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"It is imperative for primary care providers and genetic practitioners to have access to appropriate management guidelines for the diagnosis, genetic counseling and management of individuals of all ages affected by relatively common genetic syndromes. This revision of the critically acclaimed bestseller offers original insights into the medical management of 60 syndromes commonly seen by physicians. This fully revised and expanded Third Edition provides family physicians, internists, specialty physicians, medical geneticists, genetic counselors,
"It is imperative for primary care providers and genetic practitioners to have access to appropriate management guidelines for the diagnosis, genetic counseling and management of individuals of all ages affected by relatively common genetic syndromes. This revision of the critically acclaimed bestseller offers original insights into the medical management of 60 syndromes commonly seen by physicians. This fully revised and expanded Third Edition provides family physicians, internists, specialty physicians, medical geneticists, genetic counselors, and families of patients with a more precise reference for study of physical manuifestations of certain syndromes"--Provided by publisher.
Suzanne B. Cassidy Department of Pediatrics, Division of Human Genetics, University of California, Irvine, Orange, California
Judith E. Allanson Department of Pediatrics, University of Ottawa and Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada
ORGANIZATION OF THIS BOOK
Each chapter of this book is dedicated to the diagnosis and management of a specific syndrome that is encountered with regularity in specialty programs and occasionally in primary care practice. The authors are acknowledged "experts" who have considerable personal experience in the management of the disorder. Each chapter thus contains unpublished information based on that experience and on the author's personal approach to management in addition to a review of published information. Each chapter format is similar, providing general information on incidence and inheritance, pathogenesis and etiology, diagnostic criteria and testing, and differential diagnosis. The myriad manifestations of each syndrome are presented system by system, with emphasis on the features, evaluation, management, and prognosis. The first two "systems" in each chapter are Growth and Feeding and Development and Behavior. After these, the systems relevant to the specific disorder arediscussed, usually in order of importance for that disorder. Every attempt has been made to include whatever is known about the disorder in adulthood. Each chapter concludes with a listing of family support organizations and some resources available to families and professionals in print and electronic formats. Photographs of physical findings important for diagnosis or management are provided. Selected references stressing management issues and citations of good review articles have been included.
This introductory chapter is designed to inform the reader about genetics-related terms used in this book, inheritance patterns, general methods for genetic testing, measurement methods, and the role of the medical geneticist and genetic counselor in the care of genetic disorders. It also provides some important references to additional resources of information about genetic disorders, differential diagnoses, genetic testing, and support organizations.
CATEGORIZATION OF DISORDERS
The descriptive language for patterns of anomalies is somewhat unique to the field of dysmorphology and deserves a brief review. The term syndrome is used to describe a broad error of morphogenesis in which the simultaneous presence of more than one malformation is known or assumed to be the result of a single etiology. Its use implies that the group of malformations and/or physical differences has been seen repeatedly in a fairly consistent and unique pattern. The initial definition of any syndrome occurs after the publication of several similar case reports. It becomes refined over time as newly described individuals suggest the inclusion of additional anomalies and the exclusion of others. Thus a syndrome comes to be defined by the coexistence of a small but variable number of "hallmark" anomalies, whereas several other features may be observed at lower frequencies. Even after a particular syndrome is well established, the inherent variability or rarity can make diagnosis difficult.
In a specific individual, one or more of the hallmark features of a disorder may be absent and yet the person is affected. It is important to stress that not all syndromes are associated with mental retardation. Generally, no one feature or anomaly is pathognomonic of a syndrome, and even experienced dysmorphologists may disagree about diagnosis. Often, the individual clinician will have had little direct experience of the syndrome. In this environment, the addition of objective methods of evaluation may be useful. Available techniques include direct measurement (anthropometry), standard photographs (photogrammetry), and radiologic assessment (cephalometry). Each method has advantages and disadvantages, and each has its proponents (for details, see Allanson, 1997).
The term sequence is used to designate a series of anomalies resulting from a cascade of events initiated by a single malformation, deformation, or disruption (Spranger et al., 1982). A well-known example is the Robin sequence in which the initiating event is micrognathia. The small mandible then precipitates glossoptosis (posterior and upward displacement of the tongue in the pharynx) with resultant incomplete fusion of the palatal shelves. The initiating event may be a malformation of the mandible or a deformation caused by in utero constraint and thus inhibiting normal growth of the mandible. The individual components of a sequence may well involve quite disparate parts of the body. For example, lower limb joint contractures and bilateral equinovarus deformity may be found in a child with a meningomyelocele.
An association is a nonrandom occurrence in two or more individuals of multiple anomalies not known to represent a sequence or syndrome (Spranger et al., 1982). These anomalies are found together more often than expected by chance alone, demonstrating a statistical relationship but not necessarily a known causal one. For example, the CHARGE association represents a simultaneous occurrence of two or more malformations that include congenital coloboma of the iris, choroid, or optic nerve, heart defects, atresia of choanae, mental and somatic retardation, male genital hypoplasia, and ear anomalies or deafness. An association has limited prognostic significance, and the degree of variability may pose diagnostic problems for the clinician. Most affected children will not have all the anomalies described, which makes establishment of minimal diagnostic criteria difficult. Recognition of an association is useful in that it can guide the clinician, after discovery of two or more component malformations, toward a directed search for the additional anomalies. Associations are generally sporadic within a family and have a low empirical recurrence risk. It is most important to remember that associations are diagnoses of exclusion. Any child with multiple anomalies affecting several systems, with or without growth and/or intellectual retardation, should first be assessed to rule out a specific syndrome diagnosis and, lacking such a diagnosis, should have chromosome analysis.
Selected measurements, with comparison to normal standards, may be helpful in confirming the subjective impression of an abnormality. Common craniofacial dimensions, which provide detail about facial shape and size, include head circumference, inner and outer canthal distances, ear length, position, and rotation. Evaluation of stature should include height (length), upper and lower body segment, arm span, hand length, palm length, and foot length. Normal standards for these and a wide variety of other standardized measurements can be found in the Handbook of Normal Physical Measurements (Hall et al., 1989), Growth References: Third Trimester to Adulthood (Saul et al., 1998), and Smith's Recognizable Patterns of Human Malformation (Jones, 1997); however, ethnic background, for which norms may vary, should be taken into consideration. Increasingly, standard curves are being developed for particular syndromes. Many syndrome-specific standards have been compiled (Saul et al., 1998).
The best way to document dysmorphic features is to photograph them. The prudent clinician will often adopt an attitude of "watchful waiting" if the diagnosis is not apparent at the first assessment (Aase, 1990). As children's facial and body features evolve with time, they may "grow into" a syndrome, and photographs provide serial documentation of these changes. There is great value to reassessment of the individual with multiple anomalies whose diagnosis is unclear because there is significant diagnostic yield (Hall et al., 1988). The "art" of dysmorphology is eloquently discussed by Aase (1990). Photographs also facilitate consultations with colleagues and consultants by providing objective evidence of the affected individual's physical findings. They can be compared with examples of other syndromes in photographic databases such as POSSUM and the London Dysmorphology Database (see below).
COMMON GENETIC TERMINOLOGY
With the recent rapid advances in human genetics has come a proliferation of terms with which many practitioners are unfamiliar. Therefore, a summary of the common terms relating to genes and chromosomes and the major inheritance patterns is in order.
Genes are the individual pieces of coding information that we inherit from our parents, the blueprint, as it were, for an organism. It is estimated that 30,000 to 40,000 genes are required to develop and "operate" a human being. Individual genes occur in pairs, one inherited from each parent. The balance of the expression of these genes is extremely delicate, with significant abnormality resulting when this balance is disturbed for some genes. Variant forms of the same gene are known as alleles, and variation can have no apparent phenotypic effect or major consequences, depending on the specific gene and many other factors. When a variant has minimal phenotypic effect, it is often called a polymorphism.
Some syndromes are caused by a permanent structural or sequence change (or mutation) in a single gene. Many gene mutations cause their adverse effects through deficient gene expression (and often subsequent protein deficiency), which is called haploinsufficiency. This is often the case when a mutation in a gene results in failure to produce the gene product, which can be a so-called null mutation or a protein truncation mutation. However, other mutations cause their adverse effects by interfering with a process or causing a new adverse effect, and such mutations are called dominant negative mutations. The latter is often the result when a structurally abnormal protein is formed. Mutation results in alteration of the sequence and/or length of the bases composing the gene code. Such alterations may result in the substitution of one amino acid for another (a missense mutation) in the production of a sequence that does not correspond to the code for an amino acid (a nonsense mutation) or in a code that tells the translation machinery to stop prematurely. An unusual form of mutation that is present in a number of neurogenetic disorders, such as fragile X syndrome, myotonic dystrophy, Huntington disease, and the spinocerebellar ataxias, among others, is the so-called triplet repeat expansion. Some genes contain within them a string of three bases repeated a number of times. For example, CGG is repeated up to 50 times in the normal fragile X gene (CGGCGGCGG ...). Under certain circumstances, this number becomes amplified, resulting in an increase in the number of such repeated triplets of bases. Thus, in individuals who are affected with fragile X syndrome, an X-linked cause of mental retardation, there may be hundreds of such repeated triplets. This triplet repeat expansion interferes with the normal function of the gene, causing abnormality (in this case, mental retardation). In fragile X syndrome, the gene actually becomes inactivated if the expansion exceeds a certain number of repeats. Please see Chapter 22 for a more detailed explanation of this type of mutation.
The nomenclature for genes and gene products (proteins) can be quite confusing, despite the best efforts toward a logical approach. The names of genes are often put in italics, and these may represent an abbreviation of the name of the disorder, the name of the protein, or a function of the protein or the gene. For example, the gene causing neurofibromatosis type 1 is called NF1, and the protein is named neurofibromin, whereas the gene for Angelman syndrome, UBE3A, is named for its protein product, which is one of a family of ubiquitin-protein ligases (enzymes that are part of the protein degradation process). The gene responsible for fragile X syndrome is called FMR1 (fragile X-linked mental retardation 1), and the protein is called FMRP (fragile X-linked mental retardation protein). Information on the genes is included in the chapters for those who are interested, but aside from genetic testing purposes, it is not critical to know the nomenclature to understand and treat the disorder.
Human genes are "packaged" into 46 chromosomes, of which normally 23 chromosomes are transmitted to the offspring in the egg from the mother and 23 in the sperm from the father. One pair of chromosomes, the sex chromosomes, differs between males and females. Females have two copies of the X chromosome, whereas males have one copy, the second sex chromosome being the Y chromosome with a largely different set of genes. The remaining 22 pairs, the autosomes, do not differ between males and females. The autosomes are numbered in a standard way from largest to smallest. The location of a specific gene on a chromosome is called the locus (the plural is loci). Some of the syndromes described in this book are caused by the presence of an entire extra chromosome (e.g., Down syndrome, Klinefelter syndrome) or duplication of a segment of a chromosome (e.g., some cases of Beckwith-Wiedemann syndrome). Others occur because of loss of all (e.g., Turner syndrome) or part (e.g., some cases of Prader-Willi syndrome) of a chromosome.
PATTERNS OF INHERITANCE
An alteration in a gene can be dominant or recessive. A dominant gene mutation only needs to be present in one member of the gene pair to have a clinically evident impact. Any individual with an autosomal dominant gene mutation will have a 1 in 2 chance to pass it on to his or her child, male or female, with each pregnancy. An example is achondroplasia. In achondroplasia, the affected child frequently has two average-stature parents, indicating that the mutation occurred in the egg or sperm that was involved in the conception. This is referred to as a new mutation or a de novo mutation. Rarely, an apparently normal couple will have more than one child with the same apparently new mutation in an autosomal dominant gene. This suggests that the mutation is present in some of the cells of the germ line (gonads) but not in most other cells of the body of one parent. This is known as germ line (or gonadal) mosaicism.
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1 Introduction Suzanne B. Cassidy Cassidy, Suzanne B. Judith E. Allanson Allanson, Judith E. 1
2 Aarskog Syndrome Roger E. Stevenson Stevenson, Roger E. 9
3 Achondroplasia Richard M. Pauli Pauli, Richard M. 17
4 Alagille Syndrome Binita M. Kamath Kamath, Binita M. Ian D. Krantz Krantz, Ian D. 39
5 Albinism: Ocular and Oculocutaneous Albinism and Hermansky-Pudlak Syndrome Richard A. King King, Richard A. C. Gail Summers Summers, C. Gail 53
6 Angelman Syndrome Charles A. Williams Williams, Charles A. Aditi Dagli Dagli, Aditi 69
7 Arthrogryposis Judith G. Hall Hall, Judith G. 81
8 ATR-X: [alpha]-Thalassemia Mental Retardation-X-Linked Richard J. Gibbons Gibbons, Richard J. 97
9 Bardet-Biedl Syndrome Anne M. Slavotinek Slavotinek, Anne M. 111
10 Beckwith-Wiedemann Syndrome and Hemihyperplasia Rosanna Weksberg Weksberg, Rosanna Cheryl Shuman Shuman, Cheryl Bruce Beckwith Beckwith, Bruce 129
11 Cardio-Facio-Cutaneous Syndrome Maria Ines Kavamura Kavamura, Maria Ines Giovanni Neri Neri, Giovanni 149
12 CHARGE Syndrome Christine A. Oley Oley, Christine A. 157
13 Coffin-Lowry Syndrome Alasdair G. W. Hunter Hunter, Alasdair G. W. 169
14 Cohen Syndrome Kate Chandler Chandler, Kate Jill Clayton-Smith Clayton-Smith, Jill 183
15 Cornelia de Lange Syndrome David R. Fitzpatrick Fitzpatrick, David R. Antonie D. Kline Kline, Antonie D. 195
16 Costello Syndrome Bronwyn Kerr Kerr, Bronwyn Karen W. Gripp Gripp, Karen W. Angela E. Lin Lin, Angela E. 211
17 Craniosynostosis Syndromes Karen W. Gripp Gripp, Karen W. Elaine H. Zackai Zackai, Elaine H. 227
18 Deletion 1p36 Syndrome Agatino Battaglia Battaglia, Agatino 239
19 Deletion 4p:Wolf-Hirschhorn Syndrome Agatino Battaglia Battaglia, Agatino 249
20 Deletion 22q11.2 (Velo-Cardio-Facial Syndrome/DiGeorge Syndrome) Donna M. McDonald-McGinn McDonald-McGinn, Donna M. Taisa Kohut Kohut, Taisa Elaine H. Zackai Zackai, Elaine H. 263
21 Deletion 22ql3 Syndrome: Phelan-McDermid Syndrome Mary C. Phelan Phelan, Mary C. Gail A. Stapleton Stapleton, Gail A. R. Curtis Rogers Rogers, R. Curtis 285
22 Denys-Drash and Frasier Syndromes Carol L. Clericuzio Clericuzio, Carol L. 299
23 Down Syndrome Alasdair G. W. Hunter Hunter, Alasdair G. W. 309
24 Ehlers-Danlos Syndromes Brad T. Tinkle Tinkle, Brad T. Carrie L. Atzinger Atzinger, Carrie L. 337
25 Fetal Alcohol Syndrome and Fetal Alcohol Spectrum Disorder Albert E. Chudley Chudley, Albert E. Sally E. Longstaffe Longstaffe, Sally E. 363
26 Fetal Anticonvulsant Syndrome H. Eugene Hoyme Hoyme, H. Eugene Renata C. Gallagher Gallagher, Renata C. Kerry Kingham Kingham, Kerry 381
27 Fragile X Syndrome and Premutation-Associated Disorders Randi J. Hagerman Hagerman, Randi J. 397
28 Gorlin Syndrome: Nevoid Basal Cell Carcinoma Syndrome Peter Farndon Farndon, Peter 413
29 Hereditary Hemorrhagic Telangiectasia Mary E. M. Porteous Porteous, Mary E. M. Jonathan N. Berg Berg, Jonathan N. 429
30 Holoprosencephaly Andrea L. Gropman Gropman, Andrea L. Maximilian Muenke Muenke, Maximilian 441
31 Incontinentia Pigmenti Dian Donnai Donnai, Dian 461
32 Kabuki Syndrome Sarah Dugan Dugan, Sarah Louanne Hudgins Hudgins, Louanne 469
33 Klinefelter Syndrome Jeannie Visootsak Visootsak, Jeannie John M. Graham Graham, John M. Carole Samango-Sprouse Samango-Sprouse, Carole Ronald Swerdloff Swerdloff, Ronald Joe Leigh Simpson Simpson, Joe Leigh 479
34 Marfan Syndrome Uta Francke Francke, Uta 495
35 Mowat-Wilson Syndrome David Mowat Mowat, David Meredith Wilson Wilson, Meredith 517
36 Myotonic Dystrophy Type 1 Christine E. M. de Die-Smulders de Die-Smulders, Christine E. M. Frans G. I. Jennekens Jennekens, Frans G. I. Carin G. Faber Faber, Carin G. 529
37 Neurofibromatosis Type 1 David Viskochil Viskochil, David 549
38 Noonan Syndrome Judith E. Allanson Allanson, Judith E. 569
39 Oculo-Auriculo-Vertebral Spectrum Koenraad Devriendt Devriendt, Koenraad Luc de Smet de Smet, Luc Ingele Casteels Casteels, Ingele 587
40 Osteogenesis Imperfecta Joan C. Marini Marini, Joan C. 597
41 Pallister-Hall Syndrome and Greig Cephalopolysyndactyly Syndrome Leslie G. Biesecker Biesecker, Leslie G. 615
42 Prader-Willi Syndrome Suzanne B. Cassidy Cassidy, Suzanne B. Shawn E. McCandless McCandless, Shawn E. 625
43 Proteus Syndrome Leslie G. Biesecker Biesecker, Leslie G. 651
44 PTEN Hamartoma Tumor Syndrome Emily Edelman Edelman, Emily Charis Eng Eng, Charis 661
45 Rett Syndrome Eric E. Smeets Smeets, Eric E. Connie T. R. M. Schrander-Stumpel Schrander-Stumpel, Connie T. R. M. 677
46 Robin Sequence Howard M. Saal Saal, Howard M. 693
47 Rubinstein-Taybi Syndrome Raoul C. M. Hennekam Hennekam, Raoul C. M. 705
48 Russell-Silver Syndrome Howard M. Saal Saal, Howard M. 717
49 Smith-Lemli-Opitz Syndrome Christopher Cunniff Cunniff, Christopher 727
50 Smith-Magenis Syndrome Ann C. M. Smith Smith, Ann C. M. Andrea Gropman Gropman, Andrea 739
51 Sotos Syndrome Trevor R. P. Cole Cole, Trevor R. P. 769
52 Stickler Syndrome Clair A. Francomano Francomano, Clair A. 787
53 Treacher Collins Syndrome and Related Disorders Marilyn C. Jones Jones, Marilyn C. 797
54 Trisomy 18 and Trisomy 13 Syndromes John C. Carey Carey, John C. 807
55 Tuberous Sclerosis Complex Hope Northrup Northrup, Hope Michael J. Gambello Gambello, Michael J. Kit Sing Au Au, Kit Sing Mary Kay Koenig Koenig, Mary Kay 825
56 Turner Syndrome Marsha L. Davenport Davenport, Marsha L. 847
57 Vater/Vacterl Association Bryan D. Hall Hall, Bryan D. 871
58 von Hippel-Lindau Syndrome R. Neil Schimke Schimke, R. Neil Debra L. Collins Collins, Debra L. 881
59 WAGR Syndrome Carol L. Clericuzio Clericuzio, Carol L. 897
60 Williams Syndrome Colleen A. Morris Morris, Colleen A. 909