Management of Genetic Syndromes

By Suzanne B. Cassidy and Judith E. Allanson

The bestselling guide to the medical management of common genetic syndromes —now fully revised and expanded

A review in the American Journal of Medical Genetics heralded the first edition of Management of Genetic Syndromes as an "unparalleled collection of knowledge." Since publication of the first edition, improvements in the molecular diagnostic testing of genetic conditions have greatly facilitated the identification of affected individuals. This thorough revision of the critically acclaimed bestseller offers original insights into the medical management of sixty common genetic syndromes seen in children and adults, and incorporates new research findings and the latest advances in diagnosis and treatment of these disorders.

Expanded to cover five new syndromes, this comprehensive new edition also features updates of chapters from the previous editions. Each chapter is written by an expert with extensive direct professional experience with that disorder and incorporates thoroughly updated material on new genetic findings, consensus diagnostic criteria, and management strategies. Edited by two of the field's most highly esteemed experts, this landmark volume provides:

• A precise reference of the physical manifestations of common genetic syndromes, clearly written for professionals and families

• Extensive updates, particularly in sections on diagnostic criteria and diagnostic testing, pathogenesis, and management

• A tried-and-tested, user-friendly format, with each chapter including information on incidence, etiology and pathogenesis, diagnostic criteria and testing, and differential diagnosis

• Up-to-date and well-written summaries of the manifestations followed by comprehensive management guidelines, with specific advice on evaluation and treatment for each system affected, including references to original studies and reviews

• A list of family support organizations and resources for professionals and families

Management of Genetic Syndromes, Third Edition is a premier source to guide family physicians, pediatricians, internists, medical geneticists, and genetic counselors in the clinical evaluation and treatment of syndromes. It is also the reference of choice for ancillary health professionals, educators, and families of affected individuals looking to understand appropriate guidelines for the management of these disorders.

From a review of the first edition:

"An unparalleled collection of knowledge . . . unique, offering a gold mine of information." —American Journal of Medical Genetics

• Language: English
• Publisher: Wiley
• Release date: Sep 20, 2011
• ISBN: 9781118210673

Book preview

1

INTRODUCTION

SUZANNE B. CASSIDY

Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, California

JUDITH E. ALLANSON

Department of Pediatrics, University of Ottawa and Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada

THE 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 of each chapter 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. Whenever available, evidence-based treatments are included. 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 are discussed, 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, and sometimes figures of other aspects, including mechanism of pathogenesis. 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.

While we have sought to place the chapters in alphabetical order by name, for ease of locating, some chapters pose challenges in that regard. in particular, this is true of the disorders that are caused by a chromosomal abnormality and also have an associated name, most of which are deletion syndromes. in this edition, we have clustered the chromosomal syndromes under Deletion (Deletion 4p for Wolf-Hirschhorn syndrome, Deletion 22q11.2 for Velo-Cardio-Facial/DiGeorge syndrome, and Deletion 22q13 for Phalen-McDermid syndrome). The disorders with more than one causative genetic mechanisms are left under the commonly used name (e.g., Klinefelter syndrome, Smith-Magenis syndrome, and Prader-Willi syndrome). While we realize that this organization is not perfect, we hope that this will facilitate finding the reader's chapter of interest.

CATEGORIZATION OF DISORDERS

The descriptive language for patterns of anomalies is somewhat unique to the field of dysmorphology and deserves abrief review. The term syndrome is used to describe a broad error of morphogenesis in which the simultaneous presence of more than one malformation or functional defect is known or assumed to be the result of a single etiology. Its use implies that the group of malformations and/or physical or mental 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 abnormalities and the exclusion of others. Thus, a syndrome comes to be defined by the coexistence of a small but variable number of hallmark abnormalities, 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. This has become very evident as genetic testing has advanced and demonstrated the broadness of the clinical spectrum for many disorders. 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 VATER (VACTERL) association represents a simultaneous occurrence of two or more malformations that include vertebral anomalies, anal atresia/stenosis, heart defects, tracheoesophageal fistula, radial ray defects, and renal and limb abnormalities. 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.

MEASUREMENTS

Selected measurements, with comparison to normal standards, may be helpful in confirming the subjective impression of an abnormality. Common craniofacial dimensions, which provide details 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 Physical Measurements (Hall et al., 2007), Growth References: Third Trimester to Adulthood (Saul et al., 1998), and Smith's Recognizable Patterns of Human Malformation (Jones, 2005); 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 and are referenced in the chapters of this book.

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 patient's physical findings. They can be compared with examples of other syndromes inphotographic 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 whose meaning may be unclear to some practitioners. 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 socalled 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 (an X-linked cause of mental retardation) 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 27 for a more detailed explanation of this type of mutation.

In recent years, some new types of changes in the genetic apparatus have been recognized to cause human disorders. An epigenetic mutation is a biochemical change in the DNA that modifies its expression. This generally includes methylation of bases or changes in chromatin structure that change DNA's availability for transcription and therefore results in decreased protein production. Epigenetic modification of some DNA is normal, but perturbations or changes in dosage of that modification have been shown to result in disorders such as some cases of Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome, and Russell-Silver syndrome. Such changes are described in more detail in those chapters.

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., WAGR) of a chromosome.

The terms that clinical geneticists use to describe a body part may be unfamiliar to some readers. They have gradually evolved in a haphazard and uncoordinated manner, and have only recently been critically reviewed (Allanson et al., 2009; Biesecker et al., 2009; Carey et al., 2009; Hall et al., 2009; Hennekam et al., 2009; Hunter et al., 2009). While we have strived to use lay language wherever possible, there may be descriptive terms in these chapters that require definition. In the series of articles cited above, the reader will find preferred terms for each feature of the head and face, and hands and feet, with a definition and description of how to observe and measure (where possible) the feature. Each term is accompanied by at least one photograph.

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 an 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. When a parent has a gonadal cell line with a dominant mutation, the recurrence risk is significantly greater than the risk for a second child with a new mutation but less than the 50% risk expected if the parent had the mutation in all cells of the body and manifested the condition. Several different dominant disorders have been documented to recur in more than one child of an unaffected parent because of germ line mosaicism. Alternately, the autosomal dominant mutation may be carried in a proportion of a parent's somatic cells as well as the germ line. In this situation, the manifestations of the condition may differ, being milder, segmental, or focal. This somatic mosaicism may manifest as a streaky alteration in skin pigmentation. Somatic and germ line mosaicism, at the level of the gene or chromosome, occur after conception.

An autosomal recessive gene mutation, when present in a single copy in an individual, will be hidden. Such a person is known as a carrier and will be normal. If, by chance, a person inherits an abnormal gene for an autosomal recessive disorder from both parents, there is no normal gene partner and the two altered genes will cause symptoms and signs, for example, cystic fibrosis. When each parent carries a recessive mutation for the same disorder, the chance that they both will pass on the mutation to their child, who is then affected, is 25%.

Recessive genes on the X chromosome have different consequences in males and females. A mutated recessive gene on the X will tend to have little impact in a female, because there is a second, normal copy of the gene on the second X chromosome of the pair. In contrast, in the male, a mutation of a recessive X-linked gene will have an impact because the genes on the Y chromosome are different from those on the X, and no second gene copy exists. That male must pass the mutated X-linked gene to all his daughters but to none of his sons, because he passes his Y chromosome to his sons. Some disorders are X-linked dominant, and females will also be affected. However, males are generally more severely affected in such disorders.

In certain areas of the genetic code, genes behave differently if they have been inherited from the father (paternally inherited) rather than from the mother (maternally inherited). Only one copy may be active, whereas the other is inactivated, usually by a process of methylation. These genes, whose action differs depending on the parent of origin, are said to be imprinted. More can be learned about this phenomenon in the chapters on the imprinted disorders Angelman syndrome (Chapter 6), Beckwith-Wiedemann syndrome (Chapter 10), Prader-Willi syndrome (Chapter 42), and Russell-Silver syndrome (Chapter 48). A more detailed account of patterns of inheritance, imprinting, and mosaicism can be found in any standard text of human or medical genetics, such as those listed under Additional Resources below.

GENETIC TESTING

Several terms used in this book in describing genetic tests are likely to be unfamiliar to some readers. For some disorders, the appropriate test is a chromosome analysis (or karyotype, which is an ordered display of an individual's chromosomes). Chromosomes are analyzed by special staining techniques that result in visibility of dark and light bands, which are designated in a very standardized way from the centromere, or major constriction. The short arm of the chromosome is called p, the long arm is called q, and bands are numbered up from the centromere on the p arm and down from the centromere on the q arm. Each band is further subdivided according to areas within the bands or between them. Thus, the deletion found in velocardiofacial syndrome is in the first band of the q arm of chromosome 22, and is designated del22(q11.2). A standard chromosome analysis has at least 450 bands, which is quite adequate for numerical chromosome anomalies. For some disorders, however, the anomaly cannot be seen reliably on standard chromosome analysis and requires special handling while being processed called high-resolution banding. An alternative term, prometaphase banding, is used because the cell growth during culturing is adjusted to maximize the number of cells in prometaphase, where the chromosomes are much less condensed and thus longer, rather than in metaphase, where cell growth is stopped in standard chromosome studies. High-resolution banding often has 550 to 800 bands, and allows much more detailed analysis.

Another technique combines chromosome analysis with the use of fluorescence-tagged molecular markers (called probes) that are applied after the chromosome preparation is produced. This method is called fluorescence in situ hybridization, or FISH, and relies on the phenomenon of hybridization (intertwining) of complementary pieces of DNA. Thus, to test whether there is a small deletion (called a microdeletion) that is not visible using chromosome analysis alone, a fluorescence-tagged DNA probe complementary to the deleted material is applied to the chromosome preparation. If the chromosome material is present in the normal amount, a fluorescent signal will be visible at that site under the fluorescence microscope; if the normal chromosome material is absent (deleted), there will be no fluorescent signal. FISH is a very powerful tool not only for diagnosing relatively common microdeletion or microduplication disorders but also for identifying the origin of extra chromosome material that cannot be identified by inspection alone and sorting out the origin of the components of a translocation (structural rearrangement of chromosomal material).

Smaller deletions and duplications are being more frequently identified by a newer technique called array comparative genomic hybridization (commonly abbreviated to array CGH, or just CGH). This is a novel diagnostic tool that merges traditional chromosome analysis with molecular diagnostics. Array CGH detects abnormalities by comparing DNA content from two differently labeled genomes, which allows for sensitive and specific detection of single copy number variations of submicroscopic chromosomal regions throughout the entire human genome.

Other types of genetic testing rely exclusively on molecular diagnostic methodologies. Polymerase chain reaction (PCR) is a powerful technique for amplifying, thus making many, many copies of a segment of DNA so that it can be analyzed. PCR is used for many genetic disorders with a recurring mutation (such as achondroplasia) or a finite number of common mutations. It can also be used to identify the presence of alterations in the normal methylation pattern in imprinted disorders. Southern blot techniques are more time consuming; they involve breaking DNA into small pieces using restriction enzymes and then separating them out using gel electrophoresis and analyzing whether there is a deviation in the distance that a segment of the DNA travels on the gel, indicating that its size is different from usual. Both PCR and Southern blotting usually involve the use of DNA markers, or probes. These are small segments of DNA complementary to an area of interest. One special type of probe takes advantage of the fact that DNA normally contains many runs of repeated base pairs, such as CACACACACA..., which are usually located between genes and have no phenotypic consequences. These are called microsatellites. Such runs occur normally throughout the genome, and the number of repeats is inherited like a genetic trait. There are vast variations in the exact number of repeated doublets, which can be counted by molecular techniques and which represent polymorphisms or variants. These so-called microsatellite markers form the basis for paternity testing and are also used for diagnostic testing of neighboring genes or the genes within which they occur, although they are not the mutation of the relevant gene that causes disease.

Multiplex ligation-dependent probe amplification (MLPA) is a newer sensitive technique for relative quantification of up to 50 different nucleic acid sequences in a single reaction. It is a variation of the polymerase chain reaction that permits multiple targets to be amplified with only a single primer pair. Each probe consists of two oligonucleotides that recognize adjacent target sites on the DNA, one of which is fluorescently labeled. Only when both probe oligonucleotides are hybridized to their respective targets, can they be ligated into a complete probe, and the relative fluorescence can be measured. It is routinely used for copy number analysis in various syndromes and diseases to detect an abnormal number of chromosomes, gene deletions, duplications, or expansions, and methylation abnormalities.

Markers can even be used when the precise gene or mutation is unknown, through a process called linkage analysis. This is a genehunting technique that uses linked (neighboring) markers to trace patterns of heredity in families in which more than one individual is affected with a disorder in an effort to identify whether a child inherited the chromosome with the relevant marker near a coinherited disease-causing gene. Although this often does not represent identification of the disease gene itself, it can be very reliable within families with multiple affected and unaffected members, particularly when the disease gene or mutation is unknown. The closer the marker is to the gene of interest, the more accurate the result because proximity reduces the likelihood of crossing over. The disadvantage is that the technique requires DNA from several affected and unaffected family members.

The nomenclature for markers is a bit more uniform than that for genes. Markers are indicated by the letter D (standing for DNA), followed by the number of the chromosome they are on, followed by the letter S (standing for single copy) and the number representing the numerical order in which they were identified. Thus, D15S10 was the 10th marker to be identified on chromosome 15. This designation gives no hint as to which gene it is in or near, or where on the chromosome it maps. Increasingly, geneticists are moving away fromusing this nomenclature and instead identifying the genes. The nomenclature for mutations is complex and beyond the scope of this book.

The methodology for genetic testing has become highly technical and complex, and is beyond the scope of this book. The interested reader is referred to the list of glossaries at the end of this chapter. The most accessible, detailed, and current of these glossaries is to be found online at the GeneTests web site (http://www.genetests.org).

ROLE OF THE MEDICAL GENETICIST AND GENETIC COUNSELOR

Many syndromes are relatively rare, and any individual physician may have limited personal experience. Medical geneticists, on the other hand, frequently have considerable experience of many affected individuals and have ready access to additional information through the genetics literature and specialized databases. The myriad manifestations of each of the syndromes included in this book often require the care of many diverse specialties. The geneticist can assist in diagnosis, testing, and counseling of affected individuals and their family as a consultant to the nongenetics physician and can orchestrate coordination of care to focus on the whole child or adult. The role of the geneticist extends beyond the individual child to involve the care and well-being of the entire family. The primary care physician is encouraged to consult medical geneticists to assist in the management of individuals with multiple anomaly syndromes.

An important facet of the care of individuals with syndromes and their families is genetic counseling. This is the provision of nondirective information about the diagnosis and its implications not only for the individual (prognosis) but also for the family (reproductive risks and options). It includes knowledge of the inheritance pattern, likelihood of recurrence in a future pregnancy, and prenatal diagnostic options. Referral to relevant community resources, such as patient support groups, brochures, and web sites and financial, social, and educational services, can also be made during this process. Assisting the individual and/or family to understand the condition and its impact, provide optimal care, and adapt to the existence of a chronic and complex disorder are all part of the process of genetic counseling. Adjustment to a new diagnosis may put considerable strain on a family, and emotional support for the family by care providers is paramount. Genetic counseling is usually provided by medical geneticists or by genetic counselors, who are Masters-prepared professionals who are knowledgeable about genetic disorders and their inheritance, can determine genetic risks, and are trained to assist in the emotional and psychological adjustments necessitated for optimal outcome.

ADDITIONAL RESOURCES AND WEB SITES

Additional information concerning the included disorders, as well as explanations of inheritance information and diagnostic testing, may be found in standard texts on genetics and genetic disorders. A few particularly useful texts and references in this context are listed below.

Aase JM (1990) Diagnostic Dysmorphology, 1st ed. New York: Kluwer Academic/Plenum Publishers. Allanson JE (1997) Objective techniques for craniofacial assessment: What are the choices? Am J Med Genet 70:1–5.

Allanson JE, Cunniff C, Hoyme HE, McGaughran J, Muenke M, Neri G (2009) Elements of morphology: Standard terminology for the head and face. Am J Med Genet 149A:6–28.

Biesecker LG, Aase JM, Clericuzio C, Gurrieri F, Temple K, Toriello H (2009) Elements of morphology: Standard terminology for the hands and feet. Am J Med Genet 149A:93–127.

Carey JC, Cohen MM Jr, Curry C, Devriendt K, Holmes L, Verloes A (2009) Elements of morphology: Standard terminology for the lips, mouth, and oral region. Am J Med Genet 149A:77–92.

Epstein CJ, Erickson RP, Wynshaw-Boris A (2008) Inborn Errors of Development, 2nd ed. New York: Oxford University Press.

Gorlin RJ, Cohen MM Jr, Hennekam R (2001) Syndromes of the Head and Neck, 4th ed. New York: Oxford University Press.

Hall BD, Robl JM, Cadle RG (1988). The importance of diagnostic follow-up of unknown multiple congenital anomaly syndromes. Am J Hum Genet 43:A48.

Hall JG, Allanson JE, Gripp KW, Slavotinek AM (2007) Handbook of Physical Measurements, 2nd ed. Oxford: Oxford University Press.

Hall BD, Graham JM Jr, Cassidy SB, Opitz JM (2009) Elements of morphology: Standard terminology for the periorbital region. Am J Med Genet 149A:29–39.

Hennekam RCM, Cormier-Daire V, Hall J, Mehes K, Patton M, Stevenson R (2009) Elements of morphology: Standard terminology for the nose and philtrum. Am J Med Genet 149A:61–76.

Hunter A, Frias J, Gillessen-Kaesbach G, Hughes H, Jones K, Wilson L (2009) Elements of morphology: Standard terminology for the ear. Am J Med Genet 149A:40–60.

Jones KL (2005) Smith's Recognizable Patterns of Human Malformation, 6th ed. Philadelphia: Saunders.

King RA, Rotter J, Motulsky AH (2002) The Genetic Basis of Common Disease, New York: Oxford University Press.

Nussbaum RL, McInnes RR, Willard HF (2001) Genetics in Medicine, 6th ed. Philadelphia, PA: WB Saunders Co.

Rimoin DL, Connor JM, Pyeritz RE, Korf BR (2007) Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. New York: Churchill Livingstone.

Saul RA, Seaver LH, Sweet KM, Geer JS, Phelan MC, Mills CM (1998) Growth References: Third Trimester to Adulthood, 2nd ed. Greenwood: Greenwood Genetic Center.

Scriver CR, Beaudet AL, Valle D, Sly WS (2001). The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York: McGraw-Hill.

Spranger J, Benirschke K, Hall JG, Lenz W, Lowry RB, Opitz JM, Pinsky L, Schwarzacher HG, Smith DW (1982) Errors of morphogenesis: Concepts and terms. Recommendations of an International Working Group. J Pediatr 100:160–165.

In addition, important online resources on genetic disorders are readily available, including:

Online Mendelian Inheritance in Man (OMIM) (http://www3.ncbi.nlm.nih.gov/Omim) is a catalogue of inherited disorders.

GeneReviews (http://www.genetests.org) provides information on diagnosis, testing, and management of genetic disorders.

For those with a deeper interest, there are electronic databases that aid in diagnosis and provide photographs and references concerning not only common but also rare genetic disorders. These must be purchased, and include:

London Dysmorphology Database (http://www.hgmp.mrc.ac.uk/lddb)

POSSUM (Pictures of Standard Syndromes and Undiagnosed Malformations) (http://www.possum.net.au)

A resource of laboratories doing specialized diagnostic testing, both clinically and for research, for genetic disorders and syndromes is:

GeneTests (http://www.genetests.org) provides information on diagnosis, testing, and management of genetic disorders.

Further information on individual syndromes for practitioners or families can be obtained from other online resources, including:

National Organization for Rare Diseases (NORD) (http://www.rarediseases.org)

March of Dimes/Birth Defects Foundation (http://www.modimes.org)

The Alliance of Genetic Support Groups (http://www.geneticalliance.org)

Orphanet (http://www.orpha.net)

2

AARSKOG SYNDROME

ROGER E. STEVENSON

Greenwood Genetic Center, Greenwood, South Carolina

Aarskog syndrome is one of the most clinically distinctive phenotypes among the hereditary syndromes. Manifestations in the facial morphology, skeleton, and genitalia form a clinically useful triad, present from birth. Identification of an X–linked pattern of inheritance in familial cases and the presence of subtle findings in carrier females can further assist in diagnosis. Many multigenerational pedigrees have been identified because of the X–linked inheritance pattern, the presence of distinctive external manifestations, and the absence of lethal manifestations. The responsible gene, FGD1, has been identified and testing for gene mutations is available in molecular diagnostic laboratories.

INTRODUCTION

Aarskog syndrome is one of the most clinically distinctive phenotypes among the hereditary syndromes. Manifestations in the facial morphology, skeleton, and genitalia comprise a clinically useful diagnostic triad. The condition was first described in a Norwegian family by the pediatrician Dagfinn Aarskog in 1970. Aarskog syndrome is an X–linked condition with full manifestations in males and subtle findings in many carrier females. The causative gene, FGD1, located at Xp11.22, was identified in 1996.

Although the condition has been given the more descriptive names of facialgenital–digital syndrome and faciogenital dysplasia, the designations Aarskog syndrome and Aarskog–Scott syndrome have retained greatest favor.

Incidence

Over 250 affected individuals with Aarskog syndrome have been reported, providing a rich descriptive literature and precluding the reporting of most currently identified cases (Aarskog, 1970; Scott, 1971; Furukawa et al., 1972; Sugarman et al., 1973; Bermanetal., 1975; Frynsetal., 1978; Porteous and Goudie, 1991; Fryns, 1992; Teebi et al., 1993; Stevenson et al., 1994; Orrico et al., ; Shalev et al., 2006; Bottani et al., 2007). Many multigenerational pedigrees have been identified because of the X–linked inheritance pattern, the presence of distinctive external manifestations, and the absence of lethal manifestations. Aarskog syndrome has been reported worldwide and from most ethnic and racial groups. There does not appear to be an increased rate in any subpopulation. Among those clinically diagnosed, only about 20% are found to have FGD1 mutations, suggesting overdiagnosis or genetic heterogeneity among these cases.

The wide recognition and large number of ascertained cases notwithstanding, a reliable prevalence for Aarskog syndrome is not known. Subtle manifestations permit many, perhaps most, affected individuals to go undiagnosed.

Life span is said to be normal, but this too has not been documented by systematic study. Survival into the eighth decade is found within the reported pedigrees.

Diagnostic Criteria

Formal diagnostic criteria have not been developed for Aarskog syndrome. The diagnosis of Aarskog syndrome is based on clinical findings. In most cases, the pattern of craniofacial, skeletal, and genital manifestations is sufficient to make the diagnosis (Table 2.1). Identification of an X–linked pattern of inheritance and the presence of subtle findings in carrier females assist in familial cases. The responsible gene has been identified and testing for gene mutations is currently available in several diagnostic laboratories.

Manifestations of Aarskog syndrome are present from birth. Head size is usually normal, but may appear large in relation to the face. The facial appearance is distinctive and in most cases is diagnostic (Figure 2.1 ). Changes are present in the upper, middle, and lower portions of the face. Increased width of the forehead, widow's peak, ocular hypertelorism, downward slanting of the palpebral fissures, and blepharoptosis are the major features of the upper face. A short nose with anteverted nares and small, simply formed ears that may protrude are the major features of the midface. Ears often have a broad insertion. The midface may be hypoplastic, but this is rarely of sufficient degree to dominate the appearance of the face. The mouth is wide and the lips thin with a V–shaped configuration at the middle of the upper lip's vermilion and a subtle upturn to the corners of the mouth. The chin is small. A transverse crease is often present below the lower lip.

Altered appearance of the genitalia may also be helpful in diagnosis. One or both testes may fail to descend into the scrotal sac. The scrotum tends to surround the penis giving a so-calledshawl scrotum appearance (Figure 2.2 ).

Since most literature reports describe childhood cases, the clinician must be aware of the changing phenotype with age (Fryns, 1992; Stevenson et al., 1994) (Figure 2.1 ). Three changes tend to obscure the diagnosis in adults. The face elongates, and with this elongation prominence of the forehead and hypertelorism become less apparent. With puberty, growth improves, with adult height in most cases being above the third centile. Pubic hair obscures the presence of shawl scrotum, one of the key clinical findings during childhood.

Typically, female carriers show subtle manifestations. They tend to be shorter than noncarrier female relatives and generally have mild craniofacial changes including hypertelorism and fullness of the tip of the nose. They may also exhibit brachydactyly and the typical posturing of the digits with hyperextension of the proximal interphalangeal joints and flexion of the distal joints (Figure 2.3 ).

Table 2.1 Clinical Manifestations in Aarskog Syndrome

Source: Frequencies of findings estimated from data in Furukawa et al. (1972), Berman et al. (1975), Grier et al. (1983), Porteous and Goudie (1991), Tsukahara and Fernandez (1994), Fernandez et al. (1994), and Gorski et al. (2000).

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Etiology, Pathogenesis, and Genetics

From the initial description, Aarskog syndrome has been recognized as an X–linked disorder. Linkage analysis placed the gene in the pericentromeric region of the X chromosome and the responsible gene, FGD1, was isolated with positional cloning techniques utilizing an X;8 translocation in which a female carrier had manifestations of Aarskog syndrome (Bawleetal., 1984;Pasterisetal., 1994; Stevenson etal., 1994).

FGD1, a guanine nucleotide exchange factor, exerts its influence, at least in part, by activating the Rho GTPase, Cdc42 (Gorski et al., 2000). The family of Rho GTPases is expressed widely in embryonic tissues, contributing to the morphology of these tissues through organization of the actin cytoskeleton and a number of other cellular components and processes (Gao et al., 2001; Hou et al., 2003). Preliminary studies in mice indicate that fdgl, the homologous mouse gene, is expressed exclusively in skeleton, specifically during periods of incipient and active ossification of both endochondral and intramembranous bones. Postnatally, expression is also found in perichondrium, joint capsules, and cartilage. These expression studies gave little insight into the role of the gene in the development of nonskeletal tissues, for example, brain, eye, and genital system.

Over 100 different mutations, the majority of which lead to truncated proteins, have been identified. The probands include representatives of the original families reported by Aarskog (16p insertion at nucleotide 519, exon 3) and by Scott (C to T transition at nucleotide 577, exon 3). Mutations of all classes have been found distributed throughout the gene, both within and outside of the major functional domains of the gene, and no genotype–phenotype correlation has emerged.

Figure 2.1 Aarskog syndrome. Facial findings in three individuals. (A) Four–year–old with broad forehead, hypertelorism, down-slanting palpebral fissures, cupped ears, and wide mouth. (B) Seventeen-year-old with prominent forehead, ptosis, broad nasal root, and down-slanting palpebral fissures. (C) Sixty-year-old with elongation of face, ptosis, and cupped ears, but less apparent widening of the midface and forehead.

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Diagnostic Testing

Demonstration of a mutation in FGD1 confirms the clinical diagnosis of Aarskog syndrome. Several diagnostic laboratories offer FGD1 mutation analysis. About 20% of individuals with the clinical diagnosis will have FGD1 mutations (Orrico et al., 2004, 2005, 2007; Schwartz et al., 2000; Pasteris et al., 1994). Mutations have been found more frequently in familial cases and in instances with subtle expression in obligate female carriers.

In individuals who lack an FGD1 mutation, the etiology of the disorder or the accuracy of the diagnosis is uncertain (see Differential Diagnosis).

Figure 2.2 Shawl scrotum.

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Differential Diagnosis

None of the manifestations of Aarskog syndrome can be considered pathognomonic, but the manifestations in composite are unlikely to lead to confusion with many other disorders. Although there are other X-linked syndromes with hypertelorism (Atkin-Flaitz, Simpson-Golabi-Behmel, XLMR-hypotonic facies, Opitz FG, and telecanthus-hypospadias syndromes), none is likely to be confused with Aarskog syndrome. There are several autosomal syndromes that may be considered in the differential diagnosis.

Noonan syndrome (see Chapter 38) poses the greatest problem in differential diagnosis. Both Aarskog and Noonan syndromes are readily called to mind by clinicians, have short stature, craniofacial and skeletal changes of similar nature, and have mild mental disability. In most cases, however, they may be readily separable. Individuals with Noonan syndrome commonly have webbed neck and cardiac defects. In Aarskog syndrome, the hands and feet are more distinctive and shawl scrotum is a helpful finding. Noonan syndrome affects males and females equally. In Aarskog syndrome, females may have subtle craniofacial findings and may be shorter than unaffected female relatives. The Noonan-associated disorders-LEOPARD syndrome, Noonan-neurofibromatosis, and cardiofaciocutaneous syndrome (see Chapter 11) are unlikely to be confused with Aarskog syndrome.

In Teebi hypertelorism syndrome, the facial manifestations-prominent forehead, hypertelorism, short nose with long philtrum, and, in some cases, widow's peak and ptosisare similar to those in Aarskog syndrome (Tsai et al., 2002). Male-to-male transmission, normal stature in affected males and females, the presence of cardiac malformations, and the absence of shawl scrotum are distinguishing features.

Robinow syndrome has similar facial findings, particularly in infancy and early childhood, but can be distinguished by the inheritance pattern (both autosomal dominant and autosomal recessive forms occur), mesomelic or acromesomelic limb shortening, and penis hypoplasia (Patton and Afzal, 2002).

Figure 2.3 Characteristic posturing of extended fingers.

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MANIFESTATIONS AND MANAGEMENT

Growth and Feeding

Although growth may be quite variable in Aarskog syndrome, it is exceptional for stature to be above average. Most affected males, in fact, grow slowly during infancy and childhood and reach only the lower centiles of general population height in late adolescence and adulthood. The tendency to short stature notwithstanding, obesity is not a problem of note.

Birth measurements are usually within the normal range. Head growth continues at a normal rate throughout childhood, although the head may appear disproportionately large in relation to the face and body. Length, however, falls below the third centile within the first few years of life and remains there until puberty. Except for delay in its onset, sexual maturation is normal. The accompanying growth acceleration leads to adult heights in the lower centiles, usually between 160 and 170 cm.

Hormonal function is generally normal. Bone age lags several years behind height age, giving an expanded period for catchup growth. A number of males have received treatment with growth hormone (Petryk et al., 1999; Darendeliler et al., 2003). Although an increase in the rate of growth could be documented during therapy, it is not assured that adult height would be significantly above what it would have reached without therapy.

Evaluation

Growth should be monitored by taking measurements of growth parameters at all routine assessments and plotting them on standard growth curves.

In cases where statural growth appears more severely impaired (progressively falling below -3 SD), bone age determination, thyroid function, and growth hormone measurements may be indicated.

Treatment

No therapy for growth delay and pubertal delay in usually required. Stature ultimately reaches the low/ normal percentiles in adolescence and adulthood and growth may continue throughout the second decade.

Development and Behavior

Detailed observations of childhood developmental milestones and neurobehavioral manifestations in Aarskog syndrome have not been reported. A gestalt of neurodevelopmental function may be gained from the case report literature. Early childhood motor and speech development usually proceeds in normal fashion, and in so doing predicts that intellectual function will be normal as well. In a minority, early developmental milestones lag behind age-peers and it is this minority that will likely show impaired cognitive function at maturity.

Overall there appears to be a shift into the lower half of the intellectual curve among males with Aarskog syndrome. Fryns (1992) reports that about 10% of affected males have moderate intellectval disability (IQ <50) and about 20% have mild intellectval disability (IQ 50-70). In contrast, Logie and Porteous (1998) found intellectval disability to be exceptional, their males exhibiting a wide range of intellectual function with IQs between 62 and 128. The balance of reports in which objective IQ testing is available is in general agreement with 20–30% of males having IQ levels below 70. The clinician should give an attentive eye to developmental progress as an early predictor of school performance. Intellectval disability of moderate-severe degree should prompt a search for coexisting reasons for the impairment.

During childhood, attention deficient and hyperactivity may pose equal schooling challenges. Attention deficit commonly occurs among those with normal cognitive function, but moreso among those with subnormal intellectual function. Spontaneous resolution at the time of adolescence is the rule.

Evaluation

Assessment of developmental progress should be an integral part of routine evaluation of the child with Aarskog syndrome.

Testing of cognitive function and behavior using standardized tests are indicated in individuals who show signs of developmental lag and attention deficit disorder.

A careful search for a coexisting disorder should be considered in those children with moderate-severe developmental delay.

A history of attention deficit and hyperactivity should be sought from the family.

Treatment

Infant stimulation programs may benefit young children with developmental delay.

During the school year, special education may be necessary for those with learning difficulties. Individualized programming is appropriate.

Behavioral therapy and/or a trial of pharmacological agents such as methylphenidate are indicated for attention deficit and hyperactivity, although, as yet, there have been no reports of controlled trials of these approaches.

Ophthalmologic

In addition to hypertelorism, downward slanting of the palpebral fissures and ptosis, prominence of the corneas, strabismus, astigmatism, hyperopia, limitation of upward gaze, and tortuosity of the retinal blood vessels have been reported (Brodsky et al., 1990; Kirkham et al., 1975).

Evaluation

Vision and strabismus screening should be conducted at all routine clinical evaluations.

Ophthalmologic assessment is recommended in all children prior to school entry and in all who appear to have vision impairment or other ocular abnormality on screening.

Treatment

Glasses are commonly required for correction of hyperopia.

Occlusion therapy or surgical correction of strabismus should be initiated as soon as detected, as in the general population.

Significant ptosis may be surgically corrected for both vision and cosmetic reasons.

Dental

Dental abnormalities have included delayed eruption, broad central incisors, hypodontia, crowding, and excessive caries (Reddy et al., 1999; Halse et., 1979).

Evaluation

Routine dental examination should begin in the preschool years and careful attention should be given to tooth alignment.

Referral for orthodontic evaluation should be made by the early school years.

Treatment

Instruction in dental care with flossing, brushing, and use of fluoride-containing toothpaste should be given early to prevent cavities and gum disease.

Standard orthodontic treatment may be required for misaligned teeth.

Musculoskeletal

Skeletal findings including brachydactyly, pectus excavatum, and midfoot varus are common. Skeletal findings should be anticipated in most cases (Fryns, 1992; Stevenson et al., 1994; Gorski et al., 2000). The trunk is long in relation to the limbs. The hands and fingers are short and there may be some mild cutaneous webbing between the fingers. The fingers are often held in a distinctive position with flexion at the metacarpophalangeal joints, overextension at the proximal joint of the finger, and flexion at the distal joint (Figure 2.2 ). This hand posturing becomes more obvious when there is an attempt to extend and spread the fingers. Often there is only a single palmar crease. The toes are also short and tend to have bulbous tips, and nonfixed midfoot varus deformation occurs commonly.

All of the joints may be unusually hyperextensible. Malformations and excessive movement of the cervical spine may lead to impingement on the spinal cord. Pectus excavatum occurs in many cases.

Radiographic findings may include asynchronous delay of bone age, shortening of the long bones with widening of the metaphyses, hypoplasia of the middle phalanges of the fifth fingers, small ilia with anteverted femoral heads, and developmental abnormalities of the cervical spine (Lizcano-Gil et al., 1994; Petryk et al., 1999; Gorski et al., 2000).

Evaluation

Clinical evaluation should include standard assessment of all components of the skeleton with particular attention to cervical vertebrae and metatarsus adduction.

Radiographs should be made if any suspicious signs are identified on the clinical evaluation of the skeletal system.

Treatment

Progressive casting will usually correct metatarsus adduction. Recalcitrant cases may require surgical correction.

Intervention for joint laxity is usually not indicated unless it involves the cervical spine (see Neurologic below).

Neurologic

Neurological complications related to malformation and instability of the cervical spine are the most serious and perhaps the least appreciated finding in Aarskog syndrome. Hypoplasia of the first cervical vertebra and the odontoid, fusion of vertebral bodies, prolapse of intervertebral disks, and ligamentous laxity may lead to cord compression in childhood or adult life (Scott, 1971; Stevenson et al., 1994; Gorski et al., 2000). Delay of motor milestones, gait instability, paresthesia, hyperreflexia, and pain may indicate the possibility of cord compression.

Evaluation

Evaluation for signs of cervical cord impingement should be an integral part of each examination. Appropriate care should be taken to exclude causes for neurological signs and symptoms.

In individuals with neurological signs and in those participating in sports, radiographs of the cervical spine should be taken to detect anomalies that may predispose to cervical instability and cord impingement.

In those with signs of cord compression, magnetic resonance imaging of the cervical spine is helpful in locating the site and degree of cord compression..

Treatment

Referral for consideration of surgical stabilization of the cervical spine is appropriate in the presence of signs of cord compression due to cervical instability. The surgical procedure is the same as in any other circumstance.

Standard traction therapy or surgery benefit individuals with herniation of the intervertebral disks.

Genitourinary

Genital abnormalities include shawl scrotum and undescend ed testes. Hernias occur commonly in the inguinal region and less commonly at the umbilicus. Pubertal development may be delayed but full sexual maturation and fertility should be anticipated.

Evaluation

Genital examination with particular attention to undescended testes and inguinal hernias should be included in all routine clinical evaluations.

Stages of sexual maturation should be documented beginning in the preteen years.

Treatment

A standard approach to management of cryptorchidism is appropriate. This includes a trial of human chorionic gonadotropin injection or surgical correction prior to school age.

Surgical evaluation and repair of inguinal hernias follows standard practice in the general population.

Reassurance regarding pubertal development and fertility may be given. Rarely is pubertal delay sufficient to warrant hormone induction.

RESOURCES

Support Groups

Alliance of Genetic Support Groups

4301 Connecticut Ave., NW, Suite 404,

Washington, DC 20008

Telephone: [phone]

Fax: [phone]

Web site:http://www.geneticalliance.org

National Organization for Rare Disorders (NORD)

PO Box 8923

New Fairfield, CT 06812-8923

Telephone: [phone] or [phone]

Fax: [phone]

Web site:http://www.rarediseases.org

REFERENCES

Aarskog D (1970) A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J Pediatr 77:856–861.

Berman P, Desjardins C, Fraser FC (1975) The inheritance of the Aarskog facial-digital-genital syndrome. J Pediatr 86:885–891.

Brodsky MC, Keppen LD, Rice CD, Ranells JD (1990) Ocular and systemic findings in the Aarskog (facial-digital-genital) syndrome. Am J Ophthalmol 109:450–456.

Darendeliler F, Larsson P, Neyzi O, Price AD, Hagenas L, Sipila I, Lindgren AC, Otten B, Bakker B, on behalf of the KIGS International Board (2003) Growth hormone treatment in Aarskog syndrome: Analysis of the KIGS (Pharmacia International Growth Database) data. J Pediatr Endocrinol Metab 16:1137–1142.

Fernandez I, Tsukahara M, Mito H, Toshii H, Uchida M, Matsuo K, Kajii T (1994) Congenital heart defects in Aarskog syndrome. Am J Med Genet 50:318–322.

Fryns JP (1992) Aarskog syndrome: The changing phenotype with age. Am J Med Genet 43:420–427.

Fryns JP, Macken J, Vinken L, Igodt-Ameye L, van den Berghe H (1978) The Aarskog syndrome. Hum Genet 42:129–135.

Furukawa CT, Hall BD, Smith DW (1972) The Aarskog syndrome. J Pediatr 81:1117–1122.

Gorski JL, Estrada L, Hu C, Liu Z (2000) Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome). Dev Dyn 218:573–586.

Grier RE, Farrington FH, Kendig R, Mamunes P (1983) Autosomal dominant inheritance of the Aarskog syndrome. Am J Med Genet 15:39–46.

Halse A, Bjorvatn K, Aarskog D (1979) Dental findings in patients with Aarskog syndrome. J Dent Res 87:253–259.

Hou P, Estrada L, Kinley AW, Parsons JT, Vojtek AB, Gorski JL (2003) Fgd1, the Cdc42 GEF responsible for faciogenital dysplasia, directly interacts with cortactin and mAbp1 to modulate cell shape. Hum Mol Genet 12:1981–1993.

Kirkham TH, Milot J, Berman P (1975) Ophthalmic manifestations of Aarskog (facial-digital-genital) syndrome. Am J Ophthalmol 769:441–445.

Lizcano-Gil LA, Garcia-Cruz D, Cantu JM, Fryns JP (1994) The faciodigitogenital syndrome (Aarskog syndrome): A further delineation of the distinct radiological findings. Genet Couns 5:387–392.

Logie LJ, Porteous MEM (1998) Intelligence and development in Aarskog syndrome. Arch Dis Child 79:359–360.

Orrico A, Galli L, Cavaliere ML, Garavelli L, Fryns J-P, Crushell E, Rinaldi MM, Medeira A, Sorrentino V (2004) Phenotypic and molecular characterization of the Aarskog-Scott syndrome: A survey of the clinical variability in light of FGD1 mutation analysis in 46 patients. Eur J Hum Genet 12:16–23.

Orrico A, Galli L, Cavaliere ML, Garavelli L, Fryns J-P, Crushell E, Rinaldi MM, Medeira A, Sorrentino V (2004) Phenotypic and molecular characterization of the Aarskog-Scott syndrome: A survey of the clinical variability in light of FGD1 mutation analysis in 46 patients. Eur J Hum Genet 12:16–23.

Orrico A, Galli L, Obregon MG, de Castro Perez MF, Falciani M, Sorrentino V (2007) Unusually severe expression of craniofacial features in Aarskog-Scott syndrome due to a novel truncating mutation of the FGD1 gene. Am J Med Genet 143A:58–63.

Pasteris NG, Cadle A, Logie LJ, Porteous MEM, Schwartz CE, Stevenson RE, Glover TW, Wilroy RS, Gorski JL (1994) Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: A putative Rho/Rac guanine nucleotide exchange factor. Cell 79:669–678.

Patton MA, Afzal AR (2002) Robinow syndrome. J Med Genet 39:305–310.

Petryk A, Richton S, Sy JP, Blethen SL (1999) The effect of growth hormone treatment on stature in Aarskog syndrome. J Pediatr Endocrinol Metab 12:161–165.

Porteous MEM, Goudie DR (1991) Aarskog syndrome. J Med Genet 28:44–47.

Reddy P, Kharbanda OP, Kabra M (1999) Dental and craniofacial features of Aarskog syndrome: Report of a case and review of literature. J Clin Pediatr Dent 23:155–160.

Schwartz CE, Gillesen-Kaesbach G, May M, Cappa M, Gorski J, Steindl K, Neri G (2000) two novel mutations confirm FGD1 is responsible for the Aarskog Syndrome. Eur J Hum Genet 8: 869874.

Scott CI Jr (1971) Unusual facies, joint hypermobility, genital anomaly and short stature: A new dysmorphic syndrome. In: Birth Defects: Original Article Series VII. New York: Alan R. Liss, Inc. for the National Foundation-March of Dimes, pp. 240–246.

Shalev SA, Chervinski E, Weiner E, Mazor G, Friez MJ, Schwartz CE (2006) Clinical variation of Aarskog syndrome in a large family with 2189delA in the FGD1 gene. Am J Med Genet 140A:162–165.

Stevenson RE, May M, Arena JF, Millar EA, Scott CI, Schroer RJ, Simensen RJ, Lubs HA, Schwartz CE (1994) Aarskog-Scott syndrome: Confirmation of linkage to the pericentromeric region of the X chromosome. Am J Med Genet 52:339–345.

Sugarman GI, Rimoin DL, Lachman RS (1973) The facial-digital-genital (Aarskog) syndrome. Am J Dis Child 126:248–252.

Teebi AS, Rucquoi JK, MeynMS (1993) Aarskog syndrome: Report of a family with review and discussion of nosology. Am J Med Genet 46:501–509.

Tsai AC, Robertson JR, Teebi AS (2002) Teebi hypertelorism syndrome: Report of a family with previously unrecognized findings. Am J Med Genet 113:302–306.

Tsukahara M, Fernandez GI (1994) Umbilical findings in Aarskog syndrome. Clin Genet 45:260–265.

3

ACHONDROPLASIA

RICHARD M. PAULI

Clinical Genetics Center, University of Wisconsin, Madison, Wisconsin

Achondroplasia is the most common of the skeletal dysplasias, arising in approximately 1 in 26,000 individuals. Most individuals with achondroplasia can be expected to have a normal life expectancy. However, they are at increased risk for a variety of medical sequelae, most of which are explicable on the basis of abnormalities of growth of cartilaginous bone or disproportionate growth of cartilaginous bone when compared with other contiguous tissues. Issues of concern include growth, motoric development, adaptive needs, hydrocephalus, cervicomedullary junction constriction, restrictive and obstructive pulmonary disease, middle ear dysfunction, kyphosis, lumbosacral spinal stenosis, bowing of the legs and anesthetic risks. The natural history of achondroplasia can be beneficially modified by timely anticipatory medical care.

INTRODUCTION

Incidence

The external physical features of achondroplasia have been recognized for millennia and are well represented in artwork from diverse cultures in all parts of the world (Enderle et al., 1994). It is the most common, and still most readily recognizable, of the skeletal dysplasias (also known as bone dysplasias, chondrodysplasias, and osteochondrodystrophies), with best estimates of birth prevalence around 1 in 26,000-28,000 (Oberklaid et al., 1979; Orioli et al., 1995). Although achondroplasia is an autosomal dominant single gene disorder, most cases are sporadic.

Most individuals with achondroplasia can be expected to have a normal life expectancy. Nevertheless, they are at some increased risk for premature death (Hecht et al., 1987; Wynn et al., 2007). In infancy there is an estimated 7.5% risk for death (Hecht et al., 1987). Most of these deaths were sudden and unexpected, probably attributable to acute foraminal compression of the upper cervical cord or lower brain stem (see below) (Pauli et al., 1984). In addition, mean survival is about 10 years less than that of the general population (Hecht et al., 1987; Wynn et al., 2007), with much of the difference related to cardiovascular mortality in early and mid-adulthood (Wynn et al., 2007).

Diagnostic Criteria

Well-defined clinical and radiologic features allow for virtual certainty of diagnosis in all infants with achondroplasia. External physical characteristics include disproportionately short limbs, particularly the proximal or rhizomelic (upper) segments; short fingers often held in a typical trident configuration with fingers deviating distally; moderately enlarged head; depressed nasal bridge; and modestly constricted chest (Fig. 3.1). In all infants in whom this diagnosis is suspected, radiographic assessment is mandatory. Features that are most helpful in distinguishing achondroplasia from other short-limb disorders include small skull base and foramen magnum; narrowing rather than widening of the interpediculate distance in the lumbar spine and short vertebral bodies (although not present in infancy); square iliac wings, flat acetabulae, narrowing of the sacrosciatic notch and a characteristic radiolucency of the proximal femora (Fig. 3.2); short, thick long bones; flared metaphyses; and short proximal and middle phalanges (Langer et al., 1967). Although both the clinical and the radiologic features evolvewith age, virtually all instances of diagnostic uncertainty will arise in the neonate.

Figure 3.1 Primary clinical features of infants and children with achondroplasia. (A) General appearance in a child of about two months of age. (B) Facial features, which include a high forehead and depressed nasal bridge. (C) Hands, which show not only shortening of the fingers but also the typical trident configuration (with increased distance particularly between the third and fourth fingers).

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Prenatal diagnosis of achondroplasia using ultrasonographic criteria can be exceedingly difficult (Patel and Filly, 1995; Modaff et al., 1996), particularly because bone foreshortening is often not evident until about 20-24 weeks of gestation (Patel and Filly, 1995).

Etiology, Pathogenesis, and Genetics

Most, and perhaps all, of the clinical characteristics and medical complications of achondroplasia are explicable on the basis of abnormalities of growth of cartilaginous bone or disproportionate growth of cartilaginous bone when compared with other contiguous tissues.

The molecular origin of this defect in cartilaginous bone development has been elucidated (Horton et al., 2007). All instances of achondroplasia arise from a mutation in one copy of the fibroblast growth factor receptor 3 (FGFR3) gene (Shiang et al., 1994; Bellus et al., 1995) and, more remarkably, virtually always from the same nucleotide substitution at the same site in the FGFR3 gene (Bellus et al., 1995). FGFR3 is one of four receptors for a large set of growth factors. When FGFR3 is mutated, as in achondroplasia, its normal inhibitory function (Deng et al., 1996) is constitutively activated (i.e., turned on whether or not a fibroblast growth factor has bound to it), resulting in increased inhibition of growth of cartilage cells (Horton et al., 2007).

Because achondroplasia is an autosomal dominant disorder, offspring of affected