unc5h2.229 Maturation of the cerebellum includes the development of connections via mossy fibers from the spinocerebellar pathways, reticulocerebellar nuclei, pontocerebellar nuclei, and others to the deep cerebellar neurons and granule cells. Climbing fibers from the contralateral inferior oliviary nucleus connect directly to Purkinje cells and to deep cerebellar neurons that then connect to Purkinje cells. In turn, the Purkinje cells connect directly and indirectly via superficial basket cells to the parallel fibers (axons) of the granule cells. This process begins by 24 weeks gestation, but the mature Purkinje layer is not formed until 4 to 7 months, and dentritic connections continue to be laid until 20 months postnatally.7,229 At the macroscopic level, the cerebellum develops as three phylogenetically distinct lobes. The first (present in lamprey), the archecerebellum, can be seen by 2 months and consists of the flocculonodular lobe, which is hard to distinguish in humans. The anterior lobe is next to develop and includes the vermis and paravermian hemispheres in front of the primary fissure that appears by 4 months and separates the anterior from the posterior lobe. The initiation of fissuration, at least in part, appears to be related to differential origin and timing of arrival of different groups of Purkinje cells. For example, in the mouse the fissure is a marker for cells generated before and those generated after E15.3

The posterolateral fissure separates the flocculonodular and posterior lobes. The cerebellum can be further subdivided into a series of transverse lobules, labeled I-X, which in turn can be further subdivided into sublobules, each containing a number of folia, which are transversely oriented units with a core of white matter and cover of gray matter. All major fissures and subdivisions are complete in the 120-mm embryo.236 This folial pattern is highly reproducible between individuals.5 In the rat genetic fissura prima malformation, there is a breakdown of the pia, a resultant fusion of the external granule layers from adjacent folia, ectopic cells, and migration of some external granule cells to the adjacent folia.3 This is similar to findings in the Walker-Warburg syndrome in humans. An addition to the understanding of cerebellar development that will undoubtedly have significant functional significance, and perhaps shed light on the specific pattern in both syndromic and isolated cerebellar malformations, is the recognition that the cerebellum is organized in a grid fashion.233 First, expression patterns of Purkinje cell markers and the phenotype of both spontaneous and targeted mutations in mice show a division of the cerebellum into four transverse zones: anterior (AZ), containing lobules I–IV; central (CZ) with lobules VI–VII; posterior (PZ) consisting of lobules VIII– IX; and nodular (NZ) limited to lobule X. Among the better studied markers are zebrin I/II, L7-pcp-lacZ, and Hsp25.233,237 Examples of mouse mutations with localized effects include meander tail that affects the anterior vermis, lurcher that acts at the PZ/CZ boundary, and weaver in which the CZ is absent. In addition to these transverse divisions of the expression patterns of a number of antigens, the vermis and hemispheres are further divided into a series of lateral rostro-caudal stripes.237 The expression patterns within the lateral stripes can differ across different transverse zones. Thus, the cerebellum is divided into a grid-like pattern, which is reflected in, but is not dependent on, the projection pattern of the climbing and mossy fibers. The grid also appears to reflect a functional topography and is reproducible between individuals and shows evolutionary conservation. The weight of evidence favors the origin of this patterning prior to Purkinje migration and in the ventricular zone.233 The growth of the vermis predates that of the hemispheres, and anterior predates posterior. Patients with granular cell aplasia show essentially normal gross cerebellar anatomy and normal numbers of Purkinje cells.238,239 Thus, disturbed embryogenesis from early to late would tend to produce a continuous spectrum ranging from complete aplasia, aplasia of the vermis, posterior vermis aplasia, neocerebellar (hemispheric), and finally cerebellar hypoplasia, many cases of which would represent granular cell aplasia. Not only can we think of cerebellar anomalies in terms of the timing of an insult to the larger lobes or the broad category of cell type involved, but we can begin to think of specific zones, lobules, and cell subpopulations that target to a particular grid location. Despite progress in the embryology, neuroimaging, and syndrome delineation of cerebellar anomalies, the specific etiology of most cases remains obscure. Some discussion, especially of genetic aspects, has been covered in the individual sections on diagnosis. TCD and RES are uncommon, and to date there is not human evidence for a genetic cause. Their origins are early in embryogenesis, and the former may relate to a defect in neural tube closure, and the latter to an early defect in cell migration.23 Many of the genes involved in early cerebellar development have other important roles and, as a result, germ line mutations could be lethal; but this leaves open the possibility of causative local somatic mutations. There is good evidence of a role for vascular disruptions, either thrombosis, hemorrhage, or vasculitis, as a cause for unilateral hemisphere

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agenesis/hypoplasia, and presumably some bilateral cases could have a similar etiology. Some cases have had definite retrograde nuclear atrophy, suggestive of a degenerative rather than a primary malformative process.240 However, bilateral defects could have their origin early in the embryogenesis of the neocerebellum. Perinatal insults appear to be uncommon causes for cerebellar anomalies.10 In contrast, the molar tooth sign malformation appears to be highly associated with Joubert syndrome and its community of related syndromes (Table 15-17). It is therefore predominantly, if not completely, of genetic cause, of which the basis is beginning to be discovered. Although most cases of isolated hypoplasia of the vermis have been sporadic, there are well-documented examples of X-linked recessive,31–33 autosomal recessive,30,241 autosomal dominant,9 and/or X-linked dominant240 inheritance of isolated CVH, and it is a component of a number of syndromes (Table 15-17). Similarly, a broad range of syndromes, including some trisomies, has been reported with cerebellar hypoplasia (Table 15-17). Although individually rare, biochemical genetic diseases are an important consideration in this group63,238 and, notwithstanding the issue of hypoplasia versus atrophy, congenital disorders of glycosylation are of paramount concern. The majority of patients with simple cerebellar hypoplasia who come to autopsy show absence of the cerebellar granular layer, and the abnormality is not always apparent on neuroimaging. The brain is often smaller than normal but with normal architecture. This lesion can be induced by a number of agents, including cytotoxic drugs, radiation, and viral infections, and several animals provide a genetic model.59,238,242 Sibling recurrences are well established in humans, and some variation in clinical presentation raises the possibility of genetic heterogeneity.59 The experimental models show a remarkable regenerative power of the external granular layer, and repeated teratogen exposures are required to produce absence of the granular layer. Granule cell aplasia is a component of Minamata disease.243 Anoxia is more likely to damage Purkinje cells than the granule cells.59 Viruses may act through different mechanisms and produce a different spectrum of anomalies. For example, parvoviruses are cytolytic to dividing and migrating cells and may damage the brain beyond the cerebellum, whereas arenaviruses, acting through an immune-mediated pathogenesis, may be more local to the granule cell layer.59 Prognosis, Treatment, and Prevention

As is clear from the previous discussion, the prognosis for patients with cerebellar hypoplasia shows extreme variation from asymptomatic to severely retarded with early death. However, the typical presentation is of early hypotonia with significant motor delay, with onset of typical cerebellar signs of ataxia and fine motor problems as the cerebellum matures. Although there is undoubtedly an ascertainment bias, a significant proportion of children will have severe developmental problems, although most will be more mildly affected or have normal intelligence with specific learning difficulties.9,10 In the absence of diseases or syndromes known to have a progressive course, this is a static clinical condition, and death in severely retarded children is due to expected causes such as pneumonia. In some cases, but certainly not all, the difference between a benign and a severe course is explained by the presence of associated CNS abnormalities. There is some evidence that patients with isolated absence of the anterior vermian lobule have a milder course than those with a more extensive involvement.9 A symmetrically small brain may accompany granular cell hypoplasia and appears to bode a poor prognosis.59 Although most patients with granular cell aplasia are

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severely retarded and many die at a young age, in some families the impairment may be relatively mild. Intrafamilial variation is less marked than is interfamilial. There is no direct treatment for cerebellar malformations. Appropriate supportive measures, especially in the sphere of motor development and education, should be provided. Patients should be carefully examined to rule out known syndromes, and chromosomal and metabolic testing will be indicated in some cases. Parisi and Dobyns8 stress the importance of recognizing the MTS and point out that the pattern continues to be under-recognized by radiologists. The importance lays both in the genetic implications for recurrence and because of the potential to involve other systems, which requires that the patient receive structured ongoing investigation. The evaluation should include initial assessment of the risk of apnea and swallowing difficulties and a search for ocular and renal disease. Even if the latter search is negative, periodic reevaluation of vision and an annual assessment of renal function are indicated. In the presence of hepatic fibrosis there is the longer-term risk from esophageal varices. In the absence of a specific syndrome diagnosis, genetic counseling will often have to deal with inadequate recurrence risk data. A high proportion of case reports with MTS and a significant number of those with granule cell aplasia show familial recurrence, and in the absence of another clear explanation for GCA families with either of these conditions should be informed of the 25% recurrence risk. A challenge is the heterogeneous group of NPCA. Esscher et al.10 were able to find reports of 65 families with autosomal recessive, 18 with autosomal dominant, and 19 with X-linked recessive inheritance of NPCA in the literature, and estimated that 16% of their cases were genetic. However, the heterogeneity limits the value of these data and fails to address the subgroup of prime concern, those with isolated vermis hypoplasia. If one excludes the cases with associated malformations, known syndromes, and chromosome anomalies from their prenatal group, as well as the three with a perinatal cause, and assumes that the 40 patients with unknown cause had none of the above findings, one is left with 51 cases of isolated NPCA. Of these, three had a dominant pattern of inheritance, leaving 48, of whom four had a sibling recurrence. This is equivalent to the 3 of 36 cases with a sibling recurrence reported by Steinlin.9 The average family size for the two populations is not given, but assuming it is two, and that all cases were recessive and ascertained because of a first affected child, and ignoring issues of ascertainment, then one would expect one-fourth, or 21, affected siblings, whereas seven were observed. This would give an estimate of overall recurrence of 1 in 12. The Oxford Medical Database suggests a recurrence risk of one in eight, but the source for the estimate is not provided. Clearly there is need of further study in this area using optimal imaging and clinicopathologic correlations. Standard measurement of the cerebellum using midtrimester ultrasound has been developed and successfully used in the prenatal diagnosis of posterior fossa anomalies.39,244 Fetal MRI may add helpful information when an anomaly is suspected; but the difficulty in obtaining a specific diagnosis has been emphasized.8 Even with the history of an affected child with a known malformation, one has to keep in mind the variable expression of the posterior fossa anomaly that has been reported for a number of syndromes (Table 15-17). Furthermore, parents must be made aware that recurrence of NPCA, including cases of granule cell aplasia, can occur in the absence of a detectable malformation. References (Cerebellar Abnormalities) 1. Patel S, Barkovich AJ: Analysis and classification of cerebellar malformations. AJNR Am J Neuroradiol 23:1074, 2002.

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Neuromuscular Systems

2. Adamsbaum C, Merzoug V, Andre´ C, et al.: Imagerie du cervelet de l’enfant. J Neuroradiol 30:158, 2003. 3. Necchi D, Scherini E: The malformation of the cerebellar fissure prima: a tool for studying histogenetic processes. Cerebellum 1:137, 2002. 4. Park C, Falls W, Finger JH, et al.: Deletion in Catna2, encoding aNcatenin, causes cerebellar and hippocampal lamination defects and impaired startle modulation. Nat Genet 31:279, 2002. 5. Demaerel P: Abnormalities of cerebellar foliation and fissuration: classification, neurogenetics and clinicoradiological correlations. Neuroradiology 44:639, 2002. 6. Landrieu P, Kamoun F: Au carrefour de la pathologie de´veloppementale et de la pathologie de´ge´ne´rative: les maladies ce´re´rbelleuses de la premie`re enfance. Rev Neurol 159:382, 2003. 7. Niesen CE: Malformations of the posterior fossa: current perspectives. Semin Pediatr Neurol 9:320, 2002. 8. Parisi MA, Dobyns WB: Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab 80:36, 2003. 9. Steinlin M: Non-progressive congenital ataxia. Brain Dev 20:199, 1998. 10. Esscher E, Flodmark O, Hagberg G, et al.: Non-progressive ataxia: origins, brain pathology and impairments in 78 Swedish children. Dev Med Child Neurol 28:285, 1996. 11. Schmahmann JD: An emerging concept. The cerebellar contribution to higher function. Arch Neurol 48:1178, 1991. 12. Botez MI: The neuropsychology of the cerebellum: an emerging concept. Arch Neurol 49:1229, 1992. 13. Fiez JA: Cerebellar contribution to cognition. Neuron 16:13, 1996. 14. Adamsbaum C, Merzoug V, Andre´ CH, et al.: Diagnostic ante´natal des anomalies isole´es de la fosse posterieure: tentative d’approche simplifie´e. J Radiol 83:321, 2002. 15. Padget DH, Lindenberg R: Inverse cerebellum morphogenetically related to Dandy-Walker and Arnorld-Chiari syndromes: Bizarre malformed brain with occipital encephalocele. Johns Hopkins Med J 131:228, 1972. 16. Friede RL: Uncommon syndromes of cerebellar vermis aplasia. II: Tecto-cerebellar dysraphia with occipital encephalocoel. Dev Med Child Neurol 20:764, 1978. 17. Hori A: Tectocerebellar dysraphia with posterior encephalocele (Friede): report of the youngest case. Clin Neuropathol 13:216, 1994. 18. Demaerel P, Kendall BE, Wilms G, et al.: Uncommon posterior cranial fossa anomalies: MRI with clinical correlation. Neuroradiology 37:72, 1995. 19. Michaud J, Mizrahi EM, Urich H: Agenesis of the vermis with fusion of the cerebellar hemispheres, septo-optic dysplasia and associated anomalies. Acta Neuropathol 56:161, 1982. 20. Hottinger-Blanc PMZ, Ziegler A-L, Deonna T: A special type of head stereotypies in children with developmental (? cerebellar) disorder: description of 8 cases and literature review. Eur J Paediatr Neurol 6:143, 2002. 21. Yachnis AT: Rhombencephalosynapsis with massive hydrocephalus: case report and pathogenetic considerations. Acta Neuropathol 103:301, 2002. 22. Odemis E, Cakir M, Aynaci FM: Rhombencephalosynapsis associated with cutaneous pretibial hemangioma in an infant. J Child Neurol 18: 225, 2003. 23. Kuwamura M, Shirota A, Yamate J, et al.: Analysis of aberrant neuronal migrations in the hereditary cerebellar vermis defect (CVD) rat using bromodeoxyuridine immunohistochemistry. Acta Neuropathol 95:143, 1998. 24. Maria BL, Quisling RG, Rosainz LC, et al.: Molar tooth sign in Joubert syndrome: clinical, radiologic, and pathologic significance. J Child Neurol 14:368, 1999. 25. Maria BL, Bozorgmanesh A, Kimmel KN, et al.: Quantitative development of brainstem development in Joubert syndrome and Dandy-Walker syndrome. J Child Neurol 16:751, 2001. 26. Satran D, Pierpont MEM, Dobyns WB: Cerebello-oculo-renal syndromes including Arima, Senior-Lo¨ken, and COACH syndromes: more than just variants of Joubert syndrome. Am J Med Genet 86:459, 1999.

27. Saunier S, Calado J, Heilig R, et al.: A novel gene that encodes a protein with a putative src homology 3 domain is a candidate for familial juvenile nephronophthisis. Hum Mol Genet 6:2317, 1997. 28. Macchi G, Bentivoglio M: Agenesis and hypoplasia of cerebellar structures. In: Handbook of Clinical Neurology. Congenital Malformations of the Brain and Skull, part I. PJ Vinken, GW Bruyn, eds. North Holland Publishing, Amsterdam, 1977, p 367. 29. Bordarier C, Aicardi J: Dandy-Walker syndrome and agenesis of the cerebellar vermis: diagnostic problems and genetic counseling. Dev Med Child Neurol 32:285, 1990. 30. al Shahwan SA, Bruyn GW, al Deeb SM: Non-progressive familial congenital cerebellar hypoplasia. J Neurol Sci 128:71, 1995. 31. Wakeling EL, Jolly M, Fisk NM, et al.: X-linked inheritance of DandyWalker varaint. Clin Dysmorphol 11:15, 2002. 32. des Portes V, Boddaert N, Sacco S, et al.: Specific clinical and brain MRI features in mentally retarded patients with mutations in the oligophrenin-1 gene. Am J Med Genet 124A:364, 2004. 33. Bergmann C, Zerres K, Senderek J, et al.: Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain 126:1537, 2003. 34. Soto-Ares G, Devesme L, Jorriot S, et al.: Neuropathologic and MR imaging correlation in a neonatal case of cerebellar cortical dysplasia. AJNR Am J Neuroradiol 23:1101, 2002. 35. Shevell MI, Majnemer A: Clinical features of developmental disability associated with cerebellar hypoplasia. Pediatr Neurol 15:224, 1996. 36. Harris CM, Hodgkins PR, Kriss A, et al.: Familial congenital saccade initiation failure and isolated cerebellar vermis hypoplasia. Dev Med Child Neurol 40:775, 1998. 37. Nyberg DA, Mahony BS, Hegge FN, et al.: Enlarged cisterna magna and the Dandy-Walker malformation: factors associated with chromosome abnormalities. Obstet Gynecol 77:436, 1991. 38. Courchesne E, Hesselink JR, Jemigan TL, et al.: Abnormal neuroanatomy in a nonretarded person with autism. Arch Neurol 44:335, 1987. 39. Courchesne E, Yeung-Courchesne R, Press GS, et al.: Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med 318:1349, 1986. 40. Kaufmann WE, Cooper KL, Mostofsky SH, et al.: Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study. J Child Neurol 18:463, 2003. 41. Lomholt JF, Keeling JW, Hansen BF, et al.: The prenatal development of the human cerebellar field in Down syndrome. Orthod Craniofac Res 6:220, 2003. 42. Eliez S, Schmitt JE, White CD, et al.: A quantitative MRI study of posterior fossa development in velocardiofacial syndrome. Biol Psychiatry 49:540, 2001. 43. Fryer SL, Kwon H, Eliez S, et al.: Corpus callosum and posterior fossa development in monozygotic females: a morphometric MRI study of Turner syndrome. Dev Med Child Neurol 45:320, 2003. 44. Jaeken J, van den Berghe G: An infantile autistic syndrome characterized by the presence of succinyl purines in body fluids. Lancet 2:1058, 1984. 45. Hamilton RL, Grafe MR: Complete absence of the cerebellum: a report of two cases. Acta Pathol 88:258, 1994. 46. Glickstein M: Cerebellar agenesis. Brain 117:1209, 1994. 47. Stefling AM, Urich H: Crossed cerebellar atrophy: an old problem revisited. Acta Neuropathol 2:164, 1943. 48. Mendelsohn DB, Hertzanu Y, Glass RBJ, et al.: Unilateral cerebellar hypoplasia. J Comput Assist Tomogr 7:1077, 1983. 49. Boltshauser E, Steinlin M, Martin E, et al.: Unilateral cerebellar aplasia. Neuropediatrics 27:50, 1996. 50. Goraya JS, Shah D, Poddar B: Hyperkplexia in a girl with posterior fossa malformations. J Child Neurol 17:147, 2002. 51. Ramaekers VT, Heimann G, Reul J, et al.: Genetic disorders and cerebellar structural abnormalities in childhood. Brain 120:1739, 1997. 52. Robins JB, Mason GC, Watters J, et al.: Case report: cerebellar hemihypoplasia. Prenat Diagn 18:173, 1998. 53. Fuwa I, Kogo K: Cerebellar porencephaly in an adult-case report. Neurol Med Chir 34:708, 1994.

Brain 54. de Leo´n GA, Grant JA, Darling CF: Monstrous, crablike hypertrophy of the cerebellar vermis and its relationship with Lhermitte-Duclos disease. J Neurosurg 85:157, 1996. 55. Schweitzer DN, Lachman RS, Pressman BD, et al.: van den EndeGupta syndrome of blepharophimosis, arachnodactyly, and congenital contractures: clinical delineation and recurrence in brothers. Am J Med Genet 118A:267, 2003. 56. Jones W, Hesselink J, Courchesne E, et al.: Cerebellar abnormalities in infants and toddlers with Williams syndrome. Dev Med Child Neurol 44:688, 2002. 57. Pascual-Castroviejo I, Gutierrez M, Morales C, et al.: Primary degeneration of the granular layer of the cerebellum. A study of 14 patients and review of the literature. Neuropediatrics 25:183, 1994. 58. Urich H: Malformations of the nervous system, perinatal damage and related conditions in early life. In: Greenfield’s Neuropathology, ed 3. W Blackwood, JAN Corsellis, eds. Year Book Medical, Chicago, 1976, p 401. 59. Chou SM, Mizuno Y, Rother AD: Congenital granuloprival hypoplasia of cerebellar and hippocampal cortex. J Child Neurol 2:279, 1987. 60. McHale DP, Jackson AP, Campbell DA, et al.: A gene for ataxic cerebral palsy maps to 9q12-p12. Eur J Hum Genet 8:267, 2000. 61. Young ID, Moore JR, Tripp JH: Sex-Linked recessive congenital ataxia. J Neurol Neurosurg Psychiatry 50:1230, 1987. 62. Pascual-Castroviejo I, Gutierrez Milina M, Katsetos CD, et al.: Cerebellar atrophy with Purkinje cell displacement and dendritic abnormalities associated with severe encephalopathy. Brain Dev 20:357 (A77), 1998. 63. Steinlin M, Blaser S, Boltshauser E: Cerebellar involvement in metabolic disorders: a pattern recognition approach. Neuroradiology 40:347, 1998. 64. Lincke CR, van den Bogert C, Nijtmans LGJ, et al.: Cerebellar hypoplasia in respiratory chain dysfunction. Neuropediatrics 27:216, 1996. 65. Rajab A, Mochida GH, Hill A, et al.: A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 60:1664, 2003. 66. Chitayat D, Meagher-Villemure K, Mamer OA, et al.: Brain dysgenesis and congenital intracerebral calcification associated with 3-hydroxyisobutyric aciduria. J Pediatr 121:86, 1992. 67. Kurata H, Tamaki N, Sawa H, et al.: Acrania: report of the first surviving case. Pediatr Neurosurg 24:52, 1996. 68. Taravath S, Tonsgard JH: Cerebral malformations in Carpenter syndrome. Pediatr Neurol 9:230, 1993. 69. Sebesta I, Krijt J, Kmoch S, et al.: Adenylosuccinase deficiency: clinical and biochemical findings in 5 Czech patients. J Inherit Metab Dis 20: 343, 1997. 70. Sybert V, Pagon RA, Ramsdell L, et al.: True agonadism: report of a case analyzed with Y-specific DNA probes. Am J Med Genet 55:113, 1995. 71. Rosser TL, Acosta MT, Packer RJ: Aicardi syndrome: spectrum of disease and long-term prognosis in 77 females. Pediatr Neurol 27:343, 2002. 72. Autti-Ramo I, Autti T, Korkman M, et al.: MRI findings in children with school problems who have been exposed prenatally to alcohol. Dev Med Child Neurol 44:98, 2002. 73. Musumeci SA, Elia M, Ferri R, et al.: A further family with epilepsy, dementia and yellow teeth: the Kohlschutter syndrome. Brain Dev 17: 133, 1995. 74. Jung C, Wolff G, Back E, et al.: Two unrelated children with developmental delay, short stature and anterior chamber cleavage disorder, cerebellar hypoplasia, endocrine disturbances and tracheostenosis: a new entity? Clin Dysmorphol 4:44, 1995. 75. al-Gazali LI, Bakir M, Sadaghatian MR, et al.: Anterior segment anomalies of the eye associated with multiple skeletal abnormalities and early lethality: confirmation of an autosomal recessive syndrome. Clin Dysmorphol 8:87, 1999. 76. Gunderson CA, Stone R, Peiffer R, et al.: Corneal coloboma, aphakia and retinal neovascularization with anterior segment dysgenesis (Peters’ Anomaly). Ophthalmologia 210:361, 1996. 77. Arena JF, Schwartz C, Stevenson R, et al.: Spastic paraplegia with iron deposits in the basal ganglia: a new X-linked mental retardation syndrome. Am J Med Genet 43:479, 1992.

673 78. Kumada S, Hayashi M, Arima K, et al.: Renal disease in Arima syndrome is nephronophthisis as in other Joubert-related cerebellooculo-renal syndromes. Am J Med Genet 131A:71, 2004. 79. al-Ghamdi MA, Polomeno RC, Chitayat D, et al.: Arthrogryposis multiplex congenita, craniofacial, and ophthalmolgical abnormalities and normal intelligence: a new syndrome. Am J Med Genet 71:401, 1997. 80. Avegno J, Tilton AH, Lacassie Y, et al.: Provisionally unique autosomal recessive syndrome due to significant consanguinity. Am J Med Genet 102:324, 2001. 81. Baskin E, Kayiran SM, Oto S, et al.: Cerebellar vermis hypoplasia in a patient with Bardet-Biedl syndrome. J Child Neurol 17:385, 2002. 82. Barth PG, Mullart R, Stam FC, et al.: Familial lissencephaly with extreme neopallial hypoplasia. Brain Dev 4:145, 1982. 83. des Portes V, Marchiani V, Bertini E, et al.: X-linked neurodegenerative syndrome with congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration, linked to Xp22.33-pter. Am J Med Genet 64:69, 1996. 84. Mazzone D, Milana A, Carpinato C: Branchio-oculo-facial syndrome. Report of a new case with agenesis of cerebellar vermis. Eur J Pediatr 151:312, 1992. 85. de Lonlay, Seta N, Barrot S, et al.: A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. J Med Genet 38:14, 2001. 86. Turnpenny P, Ashworth M, Harding B, et al.: Hydrocephalus, severe hypoplasia, and brain stem calcification—a new autosomal recessive syndrome. Eur J Hum Genet 4:132A, 1996. 87. Charrow J, Poznanski AK, Unger FM, et al.: Autosomal recessive cerebellar hypoplasia and endosteal sclerosis: a newly recognized syndrome. Am J Med Genet 41:464, 1991. 88. Goh WHS, Lo R: A new 3C syndrome: cerebellar hypoplasia, cavernous haemangioma and coarctation of the aorta. Dev Med Child Neurol 35:637, 1993. 89. Hong SE, Shugart YY, Shahwan S, et al.: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26:93, 2000. 90. Delague V, Bareil C, Bouvagnet P, et al.: Nonprogressive autosomal recessive ataxia maps to chromosome 9q34-9qter in a large consanguineous Lebanese family. Ann Neurol 50:250, 2001. 91. Kvistad PH, Dahl A, Skre H: Autosomal recessive non-progressive ataxia with an early childhood debut. Acta Neurol Scand 71:295, 1985. 92. Lopez-Hemandez A: Craniostenosis, ataxia, trigeminal anaesthesia and parietal alopecia with pons-vermis fusion anomaly (atresia of the fourth ventricle): report of two cases. Neuropediatrics 13:99, 1982. 93. Herva R, von Wendt L, von Wendt G, et al.: A syndrome with juvenile cataract, cerebellar atrophy, mental retardation and myopathy. Neuropediatrics 18:164, 1987. 94. Guion-Almeda ML, Kokitsu-Nakata NM, Richieri-Costa A: Clinical variability in cerebro-oculo-nasal syndrome: report on two additional cases. Clin Dysmorphol 9:253, 2000. 95. Piantanida M, Tiberti A, Plebani A, et al.: Cerebro-renal-digital syndrome in two sibs. Am J Med Genet 47:420, 1993. 96. Lin AE, Siebert JR, Graham JM Jr: Central nervous system malformations in the CHARGE association. Am J Med Genet 37:304, 1990. 97. Nivelon A, Nivelon JL, Mabille JP, et al.: New autosomal recessive chondrodysplasia-pseudohermaphoditism syndrome. Clin Dysmorphol 1:221, 1992. 98. Ciske DJ, Waggoner DJ, Dowton SB: Unique cardiac and cerebral anomalies with chondrodysplasia punctata. Am J Med Genet 75:59, 1998. 99. Schinzel A: Catalogue of Unbalanced Aberrations in Man, ed 2. Walter de Gruyter, Berlin, 2001. 100. POSSUM1, Version 5.6. The Murdoch Institute Royal Children’s Hospital, Melbourne, Australia. 101. Squires LA, Raymond G, Neumeyer AM, et al.: Dysmorphic features of Joubert syndrome. Dysmorphol Clin Genet 5:72, 1991. 102. Verloes A, Lambotte C: Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. Am J Med Genet 32:227, 1989.

674

Neuromuscular Systems

103. Kajtar P, Mehes K: Bilateral Coats retinopathy associated with aplastic anaemia and mild dyskeratotic signs. Am J Med Genet 49:374, 1994. 104. Pavone P, Parano E, Polizzi A, et al.: Colobomatous microphthalmia, microcephaly with cerebellar hypoplasia: association or new syndrome. Am J Med Genet 92:278, 2000. 105. Pieh C, Goebel HH, Engle EC, et al.: Congenital fibrosis syndrome associated with central nervous system abnormalities. Graefes Arch Clin Exp Ophthalmol 241:546, 2003. 106. Mauceri L, Ruggieri M, Pavone V, et al.: Craniofacial anomalies, severe cerebellar hypoplasia, psychomotor and growth delay in a child with congenital hypothyroidism. Clin Dysmorphol 6:375, 1997. 107. Arancio O, Bongiouvanni LG, Bonadonna G, et al.: Congenital muscular dystrophy and cerebellar vermis agenesis in two brothers. Ital J Neurol Sci 9:483, 1988. 108. Richardson P, Schulenburg WE: Bilateral congenital mydriasis. Br J Ophthalmol 76:632, 1996. 109. Crome L, Duckett S, Franklin AW: Congenital cataracts, renal tubular necrosis and encephalopathy in two sisters. Arch Dis Child 38:505, 1953. 110. Curatolo P, Cilio MR, Del Giudice E, et al.: Familial white matter hypoplasia, agenesis of the corpus callosum, mental retardation and growth deficiency: a new distinctive syndrome. Neuropediatrics 24:77, 1993. 111. Fryns JP, De Cock P, Van den Berghe H: Occipital scalp defect associated with valvular pulmonary stenosis. A new entity? Clin Genet 42:97, 1992. 112. Ceballos R, Ch’ien LT, Whitly RJ, et al.: Cerebellar hypoplasia in an infant with congenital cytomegalic infection. Pediatrics 57:155, 1976. 113. Hiyasat D, Dehyyat MA, Ajlouni S, et al.: Cerebellar hypoplasia, hypergonadotrophic hypogonadism, retinitis pigmentosa, alopecia, microcephaly, psychomotor retardation, and short stature: ‘‘D-CHRAMPS syndrome’’. Eur J Pediatr 161:170, 2002. 114. Pfeiffer RA, Kapferer L: Sensorineural deafness, hypospadias and synostosis of metacarpals and metatarsals 4 and 5: a previously apparently undescribed MCA/MR syndrome. Am J Med Genet 31:5, 1988. 115. Ozkinay F, Cogulu O, Gunduz C, et al.: A case of Brachmann-de Lange syndrome with cerebellar vermis hypoplasia. Clin Dysmorphol 7:303, 1998. 116. Pai GS, Morgan S, Whetsell C: Etiologic heterogeneity in dyskeratosis congenita. Am J Med Genet 32:63, 1989. 117. Stromme P, Stokke O, Jellum E, et al.: Atypical methylmalonic aciduria with progressive encephalopathy, microcephaly and cataract in two siblings - a new recessive syndrome? Clin Genet 48:1, 1995. 118. Egger J, Bellman MH, Ross EM, et al.: Joubert-Bolthauser syndrome with polydactyly in siblings. J Neurol Neurosurg Psychiatry 45:737, 1982. 119. Faivre L, Delezoide A-L, Narcy F, et al.: A new lethal syndrome of exomphalos, short limbs, and macrogonadism. J Med Genet 36:131, 1999. 120. Mizuno Y, Kurokawa T, Numaguchi Y, et al.: Facial hemangiomata with cerebrovascular anomalies and cerebellar hypoplasia. Brain Dev 4:375, 1982. 121. Fernhoff PN, Blackston RD, Oakley GP: Intrauterine growth failure, abnormal facial appearance. Synd Ident VI(1):10, 1980. 122. Mostofsky SH, Mazzocco MMM, Aakalu G, et al.: Decreased cerebellar posterior vermis size in fragile X syndrome—correlation with neurocognitive performance. Neurology 50:121, 1998. 123. Francois J, Eggermont E, Evens L, et al.: Agenesis of the corpus callosum in the median facial cleft syndrome and associated ocular malformations. Am J Ophthalmol 76:241, 1973. 124. Toriello HV, Radecki LL, Sharda J, et al.: Frontonasal ‘‘dysplasia,’’ cerebral anomalies and polydactyly: report of a new syndrome and discussion from a developmental field perspective. Am J Med Genet (Suppl) 2:89, 1986. 125. Arnold SR, Debich-Spicer DD, Opitz JM, et al.: Documentation of anomalies not previously described in Fryns syndrome. Am J Med Genet 116A:179, 2003. 126. Guion-Almeida ML, Richieri-Costa A: CNS midline anomalies in the Opitz G/BBB syndrome: report on 12 Brazilian patients. Am J Med Genet 43:918, 1992.

127. Gentile M, Di Carlo A, Susca F, et al.: COACH syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia, and mental retardation. Am J Med Genet 64:514, 1996. 128. Coppola G, Vajro P, De Virgiliis S, et al.: Cerebellar vermis defect, oligophrenia, congenital ataxia, and hepatic fibrocirrhosis without coloboma and renal abnormalities: report of three cases. Neuropediatrics 33:180, 2002. 129. Wittig EO, Moseira CA, Freire-Maia N, et al.: Partial aniridia, cerebellar ataxia and mental deficiency (Gillespie syndrome) in two brothers. Am J Med Genet 30:703, 1988. 130. Colombo I, Finocchiaro G, Garavaglia B, et al.: Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaric acidemia type II. Hum Mol Genet 3:429, 1994. 131. Silengo M, Ferrero GB, Tornetta L: Pachygyria and cerebellar hypoplasia in a patient with a 2q22-q33 deletion that includes the ZFHX1 gene. Am J Med Genet 127A:109, 2004. 132. Herrick MK, Strefling AM, Urich H: Intrauterine multisystem atrophy in siblings: a new genetic syndrome? Acta Neuropathol 61:65, 1983. 133. Hingorani SR, Pagon RA, Shepard TH, et al.: Twin fetuses with abnormalities that overlap with three midline malformation complexes. Am J Med Genet 41:230, 1991. 134. Appleton RE, Chitayat D, Jan JE, et al.: Joubert’s syndrome associated with congenital ocular fibrosis and histidinemia. Arch Neurol 46:579, 1989. 135. Hockey A, Crowhurst J, Cullity G: Microcephaly, holoprosencephaly, hypokinesia-a second report of a new syndrome. Prenat Diagn 8:683, 1988. 136. Lo B, Faiyez-Ul-Haque M, Banwell B, et al.: The locus responsible for horizontal gaze palsy/progressive scoliosis and brainstem hypoplasia is refined to a 9-cM region on chromosome 11q23. Clin Genet 65:137, 2004. 137. Sznajer Y, Baumann C, David A, et al.: Further delineation of the congenital form of X-linked dyskeratosis congenita (HoyeraalHreidersson syndrome). Eur J Pediatr 162:863, 2003. 138. Schurig V, Van Orman A, Bowen P: Nonprogressive cerebellar disorder with mental retardation and autosomal recessive inheritance in Hutterites. Am J Med Genet 9:43, 1981. 139. Kunze J, Huber-Schumacher S, Vogel M: VACTERL plus hydrocephalus: a monogenic lethal condition. Eur J Pediatr 151:467, 1992. 140. Benke PJ: The isotretinoin teratogen syndrome. JAMA 251:3267, 1984. 141. Jespers A, Buntinx I, Melis K, et al.: Two siblings with midline field defects and Hirschsprung disease: variable expression of Toriello-Carey or new syndrome? Am J Med Genet 47:299, 1993. 142. Maria B, Boltshauser E, Palmer SC, et al.: Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol 14:583, 1999. 143. Keeler LC, Marsh SE, Leeflang EP, et al.: Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am J Hum Genet 73:656, 2003. 144. Hsu HC, Lin GS, Li WM: Keratitis, ichthyosis, and deafness (KID) syndrome with cerebellar hypoplasia. Int J Dermatol 27:695, 1988. 145. Ivarsson S-A, Bjierre I, Brun A, et al.: Joubert syndrome associated with Leber amaurosis and multicystic kidneys. Am J Med Genet 45:542, 1993. 146. Hurst JA, Hallam LA, Hockey KA: Leptomeningeal angiomatosis, absent olfactory tracts, hypoplasia of the cerebellar vermis, cleft lip and palate and congenital heart disease in a stillborn infant. Clin Dysmorphol 1:168, 1992. 147. Rutledge JC, Friedman JM, Harrod MJE, et al.: A ‘‘new’’ lethal multiple congenital anomaly syndrome: joint contractures, cerebellar hypoplasia, renal hypoplasia, urogenital anomalies, tongue cysts, shortness of limbs, eye abnormalities, defects of the heart, gallbladder agenesis, and ear malformations. Am J Med Genet 19:255, 1984. 148. El Khazen N, Faverly D, Vamos E, et al.: Lethal osteopetrosis with multiple fractures in utero. Am J Med Genet 23:811, 1986.

Brain 149. L’Hermitte MMJ, de Ajuriaguerra J, Trotot RP: Oxycephalie avec age´ne´sie de la commissure calleuse et du vermis inferieur. Rev Neurol 76:146, 1944. 150. Kerner B, Graham Jr JJ, Golden JA, et al.: Familial lissencephaly with cleft palate and severe cerebellar hypoplasia. Am J Med Genet 87:440, 1999. 151. Chen J, Yang SS, Gonzalez E, et al.: Short rib-polydactyly syndrome, Majewski type. Am J Med Genet 7:215, 1980. 152. Garcı´a-Alix A, Blanco D, Caban˜as F, et al.: Early neurological manifestations and brain anomalies in Marden-Walker syndrome. Am J Med Genet 44:41, 1992. 153. Williams TE, Buchhalter JR, Sussman MD: Cerebellar dysplasia and unilateral cataract in Marinesco-Sjogren syndrome. Pediatr Neurol 14:158, 1996. 154. Summers DA, Cooper HA, Butler MG: Marshall-Smith syndrome: case report of a newborn male and review of the literature. Clin Dysmorphol 8:207, 1999. 155. Fraser FC, Lytwyn A: Spectrum of anomalies in the Meckel syndrome, or ‘‘Maybe there is a malformation syndrome with at least a constant anomaly.’’ Am J Med Genet 9:67, 1981. 156. Me´garbane´ A, Ruchoux MM, Loeys B, et al.: Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome. Am J Med Genet 104:221, 2001. 157. Stoll C, Talon P, Alembik Y, et al.: Hypoplasie ce´re´belleuse conge´nitale avec le´sions osseuses. Ann Pediatr 33:417, 1986. 158. Paine RS: Evaluation of familial biochemically determined mental retardation in children, with special reference to aminoaciduria. N Engl J Med 262:658, 1960. 159. Slee J, Lam G, Walpole I: Syndrome of microcephaly, microphthalmia, cataracts, and intracranial calcification. Am J Med Genet 84:330, 1999. 160. Horn D, Mu¨ller D, Thiele H, et al.: Extreme microcephaly, severe growth and mental retardation, flexion contractures, and ichthyotic skin in two brothers: a new syndrome or mild form of Neu-Laxova syndrome? Clin Dysmorphol 6:323, 1997. 161. Harbord MG, Finn JP, Hall-Craggs MA, et al.: Moebius’ syndrome with unilateral cerebellar hypoplasia. J Med Genet 26:579, 1989. 162. Mubashir MA, Sabry MA, Farah S, et al.: New syndromic entity of situs inversus totalis. Clin Dysmorphol 8:23, 1999. 163. Muller F-M, Barth GM, Menger H, et al.: Cerebral malformation, seizures, hypertrichosis, distinct face, claw hands, and overlapping fingers in sibs of both sexes. Am J Med Genet 47:698, 1993. 164. Zaglul HF, Odita JC: Multiple herniae: a defect in the celomic mesoderm? Am J Med Genet 57:537, 1995. 165. Spearritt DJ, Tannenberg AEG, Payton DJ: Lethal multiple pterygium syndrome: report of a case with neurological anomalies. Am J Med Genet 47:45, 1993. 166. Zervos A, Hunt KE, Tong HQ, et al.: Clinical, genetic and histopathological findings in two siblings with muscle-eye-brain disease. Eur J Ophthalmol 12:253, 2002. 167. Saunier S, Morin G, Calado J, et al.: Large deletions of the NPH1 region in Cogan syndrome (CS) associated with familial juvenile nephronophthisis (NPH). Am J Hum Genet 61:A346, 1997. 168. Hoveyda N, Shield JPH, Garrett C, et al.: Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J Med Genet 36:700, 1999. 169. Shiihara T, Kato M, Kimura T, et al.: Microcephaly, cerebellar atrophy, and focal segmental glomerulosclerosis in two brothers: a possible mild form of Galloway-Mowat syndrome. J Child Neurol 18:147, 2003. 170. Tolmie JL, Mortimer G, Doyle D, et al.: The Neu-Laxova syndrome in female sibs: clinical and pathological features with prenatal diagnosis in the second sib. Am J Med Genet 27:175, 1987. 171. Barth PG, Uylings HBM, Stam FC: Interhemispherical neuroepithelial (glio-ependymal) cysts, associated with agenesis of the corpus callosum and neocortical maldevelopment. Child Brain 11:312, 1984. 172. Tuysuz B, Zeybek C, Zorer G, et al.: Patient with the mesomelic dysplasia, Nievergelt syndrome, and cerebellovermian agenesis and cataracts. Am J Med Genet 109:206, 2002.

675 173. Dobyns WB: Agenesis of the corpus callosum and gyral malformations are frequent manifestations of non-ketotic hyperglycinemia. Neurology 39:817, 1989. 174. Whitsel EA, Castillo M, D’Cruz O: Cerebellar vermis and midbrain dysgenesis in oculomotor apraxia: MR findings. Am J Neuroradiol 16:831, 1995. 175. Hunter AGW, Jurenka S, Thompson D, et al.: Absence of cerebellar granular layer, mental retardation, tapetoretinal degeneration and progressive glomerulopathy: an oculo-renal-cerebellar syndrome. Am J Med Genet 11:383, 1982. 176. Young ID, McKeever PA, Squier MV, et al.: Lethal olivopontoneocerebellar hypoplasia with dysmorphic features in sibs. J Med Genet 29:733, 1992. 177. Wang P-J, Maeda Y, Izumi T, et al.: An association of subtotal cerebellar agenesis with organoid nevus—a possible new variety of neurocutaneous syndrome. Brain Dev 5:503, 1983. 178. Smith RA, Gardner-Medwin D: Orofaciodigital syndrome type III in two sibs. J Med Genet 30:870, 1993. 179. al-Gazali LI, Bakalinova D, Bakir M: Central nervous system malformations, dense bones and facial dysmorphism: a new autosomal recessive syndrome. Clin Dysmorphol 7:123, 1998. 180. Lehman RAN, Stears JC, Wesenberg RL, et al.: Familial osteosclerosis with abnormalities of the nervous system and meninges. J Pediatr 90:49, 1977. 181. Stratton RF, Bluestone DL: Oto-palatal-digital syndrome type II with Xlinked cerebellar hypoplasia/hydrocephalus. Am J Med Genet 41:169, 1991. 182. Mitchel TN, Free SL, Williamson KA, et al.: Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol 53:658, 2003. 183. Erdl R, Schmidtke K, Jakobeit M, et al.: Pena-Shokeir phenotype with major CNS malformations: clinicopathological report of two siblings. Clin Genet 36:127, 1989. 184. Valmaggia C, Gottlab I: Periodic alternating nystagmus in two children with similar, unusual phenotype. Pediatr Neurol 23:432, 2000. 185. Dobyns WB, Guerrini R, Czapansky-Beilman DK, et al.: Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: a new X-linked mental retardation syndrome. Neurology 49:1042, 1997. 186. Gottschalk ME, Coker SB, Fox LA: Neurologic anomalies of Perrault syndrome. Am J Med Genet 65:274, 1996. 187. Pfeiffer RA, Stoss H, Voight HJ, et al.: Absence of fibula and ulna with oligodactyly, contractures, right-angle bowing of femora, abnormal facial morphology, cleft lip/palate and brain malformation in two sibs: a possibly new lethal syndrome. Am J Med Genet 29:901, 1988. 188. Orrico A, Galli L, Zappella M, et al.: Possible case of Pitt-Hopkins syndrome in sibs. Am J Med Genet 103:157, 2001. 189. Bonnemann CG, Meinecke P: Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 63:428, 1996. 190. Llewellyn DH, Smyth SJ, Elder GH, et al.: Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene. Hum Genet 89:97, 1992. 191. Nova HR: Familial communicating hydrocephalus, posterior cerebellar agenesis, mega cisterna magna, and port wine nevi. J Neurosurg 51:862, 1979. 192. Knoblauch H, Tennstedt C, Brueck W, et al.: Two brothers with findings resembling congenital intrauterine infection—like syndrome (pseudo-TORCH syndrome). Am J Med Genet 120A:261, 2003. 193. Towik A, Torp S, Kase BF, et al.: Infantile Refsum’s disease: a generalized peroxisomal disorder. Case report with postmortem examination. J Neurol Sci 85:39, 1988. 194. Pfeiffer RA, Palm D, Junemann G, et al.: Nosology of congenital nonprogressive cerebellar ataxia. Neuropediatrics 5:91, 1974. 195. Mainzer F, Saldino RM, Ozonoff MB, et al.: Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med 49:556, 1970.

676

Neuromuscular Systems

196. Seller MJ, Pal K, Moscoso G, et al.: Cerebellar hypoplasia, facial dysmorphism and internal abnormalities: a new recessive syndrome? Clin Dysmorphol 7:41, 1998. 197. Siber M: X-linked recessive microencephaly, microphthalmia with corneal opacities, spastic quadriplegia, hypospadias and cryptorchidism. Clin Genet 26:453, 1984. 198. Debrus S, Sauer U, Gilgenkrantz S, et al.: Autosomal recessive lateralization and midline defects: blastogenesis recessive 1. Am J Med Genet 68:401, 1997. 199. Slee J, Knowles S, Goldblatt J: Siblings with a syndrome of hydrocephalus with patent aqueduct, growth retardation and associated anomalies. Clin Dysmorphol 8:11, 1999. 200. Kelley RI: RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. Am J Hum Genet 63:322, 1998. 201. Natacci F, Corrado L, Pierri M, et al.: Patient with large 17p11.2 deletion presenting with Smith-Magenis syndrome and Joubert syndrome phenotype. Am J Med Genet 95:467, 2000. 202. Ciske DJ, Waggoner DJ, Dowton SB: Unique cardiac and cerebral anomalies with chondrodysplasia punctata. Am J Med Genet 75:59, 1998. 203. Stoll C, Huber C, Alembik Y, et al.: Dandy-Walker variant malformation, spastic paraplegia, and mental retardation in two sibs. Am J Med Genet 37:124, 1990. 204. Barkovich AJ, Peacock W: Sublobar dysplasia: a new malformation of cortical development. Neurology 50:1383, 1998. 205. Schorderet DF, Addor M-C, Maeder Ph, et al.: Two brothers with atypical syndactylies, cerebellar atrophy and severe mental retardation. Genet Couns 13:441, 2002. 206. Tsukahara M, Uchida M, Shinohara T: Teebi hypertelorism syndrome: further observations. Am J Med Genet 59:59, 1995. 207. van der Harten HJ, Brons JTJ, Dijkstra PF, et al.: Some variants of lethal neonatal short-limbed platyspondylic dysplasia: a radiological, ultrasonographic, neuropathological, and histopathological study of 22 cases. Clin Dysmorphol 2:1, 1993. 208. MacDonald MR, Schaefer GB, Olney AH, et al.: Hypoplasia of the cerebellar vermis and corpus callosum in thrombocytopenia with absent radius syndrome on MRI studies. Am J Med Genet 50:46, 1994. 209. Khabbaze Y, Karayalcin G, Paley C, et al.: Thrombocytopenia absent corpus callosum syndrome: third case of a distinct clinical entity. J Pediatr Hematol Oncol 23:469, 2001. 210. Cutler EA, Bass J, Romshe CA, et al.: A familial thyrocerebral-renal syndrome: a newly recognized disorder. Birth Defects Orig Artic Ser XIV(6B):265, 1978. 211. Silengo M, Pietragalla A, Jarre L: Trichorrhexis nodosa and lip pits in autosomal dominant ectodermal dysplasia—central nervous system malformation syndrome. Am J Med Genet 71:226, 1997. 212. Troost D, van Rossum A, Pires JV, et al.: Cerebral calcifications and cerebellar hypoplasia in two children: clinical, radiologic and neuropathological studies-a separate neurodevelopmental entity. Neuropediatrics 15:102, 1984. 213. Zampino G, Colosimo C, Balducci F, et al.: Cerebro-facio-articular syndrome of Van Maldergem: confirmation of a new MR/MCA syndrome. Clin Genet 45:140, 1994. 214. Van Staey M, De Bie S, Craen M, et al.: Craniofacial anomalies, hearing deficit and psychomotor retardation: components in still another undescribed syndrome? Zaragoza, 1st European Meeting of Dysmorphology, 1990, p 85. 215. Doss BJ, Jolly S, Quresh