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

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

297

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

Mexico South America

Australia England/Wales

USA (Atlanta) Ireland (Dublin)

England/Wales

N. Netherlands France

Mexico England/Wales

USA (Atlanta) France

England/Wales South America

Ireland (Dublin) USA (Atlanta)

England/Wales Spain

Neural Tube Defects

;

3.3

Cardiac Defects 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

:

Transposition of great vessels

5.4

4.2

4.2

Truncus arteriosus

0.9

0.6

1.2

Hypoplastic left heart syndrome

3.0

2.5

2.9

Coarctation of aorta

5.1

:

4.0

4.8

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

:

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

1.7

Canada France

South Africa Japan

Hypospadias/Epispadias

;

1.3

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

Sample Size

Major Anomalies (%)

Minor Anomalies (%)

14.7

Marden et al., 1964

USA

4412

2.1

Myrianthopoulos and Chung, 197420

USA

53,257

7.1

Mehes, 198350

Hungary

4589

2.2

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

–

Stoll, 199525

Europe

291,126

2.2

–

Queisser-Luft et al., 200224

Germany

30,940

6.9

35.8

7.26 17.2

*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

Pigmented spots Hypopigmented spots Trunk

Short palpebral fissures

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

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

Mehes, 198350 Hungary

Leppig et al., 198751 USA

0

1.4

1.2

2.3

1

2.9

3.8

3.7

2

10.8

12.5

6.7

90

26


3

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

Acrocallosal

GL13, 7p13, 200990

Type 3

3p13-p12 15q22.3-q23

Acrocapitofemoral dysplasia

IHH, 2q33-q35, 607778

Type 4

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

Barth

Xq28, 302060

Beare-Stevenson cutis gyrata

FGFR2, 10q26, 176943

Aicardi

Xp22, 304050

Alagille

JAG1, 20p12, 118450

Beckwith-Wiedemann

KIP2, 11p15.5, 130650

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

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

Brachydactyly

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 9p21-p12, 250250

Antley-Bixler

PITX3, 10q25, 107250

Cartilage–hair hypoplasia

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

Char

TFAP2B, 6p12, 169100

CHARGE

CHD7, 8q12, 214800

Arthrogryposis multiplex congenita, neurogenic

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

Cleidocranial dysplasia

CBFA1, 6p21, 119600

Coffin-Lowry

RSK2, Xp22.2-p22.1, 303600

Colonic aganglionosis, total, with small bowel involvement

RET, 10q11.2, 164761

Atelosteogenesis II

SLC26A2, 5q32-q33.1, 256050

Atrial septal defect with atrioventricular conduction defects

NKX2E, 5q34, 108900

(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

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

Diastrophic dysplasia

SLC26A2, 5q32-q33.1, 222600

Duane-radial ray

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

G

FANCG, 9p13, 602956

FLJ90130, 18q12-q21.1, 223800

L

2p16.1, 608111

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

DKC1, Xq28, 305000

Dyssegmental dysplasia, Silverman-Handmaker type

HSPG2, 1p36.1, 224410

EEC (Ectrodactyly-ectodermal dysplasia-clefting)

p63, 3q27, 129900

Ectodermal dysplasia, anhidrotic

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

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

Hutchinson-Gilford progeria

LMNA, 1q21.2, 176670

Hydrocephalus due to aqueductal stenosis

L1CAM, Xq28, 307000

Hydrolethalus

11q23-q25, 236680

Ellis-van Creveld

4p16, 225500

Emery-Dreifuss muscular dystrophy

LMNA, 1q21.2, 181350

Epidermolysis bullosa dystrophica, AD

COL7A1, 3p21.3, 131750

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

(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

Microcephaly, autosomal recessive, type 1

MCPH1, 8p23, 251200

Hypodontia

PAX9, 14q12-q13, 106600

Hypodontia with orofacial cleft

MSX1, 4p16.1, 106600

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

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

Langer mesomelic dysplasia

SHOX, Xpter-p22.32, 249700

Mucopolysaccharidosis

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

Kallmann

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

Lowe

Muscle-eye-brain disease

POMGNT1, 1p34-p33, 253280

OCRL, Xq26.1, 309000

Nail-patella

LMX1B, 9q34.1, 161200

Nance-Horan

NHS, Xp22.13, 302350

Lymphedema and ptosis

FOXC2, 16q24.3, 153000

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

Oculodentodigital dysplasia

GJA1, 6q21-q23.2, 164200

MASS

FBN1, 15q21.1, 604308

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

Type I

COL1A1, 17q21.31-q22, 166200

Type II

COL1A1, 17q21.31-q22, 166210

17q22-q23, 249000

Type III

COL1A1, 17q21.31-q22, 259420

Type 2

11q13, 603194

Type IV

COL1A1, 17q21.31-q22, 166220

Type 3

8q24, 607361

Meckel Type 1

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

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

Gene/Locus/OMIM

Sjogren-Larsson

17p11.2, 270200

OPD1, Xq28, 311300

Smith-Fineman-Myers

XNP, Xq13, 309580

Otopalatodigital Type I

Disorder

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

Pallister-Hall

GLI3, 7p13, 146510

Parietal foramina 1

MSX2, 5q34-q35, 168500

Peutz-Jeghers

19p13.3, 175200

Pfeiffer

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

Type II

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)

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

SEMD, Pakistani type (spondyloepimetaphyseal dysplasia)

10q22-q24, 603005

SMD (spondylometaphyseal dysplasia)

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

SMED, Strudwick type (spondyloepimetaphyseal dysplasia)

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

Saethre-Chotzen

Smith-Magenis

17p11.2, 182290

Smith-McCort dysplasia

18q12-q21.1, 607326

Sotos

NSD1, 5q35, 117550

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

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

FBLN1, 22q13.3, 608180

Synpolydactyly, type II

HOXD13, 17q22, 186000

Tarsal-carpal coalition

NOG, 17q22, 186570

Tetralogy of Fallot

JAG1, 20p12, 187500 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

Schwartz-Jampel, type 1

HSPG2, 1p36.1, 255800

Septooptic dysplasia

3p21.2-p21.1, 182230

Type I

8q24.12, 190350

Type III

8q24.12, 190351

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

Ulnar-mammary

TBX3, 12q24.1, 181450

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

Shah-Waardenburg

28

(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

1

Cleft lip/palate

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

8 8 71

Skull

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

41

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

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

Table 1-16. Indications for chromosome analysis Individual with

Features of recognizable chromosomal syndrome

Amyoplasia

Mental retardation of unknown cause

de Lange syndrome

Unexplained major and minor anomalies

Diastrophic dysplasia

Multiple congenital anomalies

Distal arthrogryposis 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

Family Members of 496

From Saul et al. 1998.

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.

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)

Congenital Disorders of N-Glycosylation

Disorders of O-Glycosylation 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

–

Short stature, exostoses

–

DOOR (deafness, onychodystrophy, onycholysis, mental retardation)

Hereditary Multiple Exostoses

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.

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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*

Cardiovascular Malformation

Ventricular septal defect (includes membranous, muscular, unspecified)

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 4.7

Tetralogy of Fallot

3.3

3.8

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

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

0.4

0.3

0.3

NA

6.4

9.7

Tricuspid atresia Other major CVMs

*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

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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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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

179613

Unknown

Unknown

Chromosome Abnormality Recombinant 8 (partial trisomy 8q)

TOF, DORV Truncus

Deletion 17p11.2 (Smith-Magenis)

TOF

NA

Unknown

Unknown

Trisomy 13

VSD conoventricular

NA

Unknown

Unknown

NA

Unknown

Unknown

NA

Unknown

Unknown

TBX1

22q11

JAG1

20p12

DORV, TOF Trisomy 18

VSD conoventricular TOF, DORV

Trisomy 21 Deletion 22q11.2 spectrum

TOF Truncus

DGS 188400

DiGeorge sequence

IAA, type B

VCF 192430

Velocardiofacial syndrome

TOF, TOF/PA, DORV, VSD conoventricular

Autosomal Dominant Alagille

TOF

118450

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

Autosomal recessive

Teratogen Diabetes23

Truncus

NA

NA

NA

Retinoic acid

IAA, type B, TA

NA

NA

NA

Alcohol

TOF

NA

NA

NA

Thalidomide

TOF

NA

NA

NA

dTGA, TOF, DORV

Truncus Maternal phenylketonuria

TOF

NA

NA

NA

Trimethadione

TOF, d-TGA

NA

NA

NA

TOF

164210

Unknown

Unknown

Other Hemifacial microsomia FAVS, OAVD, Goldenhar Ectopia cordis

Heterogeneous TOF

NA

NA

NA

Compiled from Clark,2 Ferencz et al.,4 Burn and Goodship,20 Lofreddo.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

Complete AVC

606217

CRELD1

3q25

Chromosome Abnormality Deletion 3p25 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

Complete AVC, ASD primum

142900

TBX5

12q2

Autosomal Dominant Holt-Oram 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

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 Ellis-van Creveld

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-

103

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

Autosomal Dominant

16

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

LEOPARD/Multiple lentigines

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 29

(Jacobsen syndrome)

COA

Trisomy 13

BAV, HLHS

NA

Unknown

Unknown

Trisomy 18

BAV, COA, HLHS

NA

Unknown

Unknown

Trisomy 21

COA

NA

Unknown

Unknown

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

28

Turner

MS, HLHS Autosomal Dominant Williams26

SVAS

Familial SVAS27

SVAS

Aortic stenosis, valvar Aortic stenosis, valvar Pallister-Hall

BAV

Adams-Oliver24

COA, BAV

MV anomalies 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

4p16.3

Chromosome Abnormality Deletion 4p (Wolf-Hirschhorn)

194190

WHSC1

Deletion 4q

NA

Unknown

Unknown

Trisomy 13

NA

Unknown

Unknown

NA

Unknown

Unknown

Trisomy 21 4

Derivative (22),t(11;22)

NA

Unknown

Unknown

Trisomy 22

NA

Unknown

Unknown

Holt-Oram5

142900

TBX5

12q2

ASD and conduction defect8

108900

NKX2.5

5q34

Autosomal Dominant

7

Noonan

163950

PTPN11

12q24

Kabuki

147920

Unknown

Unknown

Rubinstein-Taybi

180849

CREBBP

16p13

Familial septal defects9

607941

GATA4

8p22-23

Autosomal Recessive Ellis-van Creveld

225500

EVC

4p16

Thrombocytopenia-absent radius (TAR)

274000

Unknown

Unknown

Toriello-Carey

217980

Unknown

Unknown

NA

NA

NA

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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115

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

Rubinstein-Taybi

180849

CREBBP

16p13

Familial septal defects6

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

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

Chromosome Abnormality

Autosomal Dominant

Autosomal Recessive

X-Linked Simpson-Golabi-Behmel Teratogen

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 Causation

Type of Anomalous Venous Connection

MIM #

Gene

Locus

Chromosome Abnormality Cat eye

Total

NA

unknown

22q

Turner

Partial

NA

unknown

X

Partial

142900

TBX5

12q2

Total

270400

DHCR7

11q12

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

Compiled from Burn and Goodship3 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

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

Cytogenetic Aberrations

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

Cytogenetic Abberrations

Genetic Syndromes

Teratogenic Abnormalities

Diabetes22

Various major malformations

Maternal diabetes

Hydantoin15

Broad nasal bridge, short nose, nail hypoplasia

Prenatal exposure to hydantoins

Rubella23

Microcephaly, deafness, cataracts

Prenatal rubella infection

Broad nasal bridge, short nose, meningomyelocele

Prenatal exposure to valproic acid

Valproate

24

(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

Cleft lip, cerebral malformations, polydactyly

Chromosomal

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 syndrome

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

Maternal PKU18

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

Trisomy 133,10 11

Williams syndrome

Single-gene Conditions

3

Teratogenic Abnormalities

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 II

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)

37

(continued)

166

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

Nuchal blebs40,41

Hydrops, short neck

AR (257350)

Oculodentodigital13

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

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)

170

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

13

1

Mediastinum Abdomen/genitalia Total

39

3

1075

100

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

184

Cardiorespiratory Organs

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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Cardiorespiratory Organs

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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Cardiorespiratory Organs

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

Gastrointestinal

36,40,42,44,125,126,130–133

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

125,126

Genital

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

189

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)

Situs ambiguus, polysplenia, bilateral split hand malformation146

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)

24

Dextrocardia

22q11 deletion

Left isomerism sequence24

22q11 deletion

Primary ciliary dyskinesia, situs inversus154,155

45,X/46,X þ mar (80%/20%)

Mirror-image dextrocardia, complete situs inversus, 19 week fetus155

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.

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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

226

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)

Say-Meyer

Trigonocephaly, short stature, developmental delay

Metopic

XLR (314320)

Say-Poznanski11

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

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)

Beta glucuronidase deficiency

dup(6)(q25-qter) del(7)(pter-p15) del(8)(q21-q22)

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) del(12)(pter-p13.1)

Congenital hemolytic icterus 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

Atelencephaly

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)

Trigonocephaly

Agenesis of olfactory bulbs

AR (275600)

Valproic acid embryopathy

Low nasal bridge, midface hypoplasia, long philtrum, meningomyelocele, cleft lip

Prenatal exposure

11

Chromosomal abnormalities -7p deletion

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

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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 mu