MANAGEMENT OF GENETIC
SYNDROMES

Second Edition
MANAGEMENT OF GENETIC
SYNDROMES
Second Edition

Edited by



SUZANNE B. CASSIDY, M.D.
Department of Pediatrics
Division of...
Copyright  2005 by John Wiley & Sons, Inc., Hoboken, New Jersey. All rights reserved.

Published by John Wiley & Sons, In...
CONTENTS




FOREWORD TO THE SECOND EDITION                        ix

FOREWORD TO THE FIRST EDITION                      ...
vi    CONTENTS


12 Coffin-Lowry Syndrome                                                                   127
   Alasdair...
CONTENTS   vii

35 Pallister-Hall and Greig Cephalopolysyndactyly Syndromes                421
   Leslie G. Biesecker
36 P...
FOREWORD TO THE SECOND EDITION




It was not very many years ago that the coupling of the terms           development, an...
x     FOREWORD TO THE SECOND EDITION

be quite flexible. Nevertheless, someone must be responsible for       required to pr...
FOREWORD TO THE FIRST EDITION




This is a book whose time has come. Genetic disorders                     What every fam...
xii    FOREWORD TO THE FIRST EDITION

groups will continue to play an important role in improving             development,...
PREFACE




This book is designed to assist primary care physicians, medical      “personal experience” or “personal obser...
CONTRIBUTORS




Deborah M. Alcorn, M.D., Department of Ophthalmology,             Debra L. Collins, M.S., CGC, Department...
xvi    CONTRIBUTORS

Theresa A. Grebe, M.D., Phoenix Genetics Program, Univer-          Kerry Kingham, M.S., Department of...
CONTRIBUTORS         xvii

R. Neil Schimke, M.D., FACP, FACMG, Departments of              Roger E. Stevenson, M.D., Green...
MANAGEMENT OF GENETIC SYNDROMES
MANAGEMENT OF GENETIC SYNDROMES
MANAGEMENT OF GENETIC SYNDROMES
MANAGEMENT OF GENETIC SYNDROMES
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MANAGEMENT OF GENETIC SYNDROMES

  1. 1. MANAGEMENT OF GENETIC SYNDROMES Second Edition
  2. 2. MANAGEMENT OF GENETIC SYNDROMES Second Edition Edited by SUZANNE B. CASSIDY, M.D. Department of Pediatrics Division of Human Genetics University of California, Irvine Orange, California JUDITH E. ALLANSON, M.D. Department of Pediatrics University of Ottawa Children’s Hospital of Eastern Ontario Ottawa, Canada A JOHN WILEY & SONS, INC., PUBLICATION
  3. 3. Copyright  2005 by John Wiley & Sons, Inc., Hoboken, New Jersey. All rights reserved. Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada. 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, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400, fax 978-646-8600, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. For general information on our other products and services please contact our Customer Care Department within the U.S. at 877-762-2974, outside the U.S. at 317-572-3993 or fax 317-572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print, however, may not be available in electronic format. Library of Congress Cataloging-in-Publication Data Management of genetic syndromes / edited by Suzanne B. Cassidy, Judith E. Allanson.—2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 0-471-30870-6 (cloth : alk. paper) 1. Genetic disorders. [DNLM: 1. Genetic Diseases, Inborn—diagnosis. 2. Abnormalities, Multiple—diagnosis. 3. Abnormalities, Multiple—therapy. 4. Genetic Diseases, Inborn—therapy. QZ 50 M2655 2005] I. Cassidy, Suzanne B. II. Allanson, Judith E. RB155.5.M36 2005 616 .042—dc22 Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1
  4. 4. CONTENTS FOREWORD TO THE SECOND EDITION ix FOREWORD TO THE FIRST EDITION xi PREFACE xiii 1 Introduction 1 Suzanne B. Cassidy and Judith E. Allanson 2 Aarskog Syndrome 7 Roger E. Stevenson 3 Achondroplasia 13 Richard M. Pauli 4 Alagille Syndrome 31 Binita M. Kamath and Ian D. Krantz 5 Albinism and Hermansky-Pudlak Syndrome 41 Richard A. King and C. Gail Summers 6 Angelman Syndrome 53 Charles A. Williams 7 Arthrogryposis 63 Judith G. Hall 8 ATR-X 77 Richard J. Gibbons 9 Bardet-Biedl Syndrome 87 Anne M. Slavotinek 10 Beckwith-Wiedemann Syndrome and Hemihyperplasia 101 Rosanna Weksberg and Cheryl Shuman 11 CHARGE Association 117 Christine A. Oley v
  5. 5. vi CONTENTS 12 Coffin-Lowry Syndrome 127 Alasdair G. W. Hunter 13 Cornelia de Lange Syndrome 139 David R. Fitzpatrick and Antonie D. Kline 14 Costello Syndrome 151 Angela E. Lin, Karen W. Gripp, and Bronwyn Kerr 15 Craniosynostosis Syndromes 163 Karen W. Gripp and Elaine H. Zackai 16 Deletion 22q13 Syndrome (Phelan-McDermid Syndrome) 171 Mary C. Phelan, Gail A. Stapleton and R. Curtis Rogers 17 Denys-Drash and Frasier Syndromes 183 Carol L. Clericuzio 18 Down Syndrome 191 Alasdair G.W. Hunter 19 Ehlers-Danlos Syndromes 211 Richard J. Wenstrup and Leah B. Hoechstetter 20 Fetal Alcohol Syndrome and Fetal Alcohol Spectrum Disorder 225 Albert E. Chudley and Sally E. Longstaffe 21 Fetal Anticonvulsant Syndrome 239 Renata C. Gallagher, Kerry Kingham and H. Eugene Hoyme 22 Fragile X Syndrome 251 Randi J. Hagerman 23 Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome) 265 Peter Farndon 24 Hereditary Hemorrhagic Telangiectasia 279 Mary E. M. Porteous and Jonathan N. Berg 25 Holoprosencephaly 291 Andrea L. Gropman and Maximilian Muenke 26 Incontinentia Pigmenti 309 Dian Donnai 27 Kabuki Syndrome 315 Louanne Hudgins 28 Klinefelter Syndrome 323 Joe Leigh Simpson, John M. Graham, Jr., Carole Samango-Sprouse, and Ronald Swerdloff 29 Marfan Syndrome 335 Iris Schrijver, Deborah M. Alcorn, and Uta Francke 30 Myotonic Dystrophy Type 1 351 Christine E. M. De Die-Smulders, Frans G. I. Jennekens, and Chris J. H¨ weler o 31 Neurofibromatosis Type 1 369 David Viskochil 32 Noonan Syndrome 385 Judith E. Allanson 33 Oculo-Auriculo-Vertebral Spectrum 399 Robert J. Gorlin 34 Osteogenesis Imperfecta 407 Joan C. Marini, Anne D. Letocha, and Edith J. Chernoff
  6. 6. CONTENTS vii 35 Pallister-Hall and Greig Cephalopolysyndactyly Syndromes 421 Leslie G. Biesecker 36 Prader-Willi Syndrome 429 Suzanne B. Cassidy and Shawn E. McCandless 37 Proteus Syndrome 449 Leslie G. Biesecker 38 Rett Syndrome 457 Eric E. Smeets and Connie T. R. M. Schrander-Stumpel 39 Robin Sequence 469 Robert J. Shprintzen 40 Rubinstein-Taybi Syndrome 479 Raoul C. M. Hennekam 41 Russell-Silver Syndrome 489 Howard M. Saal 42 Smith-Lemli-Opitz Syndrome 497 Christopher Cunniff and Theresa A. Grebe 43 Smith-Magenis Syndrome 507 Ann C. M. Smith and Andrea Gropman 44 Sotos Syndrome 527 Trevor R. P. Cole 45 Stickler Syndrome 539 Clair Francomano, Douglas J. Wilkin, and Ruth M. Liberfarb 46 Treacher Collins Syndrome 547 Marilyn C. Jones 47 Trisomy 18 and Trisomy 13 Syndromes 555 John C. Carey 48 Tuberous Sclerosis 569 John R. W. Yates 49 Turner Syndrome 589 Virginia P. Sybert 50 VATER Association 607 Bryan D. Hall 51 Velo-Cardio-Facial Syndrome 615 Robert J. Shprintzen 52 Von Hippel–Lindau Syndrome 633 R. Neil Schimke and Debra L. Collins 53 WAGR Syndrome 645 Carol L. Clericuzio 54 Williams Syndrome 655 Colleen A. Morris 55 Wolf-Hirschhorn (4p-) Syndrome 667 Agatino Battaglia INDEX 677
  7. 7. FOREWORD TO THE SECOND EDITION It was not very many years ago that the coupling of the terms development, and an overall improvement in the quality of life, management and genetic syndromes would have been regarded both physically and socially. as an oxymoron. With the exception of the inborn errors of In addition to the attitudinal shift, there have been many metabolism, the notion of managing genetic disorders would medical and scientific advances that have altered our approach have been considered quite foreign and of managing genetic to genetic syndromes. The mutations that cause many of the syndromes, by which we mean conditions in which several organ monogenic or contiguous gene syndromes are now known, systems and/or parts of the body are affected, even more so. and more are being discovered almost daily. The functions The principal role of the medical geneticist was to diagnose of the genes that these mutations affect are gradually being these conditions as best he or she could. Management, such elucidated. For the aneuploidies, the mapping of the human as it was, was essentially symptomatic and was usually left genome is providing information about how many and which to primary care physicians and medical specialists with little genes are at dosage imbalance. All of this has changed genetic direct knowledge of the syndromes themselves. The literature on syndromes from being curiosities that could not be understood genetic syndromes reflected this situation. It was, for the most to disorders that can be rationally approached in terms of part, descriptive, and the emphasis was on diagnosis. Although cause and potential therapy, another and quite major change many admirable reference books on diagnosis were written, in attitude. This information has also led to the development most notable of which was (and still is), Smith’s Recognizable of molecularly based tests that are greatly improving disease Patterns of Human Malformations, it was frequently difficult to diagnosis and are permitting discrimination among conditions find definitive information about how to manage these conditions that had hitherto been confused with one another. In the future, once the diagnoses had been made. this genetic information promises to lead to therapies that are But much has changed recently with regard to genetic tailored to individual diseases. In addition, medical diagnostic syndromes, with perhaps the most important change being procedures and therapeutic approaches have become much more societal, not medical or scientific. It is now generally accepted powerful. These include, for example, the various forms of that persons with genetic syndromes, whether associated with imaging, surgical techniques such as for complex congenital mental retardation or not, should, if possible, be treated. This heart defects or ambiguous genitalia, and highly specific and was not always so, and a graphic example of how thinking potent pharmacologic agents. And, finally, more is continually has altered is provided by Down syndrome, certainly one of being learned about the long-term consequences of genetic the quintessential genetic syndromes. Within my professional syndromes—about their natural histories—which is essential if lifetime there has been a shift from exclusion from society, comprehensive approaches to management are to be developed. generally by institutionalization, to rearing at home, educational So, if societal attitudes have changed and genetic and inclusion, and participation in all aspects of daily life. Similarly, medical information and capabilities are rapidly expanding, a policy of nonintervention, often with certain death, when who should be undertaking the management of persons with major heart or gastrointestinal abnormalities were present has genetic syndromes? Who should be reading this book? There been replaced by aggressive surgical correction. Guidelines for is no simple answer to this question since in a sense each the prevention of known complications have been developed, syndrome must be dealt with on its own merits. Given the and their implementation is now commonplace. As a result, multitude of systems that these syndromes may affect and the these changes have led, even without any specific therapy for different combinations of abnormalities that may occur in one Down syndrome, to an increase in life span, better cognitive as compared to another, the approach to management needs to ix
  8. 8. x FOREWORD TO THE SECOND EDITION be quite flexible. Nevertheless, someone must be responsible for required to properly care for the affected individual and his the overall coordination of care. Who this will be will depend on or her family, and it is here that this volume, Management of local circumstances, but the important thing is that it be someone Genetic Syndromes, uniquely fills a void that has long existed in who is knowledgeable and willing to act in the interests of the the literature on genetic syndromes. Gathered together within affected individual. a reasonably compact volume are authoritative descriptions In most instances, persons with genetic syndromes are written for a diverse readership of the management of over 50 usually managed by a mix of genetic professionals, primary of the most common conditions that fall within the rubric of care physicians, and medical and other specialists. By “genetic genetic syndromes (including two that are primarily teratogenic professional” I mean medical geneticists, genetic counselors but are usually grouped with the others). The concept of what is and genetic nurses, and laboratory geneticists who have entailed in management is broadly interpreted. Therefore, each special knowledge about and experience in dealing with a chapter begins with considerations of etiology, pathogenesis, large number of genetic syndromes that are individually quite genetics, and diagnosis (including diagnostic criteria, testing, uncommon or rare. For the most part, genetic professionals have and differential diagnosis), all of which are necessary if the traditionally been engaged in the diagnosis and counseling of affected person and his or her condition are to be fully these conditions. Unlike the situation with inherited metabolic understood. These are then followed by detailed discussions of disorders, in which geneticists do participate directly in therapy, what might be considered to be at the heart of management—the their involvement in the therapeutic aspects of the management evaluation of each of the relevant systems and the treatment of genetic syndromes has generally involved referrals to of the abnormalities that are likely to be present. The appropriate specialists for specific forms of medical or surgical chapter concludes with selected references and a listing of therapy. Primary care physicians, in addition to providing day- available support groups and other resources. The evaluation and to-day care of individuals with genetic syndromes, often act treatment sections are greatly enhanced by the use of an outline as intermediaries in the referral process. And, beyond this list form of presentation, with bullets to highlight individual points. of medical personnel are a variety of other professionals and When it appeared in 2001, the first edition of this book was social and educational organizations, both governmental and eagerly seized upon by the medical genetics community. The voluntary, that also provide many services to affected individuals need was there, and there was nothing else like it. From my and their families. own personal experience and observation in a genetics service In some instances, the medical specialists, genetic profession- that handles a large number of persons with genetic syndromes, als, and allied health professionals work together in multidisci- I can testify that the book rapidly proved to be of great plinary clinics devoted to individual disorders (such as Marfan value to all of the clinic personnel—geneticists and counselors, or Down syndrome) or groups of related disorders (craniofacial physicians and nonphysicians, students, residents, and fellows. anomalies or skeletal dysplasias) or perhaps even to birth defects The rapid appearance of this second edition indicates that my more generally. These clinics provide a coordinated approach to own experience has been more generally shared, and the near management that is usually more efficient from the point of view doubling of the number of conditions covered will make the of providers and of affected individuals and their families than book even more valuable than before. Given the rapid progress is possible when many independent providers are involved in that is being made in genetics and medicine and in the ability to the care of the patient and may be a model for the provision of diagnose and treat genetic syndromes, it is likely that frequent services in the future. revisions will be required. Regardless of how the services are organized and of who is actually coordinating management, many providers with Charles J. Epstein different degrees of knowledge about any particular condition are likely to be involved. It is therefore essential that each Department of Pediatrics understand what he or she is dealing with and what will be University of California, San Francisco
  9. 9. FOREWORD TO THE FIRST EDITION This is a book whose time has come. Genetic disorders What every family and physician wants is to provide the and syndromes are usually thought of as being rare, and best care possible for the affected individual. Nobody wants yet for affected individuals, their families, and their primary to miss the opportunity for that individual to reach his or her and specialty care physicians, it is essential to have reliable full potential, to benefit from a useful therapy, or to avoid a information about the natural history and management of the complication. Parents need an understanding of what will happen specific disorders. over time so that they can plan. They don’t want to waste money The thirty conditions described in this book may seem rare and effort going from expert to expert or doing test after test. (with incidences between 1 in 600 and 1 in 60,000). However, They need a realistic approach to what they should expect both when you put together all the individual cases of a particular in childhood and adulthood. They also usually want to know condition in North America, in Europe, and in the world, a whether there is some risk of recurrence of the condition in their very large number of affected individuals will benefit from the other children, in other family members, and in the affected information in this book. In the past it has been difficult to bring individual’s offspring. They want to know whether prenatal together information of this type about specific disorders, and diagnosis is available, and they want to know the spectrum of that is why this book fills a very important niche. It becomes variation that can occur. The beauty of this new book is that it a model for how to organize information that is needed for the provides that kind of information for each specific disorder in a families and primary care providers to manage the many, many logical and understandable form. Most families and physicians other genetic disorders, congenital anomalies, and syndromes will focus in on the chapter relevant to a specific individual. that are known to occur. The book is written in understandable However, they can’t help but glance at other chapters and see language appropriate for families and for primary care and the remarkable spectrum of complications that are not present specialty physicians. It is a major contribution. in the disorder of interest to them. They are likely to benefit Over the last two decades, remarkable progress has been from this broader perspective. made with regard to developing diagnostic tests and unraveling Most pediatricians will have heard of all thirty disorders; the human genome. Within the next few years all of the however, some primary care and specialty physicians may not human genes will have been defined. The next major goal have heard of a specific disorder until they have the affected in genetics will be to understand how genes interact and individual in their practice. The book should help to alert health function, both in the course of development and over a lifetime. care professionals to consider these conditions and should lead In addition to the remarkable progress in basic and clinical to appropriate testing to make a correct diagnosis, reducing the genetics, there has been increasing communication and access time it takes to make a specific diagnosis. Two-thirds of the to information. Through the Internet, the public has access to conditions in this book have a specific diagnostic test, but the research reports and data that were usually not readily available other one-third require “pattern recognition” and an alert, trained in the past. However, it is essential to put that information into health care professional to consider the diagnosis. a meaningful form and context. That is exactly what this book It can be expected that additional advances will be made does. The communication explosion has allowed the networking over the next few decades leading to better understanding and of researchers and families. The development of parent/lay better management. So this book is already dated! There is still support groups has led to a cooperation between researchers a lot to be learned! In fact, every family and every affected and families that has helped to define the natural history and the individual will contribute to that increased knowledge by giving variation that can be seen in a specific disorder. feedback to the authors. Disorder-specific parent/lay support xi
  10. 10. xii FOREWORD TO THE FIRST EDITION groups will continue to play an important role in improving development, and on social skills. However, information on our understanding. The authors of each chapter have worked adults is also beginning to accumulate and has been included in together with the support groups and are very aware that it is the this book. In some conditions there is a stable situation, in others process of working together with these groups and the members’ there is improvement with aging, and in still others deterioration willingness to provide information that has led to present-day can be expected. For many of the conditions described in this understanding. We are all very grateful to each of the parents book, behavioral patterns have been recognized. and affected individuals who have taken part in studies that have How should a family and their primary care physician use advanced our knowledge. the experts? It would be impossible for the authors of these To write a book about management, it is necessary to know chapters to see every individual with the condition, but it is the natural history of the disorder. The authors of each of these usually helpful for a family and the affected individual to see a chapters have a wealth of experience and knowledge that has clinical geneticist, to visit a developmental center, or to use the been collected over the last couple of decades. Understanding multidisciplinary team that is available in their area. Over the the natural history not only tells us what to expect at various ages years, specialty clinics to deal with specific conditions have been but also how to recognize various complications. It is important developed. At some time it is probably appropriate to visit such to understand the natural history of the condition to determine a clinic at least once to review the affected individual’s progress whether various therapies actually improve the outcome. It and to consider any special complications or responses. On the is important to understand the natural history to recognize other hand, it is very important to have a knowledgeable primary subgroups representing the variability and heterogeneity within care physician who cares for day-to-day medical needs and is the disorder. It is important to understand the natural history to aware of the unique complications of the condition. learn the mechanisms that lead to the disorder, e.g., what sort of The parent/lay support groups form an international network gene is likely to be involved? Where is the mutation in the gene? keeping up with new information on the specific disorders, How does that mutation relate to severity of complications? and new information is sure to come. Some new information How big is the deletion? Does that size relate to severity of will come through organized studies of natural history; other complications? How does this gene act against the background data will come through clinical trials of new therapies; and of other genes or pathways? Is it possible to recognize a cellular further information will come from basic work on cellular mechanism leading to this disorder? Are there parent-of-origin mechanisms and biochemical pathways. For many of these effects on the expression of the gene or the mutation rate? Are disorders animal models will be developed, such as mice there hot spots that have markedly increased mutation rates? with the specific disorder, so that various therapies can be Does the place on the chromosome where the gene lies put it considered before trials in human beings. We live in a very at increased risk for mutation? These are only a few of the exciting age and can anticipate major advances over the next questions we hope to answer over the next few decades. few decades for each of the disorders described in this book. No one is more motivated than the family or the affected The international network of families, affected individuals, individual to learn about these disorders. It is important for and researchers should and will communicate about new them to be as knowledgeable as possible. The families of an ideas, innovative approaches, and better understanding about affected person usually know more about the condition than these conditions. most of the physicians they visit. It is important for families to We have begun to enter an era of evidence-based medicine. continue to ask questions and to gain as much knowledge as Only by having natural history information is it possible to possible to ensure the best outcome for the affected individual. understand the benefits of new interventions and therapies. It is important for families and affected individuals to keep their We will hope that this book is outdated very rapidly because own records about the affected individual, such as a notebook of such new developments, but in the meanwhile this book of their visits to health care facilities, copies of the reports, and on management of common genetic syndromes is extremely the results of the tests that have been done. It is also important welcome to families and health care providers alike. to keep a photographic record of changes over time. Once a family or an affected individual becomes involved in collecting information about the disorder, they often develop quite creative ideas that challenge the standard way of thinking JUDITH G. HALL about the disorder. Part of the advantage of participating Professor and Head, Department of Pediatrics in a support group is that those ideas then can be shared University of British Columbia and with the medical advisors and researchers and may lead to British Columbia Children’s Hospital new knowledge. Professor, Medical Genetics Much of our understanding of these disorders is based on James and Annabelle McCreary Professor the manifestations in childhood, on feeding, on growth and University of British Columbia
  11. 11. PREFACE This book is designed to assist primary care physicians, medical “personal experience” or “personal observation” has been noted, specialists, other care providers, and families in assuring optimal to reflect non-peer-reviewed information. care for individuals who have the multiple problems represented Deciding upon which disorders to include is no mean task, by genetic syndromes. It reflects the combined experience and there are some disorders for which there is little accumulated and knowledge of many experts in medical genetics and experience in management. There are numerous disorders that related fields, each of whom has spent years participating in are included in this second edition that were not in the first the diagnosis and clinical management of a specific genetic edition. Others will be included in future editions as new syndrome. Most of the chapter authors have conducted major experience accumulates. In addition to more than 50 genetic clinical research on “their” disorder. (or probably genetic) conditions, 2 teratogenic disorders, fetal The syndromes selected for inclusion in this book are those alcohol syndrome and fetal anticonvulsant syndrome, are also that are sufficiently common as to be regularly encountered included because of their frequency and because genetic factors in clinics specializing in genetics, development, neurology, or influence susceptibility. craniofacial disorders. Many of these disorders will not have The editors hope that this continues to be a useful text been seen in the practice of most primary care physicians to primary care physicians, medical geneticists, and other or nongenetics specialists. When they are encountered, the medical specialists, educators, and other providers of care physician typically has little knowledge of how to confirm for the individuals and families affected with these common the diagnosis, identify the associated problems and clinical genetic syndromes. Like those with more frequent medical manifestations, and optimally care for the affected individual. conditions, they deserve the best possible medical, educational, This lack of knowledge is due only partly to infrequent exposure and psychological care. to the disorder. For many of these conditions, very little We are extremely grateful to Terri-Lyn Mason for her many has been published concerning management, and a search for long hours of manuscript preparation. We are appreciative to such knowledge is extremely time consuming, often provides two editors from Wiley-Liss, Collette Bean for giving us the incomplete information, and is frequently futile. This book was opportunity to compile this book and Luna Han for her assistance designed to provide that knowledge, based on the cumulative in editing. Most importantly, we thank the contributors and the experience of an expert or experts on each condition. As a many affected individuals for their willingness to have their result, a significant proportion of the information found in this photographs published in this book and for their participation in source will be personal experience or observation. In most cases, the clinical research that provided the information for its content. there is no established “standard of care” based on controlled trials or outcome studies. Nonetheless, the editors have sought to provide the reader with information that is as reliable as Suzanne B. Cassidy possible. Where available, reference to published sources has been included: Where unavailable, reference to the author(s) Judith E. Allanson xiii
  12. 12. CONTRIBUTORS Deborah M. Alcorn, M.D., Department of Ophthalmology, Debra L. Collins, M.S., CGC, Department of Medicine, Stanford University Medical Center, Stanford, California Kansas University School of Medicine, Kansas City, Kansas Judith E. Allanson, MB ChB, FRCP, FRCP(C), FCCMG, Christopher Cunniff, M.D., Section of Medical and Molecular DABMG, Department of Pediatrics, University of Ottawa, Genetics, University of Arizona, College of Medicine, and Department of Genetics, Children’s Hospital of Eastern Tucson, Arizona Ontario, Ottawa, Canada Christine E. M. de-Die Smulders, M.D., Ph.D., Department of Agatino Battaglia, M.D., Stella Maris Clinical Research Insti- Clinical Genetics, Academic Hospital Maastricht, Maastricht, tute for Child and Adolescent Neurology and Psychiatry, The Netherlands Pisa, Italy Dian Donnai, FRCP, FRCPCH, FRCOG, FmedSci, Depart- Jonathan N. Berg, M.D., Department of Clinical Genetics, ment of Medical Genetics, University of Manchester, Division of Pathology and Neuroscience, Ninewells Hospital Manchester, United Kingdom and Medical School, Dundee, United Kingdom Peter Farndon, M.D., Clinical Genetics Unit, Birmingham Leslie G. Biesecker, M.D., Genetic Diseases Research Branch, Women’s Hospital, Birmingham, United Kingdom National Human Genome Research Institute, National Insti- tutes of Health, Bethesda, Maryland David R. FitzPatrick, M.D., MRCP, Medical Research Coun- cil Human Genetics Unit, Edinburgh, United Kingdom John C. Carey, M.D., Department of Pediatrics, Division of Medical Genetics, University of Utah, Health Sciences Uta Francke, M.D., Departments of Genetics and Pediatrics, Center, Salt Lake City, Utah Stanford University School of Medicine, Stanford, California Suzanne B. Cassidy, M.D., Department of Pediatrics, Divi- Clair Francomano, M.D., National Institute on Aging, sion of Human Genetics, University of California, Irvine, National Institutes of Health, Bethesda, Maryland Orange, California Renata C. Gallagher, M.D., Ph.D., Department of Pediatrics, Edith J. Chernoff, M.D., Department of Chronic Disease, La Division of Medical Genetics, Stanford University School of Rabida Children’s Hospital, and Department of Pediatrics, Medicine, Stanford, California University of Chicago, Chicago, Illinois Richard J. Gibbons, M.A., D. Phil., FRCP, The Medical Albert E. Chudley, M.D., FRCPC, FCCMG, Section of Research Council Molecular Haematology Unit, Weatherall Genetics and Metabolism, Children’s Hospital, and Depart- Institute of Molecular Medicine, University of Oxford, ments of Pediatrics, Child Health, Biochemistry, and Medical Oxford, United Kingdom Genetics, University of Manitoba, Manitoba, Canada Robert J. Gorlin, M.S., D.D.S. D.Sc. (Hon), Department of Carol L. Clericuzio, M.D., Department of Pediatrics, Division Oral Pathology and Genetics, University of Minnesota School of Dysmorphology and Clinical Genetics, University of New of Dentistry, Minneapolis, Minnesota Mexico School of Medicine, Albuquerque, New Mexico John M. Graham Jr., M.D., Sc.D., Department of Pediatrics, Trevor R. P. Cole, M.D., Clinical Genetics Unit, Birmingham University of California Los Angeles, Cedars Sinai Medical Women’s Hospital, Birmingham, United Kingdom Center, Los Angeles, California xv
  13. 13. xvi CONTRIBUTORS Theresa A. Grebe, M.D., Phoenix Genetics Program, Univer- Kerry Kingham, M.S., Department of Pediatrics, Division sity of Arizona, Phoenix, Arizona of Medical Genetics and California Teratogen Information Karen W. Gripp, M.D., Department of Pediatrics, Jefferson Service, Stanford University School of Medicine, Stan- Medical College, Thomas Jefferson University, Philadelphia, ford, California Pennsylvania, and Division of Medical Genetics, A. I. Antonie D. Kline, M.D., Harvey Institute for Human Genetics, DuPont Hospital for Children, Wilmington, Delaware Baltimore, Maryland Andrea L. Gropman, M.D., FAAP, FACMG, Medical Genet- Ian D. Krantz, M.D., Division of Human Genetics and ics Branch, National Human Genome Research Institute, Molecular Biology, The Children’s Hospital of Philadelphia National Institutes of Health, Bethesda, Maryland and The University of Pennsylvania School of Medicine, Randi J. Hagerman, M.D., Medical Investigation of Neurode- Philadelphia, Pennsylvania velopmental Disorders (M.I.N.D.) Institute, University of Anne D. Letocha, M.S.N., C.R.N.P., Heritable Disorders California Davis Health System, Sacramento, California Branch, National Institute of Child Health and Human Devel- Bryan D. Hall, M.D., Division of Genetics/Dysmorphology, opment, National Institutes of Health, Bethesda, Maryland Chandler Medical Center, Lexington, Kentucky Ruth M. Liberfarb, M.D., Ph.D., Medical Genetics Branch, Judith G. Hall, M.D., Department of Pediatrics, University National Human Genome Research Institute, National Insti- of British Columbia and British Columbia’s Children’s tutes of Health, Bethesda, Maryland Hospital, Vancouver, Canada Angela E. Lin, M.D., Genetics and Teratology Unit, Pedi- Raoul C. M. Hennekam, M.D., Ph.D., Department of Pedi- atric Service, Massachusetts General Hospital, Boston, Mas- atrics and Institute of Human Genetics, University of Ams- sachusetts terdam, Academic Medical Center, Amsterdam, The Nether- lands Sally E. Longstaffe, M.D., FRCPC, Child Development Clinic, Children’s Hospital, and Department of Pediatrics and Leah B. Hoechstetter, M.S., CGC, Division of Human Genet- Child Health, University of Manitoba, Manitoba, Canada ics, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio Joan C. Marini, M.D., Ph.D., Heritable Disorders Branch, National Institute of Child Health and Human Development, Chris J. H¨ weler, M.D., Department of Neurology, Academic o National Institutes of Health, Bethesda, Maryland Hospital Maastricht, Maastricht, The Netherlands Shawn E. McCandless, M.D., Departments of Genetics and H. Eugene Hoyme, M.D., Department of Pediatrics, Divi- Pediatrics, Case Western Reserve University and University sion of Medical Genetics and California Teratogen Infor- Hospitals of Cleveland, Cleveland, Ohio mation Service, Stanford University School of Medicine, Stanford, California Colleen A. Morris, M.D., M.S., FACMG, FAAP, Department of Pediatrics—Division of Genetics, University of Nevada Louanne Hudgins, M.D., Department of Pediatrics, Division of School of Medicine, Las Vegas, Nevada Medical Genetics, Stanford University School of Medicine, Stanford, California Maximilian Muenke, M.D., Medical Genetics Branch, Na- Alasdair G. W. Hunter, M.Sc., M.D., CM, FCCMG, FRCP tional Human Genome Research Institute, National Institutes (C), Department of Pediatrics, University of Ottawa, and of Health, Bethesda, Maryland Children’s Hospital of Eastern Ontario, Ottawa, Canada Christine A. Oley, MBBS, FRACP, FRCPH, West Midlands Frans G. I. Jennekens, M.D., Department of Neurology, Regional Genetics Service, Birmingham Women’s Hospital, University of Utrecht, Utrecht, The Netherlands Birmingham, United Kingdom Marilyn C. Jones, M.D., Department of Pediatrics, Uni- Richard M. Pauli, M.D., Ph.D., Clinical Genetics Center, versity of California, San Diego, and Cleft Palate and University of Wisconsin, Madison, Wisconsin Craniofacial Treatment Programs, Children’s Hospital, San Mary C. Phelan, Ph.D., Genetic Diagnostic Laboratory, T. C. Diego, California Thompson Children’s Hospital, Chattanooga, Tennessee Binita M. Kamath, M.D., Division of Gastroenterology and Mary E. M. Porteous, M.Sc., M.D., MRCP, South East Nutrition, The Children’s Hospital of Philadelphia, Philadel- Scotland Genetic Service, Edinburgh, United Kingdom phia, Pennsylvania R. Curtis Rogers, M.D., Greenwood Genetic Center, Green- Bronwyn Kerr, MBBS, FRACP, FRCPCH, Regional Genetic wood, South Carolina Service, Central Manchester and Manchester Children’s Hos- pitals University NHS Trust, Manchester, United Kingdom Howard M. Saal, M.D., Division of Human Genetics, Cincin- nati Children’s Hospital Medical Center, Cincinnati, Ohio Richard A. King, M.D., Ph.D., Institute of Human Genetics and Genetics Division, Department of Medicine, University Carole Samango-Sprouse, Ph.D., Department of Pediatrics, of Minnesota, Minneapolis, Minnesota George Washington University, Washington, D.C.
  14. 14. CONTRIBUTORS xvii R. Neil Schimke, M.D., FACP, FACMG, Departments of Roger E. Stevenson, M.D., Greenwood Genetic Center, Green- Medicine and Pediatrics, Kansas University School of wood, South Carolina Medicine, Kansas City, Kansas C. Gail Summers, M.D., Departments of Ophthalmology and Connie T. R. M. Schrander-Stumpel, M.D., Ph.D., Depart- Pediatrics, University of Minnesota, Minneapolis, Minnesota ment of Clinical Genetics, Academic Hospital Maastricht, Ronald Swerdloff, M.D., Department of Endocrinology and Maastricht, The Netherlands, and Research Institute Metabolism, University of California Los Angeles, Research Growth and Development (GROW), Maastricht University, and Education Institute, Torrance, California Maastricht, The Netherlands Virginia P. Sybert, M.D., Division of Medical Genetics, Iris Schrijver, M.D., Department of Pathology, Stanford Uni- Department of Medicine, University of Washington, Seat- versity School of Medicine, Stanford, California tle, Washington Robert J. Shprintzen, Ph.D., State University of New York David Viskochil, M.D., Ph.D., Department of Pediatrics, Upstate Medical University, Syracuse, New York Division of Medical Genetics, University of Utah, Salt Lake Cheryl Shuman, M.S., CGC, Division of Clinical and City, Utah Metabolic Genetics, The Hospital for Sick Children, and Rosanna Weksberg, M.D., Ph.D., FRCPC, FACMG, Division Department of Medical Genetics and Microbiology, Univer- of Clinical and Metabolic Genetics, The Hospital for Sick sity of Toronto, Ontario, Canada Children, and Department of Paediatrics, University of Joe Leigh Simpson, M.D., Departments of Obstetrics, Gyne- Toronto, Ontario, Canada cology, and Molecular and Human Genetics, Baylor College Richard J. Wenstrup, M.D., Division of Human Genetics, of Medicine, Houston, Texas Cincinnati Children’s Hospital Research Foundation, Cincin- Anne M. Slavotinek, MBBS, Division of Genetics, Department nati, Ohio of Pediatrics, University of California, San Francisco, San Douglas J. Wilkin, Ph.D., Medical Genetics Branch, National Francisco, California Human Genome Research Institute, National Institutes of Eric E. Smeets, M.D., Department of Clinical Genetics, Health, Bethesda, Maryland Academic Hospital Maastricht, Maastricht, The Netherlands, Charles A. Williams, M.D., Departments of Pediatrics and and Department of Human Genetics, University Hospital Genetics, University of Florida College of Medicine, Gasthuisberg, Leuven, Belgium Gainsville, Florida Ann C. M. Smith, M.A., D.Sc. (Hon.), CGC, Smith-Magenis John R. W. Yates, M.D., Department of Medical Genetics, Syndrome Research Unit, Medical Genetics Branch, National University of Cambridge, Cambridge, United Kingdom Human Genetics Research Institute, National Institutes of Elaine H. Zackai, M.D., Department of Pediatrics, University Health, Bethesda, Maryland of Pennsylvania School of Medicine, and Clinical Genetics Gail A. Stapleton, M.S., Greenwood Genetic Center, Green- Center, Children’s Hospital of Philadelphia, Philadelphia, wood, South Carolina Pennsylvania

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