Cohen Syndrome

Clinical Diagnosis

Although diagnostic criteria have been proposed by several groups based on studies of individuals with confirmed COH1(VPS13B) gene mutations, no clinically based diagnostic criteria have been widely accepted at this time.

Prior to identification of the causative gene COH1 in 2003, Kivitie-Kallio & Norio (2001) and Chandler, Kidd et al (2003) identified a variety of clinical features most suggestive of Cohen syndrome including facial dysmorphism, pigmentary retinopathy, neutropenia, and neurologic abnormalities (psychomotor retardation, motor clumsiness, hypotonia, microcephaly).

Subsequently, evaluation of individuals in different ethnic populations with known COH1 mutations revealed that overall "facial gestalt" was an unreliable indicator of Cohen syndrome [Falk et al 2004]. However, specific facial features were seen across ethnicities including thick hair and eyebrows, long eyelashes, wave-shaped palpebral fissures, bulbous nasal tip, smooth or shortened philtrum, and hypotonic appearance.

In contrast to facial gestalt, features common to almost all individuals with COH1 mutations appear to be better clinical indicators of Cohen syndrome:

• Retinal dystrophy appearing by mid-childhood

• Progressive high myopia

• Acquired microcephaly

• Non-progressive mental retardation, global developmental delay

• Hypotonia

• Joint hyperextensibility

Other features suggestive of Cohen syndrome are seen in a minority of individuals from various ethnic backgrounds with proven COH1 mutations [Falk et al 2004]:

• Short stature

• Small or narrow hands and feet

• Truncal obesity appearing in or after mid-childhood

• Friendly disposition

• Non-cyclic granulocytopenia or low total white blood cell count with or without aphthous ulcers

Kolehmainen et al (2004) studied 76 individuals from 59 families with a provisional diagnosis of Cohen syndrome to correlate molecular and clinical findings. The individuals were assessed for eight clinical criteria:

• High myopia and/or retinal dystrophy

• Microcephaly

• Developmental delay

• Joint hypermobility

• Typical Cohen syndrome facial gestalt

• Truncal obesity with slender extremities

• Overly sociable behavior

• Neutropenia

Individuals fulfilling six or more criteria were considered likely to have "true Cohen syndrome." Those fulfilling five or fewer criteria were considered to have a provisional "Cohen-like syndrome."

Using the above criteria, Kolehmainen et al (2004) found 22 different COH1 mutations in probands identified as having "true Cohen syndrome." In addition, they identified another three novel mutations in individuals with incomplete clinical data. By contrast, no COH1 mutations were found in individuals who only met the provisional diagnosis of "Cohen-like syndrome."

The broad clinical spectrum of Cohen syndrome and difficulty establishing definitive clinical diagnostic criteria were confirmed recently by Seifert et al (2006), who identified 25 different COH1 mutations in 24 ethnically diverse individuals age two to 60 years. The "typical facial gestalt" was seen in 23/24 individuals. Early-onset progressive myopia was present in all individuals older than age five years (14/14) while widespread pigmentary retinopathy was found in 12/14. Some individuals did not have the characteristic facial gestalt and pigmentary retinopathy at school age. Development and growth parameters varied significantly.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene.   COH1 (also known as VPS13B as first identified in yeast) is the only gene known to be associated with Cohen syndrome.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing

• Carrier testing

• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• Targeted mutation analysis.  The common Finnish mutation c.3348_3349delCT accounts for 75% of mutant alleles in Finland [Kolehmainen et al 2003].

• Sequence analysis of select exons.  Sequence analysis of exon 23 detected mutations in 26 of 27 individuals of Finnish heritage [Kolehmainen et al 2003]; the mutation detection rate in other populations is unknown.

Molecular genetic testing: Research

• Targeted mutation analysis.  Two mutations are common in individuals of Amish heritage [Falk et al 2004]:

  • A frameshift mutation with 1-bp insertion, c.9258_9259insT

  • A missense substitution, c.8459T>C (p.I2820T)

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Cohen Syndrome

Test Methods	Mutations Detected	Mutation Detection Rate  1	Test Availability
Targeted mutation analysis	c.3348_3349delCT	75% of mutant alleles in Finland  2	Clinical
Sequence analysis of exon 23	COH1(VPS13B) sequence variants	26/27 in the Finnish population; unknown in other populations
Sequence analysis		Unknown
Targeted mutation analysis	c.9258_9259insT, c.8459T>C	Observed in the Amish	Research only

1. Mutation detection rate depends on diagnostic criteria used and ethnicity.
2. Kolehmainen et al 2003

Interpretation of test results.  Because the mutations in COH1 are distributed throughout the gene, only sequencing of the entire gene can confirm or exclude a diagnosis of Cohen syndrome. However, it should be noted that currently the clinical availability of such testing is limited because of the large size of the COH1 gene.

For other issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy for a Proband

• In the Finnish, the common founder mutation present in at least 75% of mutant alleles is c.3348_3349delCT [Kolehmainen et al 2003].

• In individuals of other ethnic backgrounds, full COH1 sequence analysis is available clinically. However, the percentage of individuals with clinically diagnosed Cohen syndrome who have identifiable mutations in COH1 is not yet known.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in COH1.

Natural History

Phenotypic features of Cohen syndrome variably include moderate to severe psychomotor retardation, motor clumsiness, acquired microcephaly, childhood hypotonia and joint laxity, progressive retinochoroidal dystrophy and myopia, neutropenia, truncal obesity, a cheerful disposition, and generally, characteristic facial features. Clinical features among the approximately 100 individuals with Cohen syndrome reported to date have been variable, leading to the impression of disease heterogeneity.

The following are prominent clinical features of Cohen syndrome, presented by system.

Note: Among individuals included in the NCSD, the diagnosis of Cohen syndrome has been confirmed by molecular genetic testing primarily in those of Amish heritage; the diagnosis has been genetically confirmed in a limited number of individuals of other ethnic backgrounds.

• Perinatal.  Half of mothers whose children are included in the NCSD recalled reduced fetal movement during an otherwise normal pregnancy. Although most infants were born at term (average gestational age: 38.5 weeks), average birth weight (2.5 kg) length (47.8 cm) were in the 10th to 25th centile.

  Infants with Cohen syndrome frequently have feeding and breathing difficulties during the first days of life, likely related to hypotonia. The majority of newborns with Cohen syndrome are hypotonic. Hypotonia is present in all infants by age one year [Kivitie-Kallio & Norio 2001].

  A majority of infants with Cohen syndrome have an unusually high-pitched and weak cry. In the NCSD, this is seen in 95% of children of Amish ancestry and 65% of non-Amish children. Overall, 80% of parents with children in the NCSD database recall this cry as resembling a kitten mewing. However, this unique cry is frequently overlooked by clinicians and has not been reported in the medical literature. The cause of the unusual cry in Cohen syndrome remains unknown, although laryngeal abnormalities postulated to be cause for the "mewing cry" seen in cri-du-chat syndrome have also been found in some individuals with Cohen syndrome [Chandler, Kidd et al 2003].

• Craniofacial.  Microcephaly develops during the first year of life and continues into adulthood. Although 80% of mothers providing data to the NCSD database reported that their infants had a small head size at birth, the average birth head circumference (35 cm) was in fact in the 50th centile. Earlier studies also reported normal head circumference at birth [Kivitie-Kallio & Norio 2001; Chandler, Kidd et al 2003; Hennies et al 2004].

  Distinctive features have been variably described in different ethnic populations. Features include thick hair, low hairline, high-arched, waved-shaped eyelids, long and thick eyelashes, thick eyebrows, prominent nasal root, high and narrow palate, short philtrum and prominent upper central incisors; the latter two together result in an open-mouth appearance. Horn et al (2000) and Falk et al (2004) both concluded that although quite consistent among affected individuals within a particular ethnic group, facial gestalt appears to be inconsistent between ethnic populations.

  Despite some variability in the facial appearance, several specific features can be identified in affected individuals of different ethnicities. These include thick hair and eyebrows, long eyelashes, wave-shaped palpebral fissures, bulbous nasal tip, smooth or shortened philtrum, and hypotonic appearance [Falk et al 2004]. Systematic anthropometric and cephalometric analysis of 14 individuals confirmed microcephaly, short philtrum, forward-inclined upper incisors, and maxillary prognathia [Hurmerinta et al 2002].

• Developmental.  All children with Cohen syndrome have delayed developmental milestones in the first year of life. Analysis of individuals in the NCSD showed fairly consistent findings on certain developmental milestones compared with other cohorts with Cohen syndrome (Table 2) [Kivitie-Kallio & Norio 2001; Chandler, Kidd et al 2003; Nye et al 2005]. The psychomotor retardation in children with Cohen syndrome appears non-progressive and non-regressive. All but one of the individuals in the NCSD is able to walk without assistance, but at least 20% are unable to communicate verbally. The degree of developmental delay varies considerably, even among siblings [Horn et al 2000].

• Ophthalmologic.  The range of ophthalmologic findings first identified in affected individuals of Finnish descent includes decreased visual acuity, night blindness, constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and retinal pigmentary deposits, optic atrophy, and abnormal (isoelectric) electroretinograms (ERGs) [Norio et al 1984].

  Many of the same ophthalmologic findings have since been confirmed in individuals of non-Finnish descent. Individuals registered in the US NCSD had a first ophthalmologic visit and first pair of glasses at an average age of 4.5 years. Defective dark adaptation/night blindness was typically noticed after age seven years. However, studies of younger individuals with Cohen syndrome demonstrate that abnormal retinal findings and ERG changes are present much earlier in life [Kivitie-Kallio et al 2000, Chandler et al 2002]. The studies further show that the two most prominent ophthalmologic findings, myopia and retinal dystrophy, progress markedly in severity over time. The progressive myopia and late-onset lens subluxation that occur in some individuals result from progressive laxity of zonules and progressive rounding up of the lens (spherophakia). Older individuals can have tremulousness of the iris and lens (phako-iridodonesis).

  More than 70% of individuals in the NCSD fall often or trip easily, most likely because of limited peripheral visual fields from retinal degeneration.

  Congenital ptosis has also been noted in some individuals.

• Endocrine and metabolism.  Among individuals in the NCSD, the prevalence of short stature is approximately 65%, delayed puberty 74%, and obesity 60%; clinical endocrinologic evaluations were negative.

  Extensive endocrine evaluations of pituitary, adrenal, and thyroid function in the cohort of Finnish descent showed no significant abnormalities [Kivitie-Kallio, Eronen et al 1999].

  Growth hormone deficiency was reported in a girl who was clinically diagnosed with Cohen syndrome [Massa et al 1991] but whose phenotype differed considerably from that seen in individuals with genetically confirmed Cohen syndrome. Three other individuals with Cohen syndrome with growth hormone deficiency displayed catch-up growth with growth hormone replacement therapy [author, personal observation]. The prevalence of growth hormone deficiency in Cohen syndrome is unknown.

  Individuals with Cohen syndrome tend to manifest failure to thrive in infancy and early childhood, but then proceed to become significantly overweight in their teenage years. More than 80% of individuals in the NCSD were reported to be underweight during early childhood, but overweight afterward. The obesity tends to be truncal in nature. The average age of the onset of obesity is 11.3 years (14.6 years in individuals of Amish descent and 8.4 years in individuals of non-Amish ancestry). The authors have noted that this change usually occurs very rapidly, with a weight gain of 10-15 kg seen over a period of four to six months. In contrast to Prader-Willi syndrome, appetite and food intake are not increased during this time period and activity is not decreased.

• Hematologic.  Neutropenia, defined as an absolute neutrophil count (ANC) lower than 1,500/mm³, was initially documented in individuals of Finnish ancestry [Norio et al 1984] and later found in many who were not of Finnish descent [De Ravel, Dillen et al 2002; Chandler, Kidd et al 2003]. The neutropenia is mild to moderate, non-cyclic, and usually not fatal [Kivitie-Kallio et al 1997; author, unpublished data]. However, recurrent infections and aphthous ulcers have been described in some individuals [Falk et al 2004] (see Immunologic section below). ANC usually falls into the range of 500 to 1,200/mm³ in all age groups [author, unpublished data]. Furthermore, low-normal neutrophil counts are common in individuals who do not have neutropenia.

  More than 65% of affected individuals experience repeated oral mucosal ulcers and gingival infections, with at least three individuals requiring prophylactic granulocyte colony-stimulating factor (G-CSF) therapy.

  The neutropenia may not necessarily result in an overall low white blood cell count and therefore may be overlooked for many years in some individuals. The etiology of the neutropenia remains unclear. Bone marrow examination performed by the Finnish groups showed a normocellular or hypercellular marrow, with a left-shifted granulopoiesis in about half of those affected. No bone marrow malignancies have been seen.

  Whether other hematologic findings reported in clinically diagnosed individuals —including combined deficiency of protein C, protein S, and antithrombin III causing venous thrombosis [Schlichtemeier et al 1994] in one individual and asymptomatic thrombocytopenia in another [De Ravel, Dillen et al 2002] — are present in individuals with molecularly confirmed Cohen syndrome remains to be determined.

• Immunologic and rheumatologic.  While neutropenia may contribute to compromised immune dysfunction in some individuals with Cohen syndrome, it is not clear if it is the sole cause. More than 80% of children in the NCSD have had more than five episodes of otitis media per year and most of them had tympanostomy tubes placed during early childhood. The majority of children also had an average of 2.5 lifetime episodes of pneumonia.

  The frequency and severity of infections in individuals with Cohen syndrome seems to correlate poorly with ANC; affected individuals are generally more symptomatic than non-affected individuals with an ANC in the same range (500-1,200/mm³). The authors have also observed that when treated with immunomodulators, some individuals with Cohen syndrome appear to have significantly fewer oral ulcers with no change in ANC. Indeed, increased neutrophil adhesive capability has been reported in an individual with Cohen syndrome [Olivieri et al 1998].

  Other immune disturbances have been observed; De Ravel, Azou et al (2002) found rheumatoid arthritis in an individual with Cohen syndrome. In addition to rheumatoid arthritis, frequent uveitis and recurrent pericarditis have been seen in affected individuals [Wang, personal observation].

• Neurologic.  Seizures have been reported in a minority of individuals with Cohen syndrome [Coppola et al 2003, Atabek et al 2004]. Anecdotally, two individuals with epilepsy in the NCSD currently on anticonvulsants have phenotypes at the more severe end of the Cohen syndrome spectrum, characterized by inability to communicate verbally. Most individuals, however, particularly those older than age five years in the Finnish cohort, were reported to have low-voltage EEGs without irritative spikes or epileptoform foci [Kivitie-Kallio, Larsen et al 1999].

  Childhood hypotonia, one of the most common features in Cohen syndrome, seems to improve over time regardless of intervention. The mechanism of hypotonia is unknown but speculated to be of central nervous system origin [Kivitie-Kallio et al 1998].

  Magnetic resonance imaging (MRI) of 18 individuals with Cohen syndrome found normal gray and white matter signal intensity and a relatively enlarged corpus callosum compared to 26 controls [Kivitie-Kallio et al 1998]. Although this abnormal finding appeared to be subtle and nonspecific, it warrants further study.

  Electromyography (EMG) is reported to be normal [Kivitie-Kallio, Larsen et al 1999].

• Musculoskeletal.  Joint hypermobility, kyphosis, scoliosis, and pes planovalgus are most likely the consequence of hypotonia. The relatively disease-specific motor clumsiness appears to be quite common [Kivitie-Kallio et al 2000; Chandler, Kidd et al 2003].

  Individuals with Cohen syndrome have characteristic narrow hands and feet, and slender fingers that have frequently been falsely reported to be long. In fact, the fingers are short, based on the hand x-ray analysis of the metacarpophalangeal pattern [Kivitie-Kallio, Eronen et al 1999].

• Psychological and behavioral.  Individuals with Cohen syndrome are typically described as having a "cheerful and friendly disposition."

  While cognitive ability varies, the majority of affected individuals fall into the moderate-to-profound range of mental retardation [Kivitie-Kallio, Larsen et al 1999; Chandler, Moffett et al 2003; Karpf et al 2004]. Independence levels are generally poor but socialization skills are relatively less impaired; indeed, sociability is characteristic of individuals with Cohen syndrome. In contrast, psychological evaluations performed in previous studies have identified maladaptive and autistic-type behavior in some individuals [Kivitie-Kallio, Larsen et al 1999; Chandler, Moffett et al 2003; Karpf et al 2004].

• Cardiovascular.  The cardiovascular system is not commonly affected in individuals with Cohen syndrome. Mitral valve prolapse has been reported in individuals with Cohen-like syndrome of Ashkenazi Jewish ancestry [Sack & Friedman 1980] but not in individuals with classic Cohen syndrome who have documented COH1 mutations. Cardiac evaluation in 22 individuals of Finnish descent identified decreased left ventricular function with advancing age but no evidence for clinically significant mitral prolapse [Kivitie-Kallio, Eronen et al 1999]. Of the approximately 20 individuals in the NCSD who have had echocardiograms, none showed evidence of mitral valve prolapse.

  Similarly, while carotid aneurysms and tortuous descending aortas have been reported in the literature [Schlichtemeier et al 1994], they have not been found in individuals with a confirmed COH1 mutation.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

Cohen et al (1973) described a pattern of abnormalities including mental deficiency, hypotonia, obesity, high nasal bridge, and prominent central incisors, observed in a sib pair and an unrelated individual.

Norio et al (1984) observed six individuals of Finnish descent with the same disorder, known by them as the "Pepper syndrome," from the family name. They identified consanguinity among two pairs of parents (confirming the autosomal recessive inheritance of the disorder), intermittent granulocytopenia, and marked ophthalmologic changes including decreased visual acuity, hemeralopia, constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and pigmentary deposits, optic atrophy, and isoelectric electroretinogram.

Prevalence

The worldwide prevalence of Cohen syndrome is not known. More than 100 individuals have been reported in the literature since the first individual was described in 1973 by Cohen et al.

As more than 80% of individuals with molecularly confirmed Cohen syndrome who are registered in the National Cohen Syndrome Database (NCSD) have not been reported in the literature, it is estimated that at least 500 to 1,000 individuals have been diagnosed, and many more undiagnosed, worldwide.

Cohen syndrome has now been confirmed on almost all continents and in a wide variety of ethnic groups [Falk et al 2004, Hennies et al 2004, Kolehmainen et al 2004, Mochida et al 2004, Kondo et al 2005].

Cohen syndrome is overrepresented in the Finnish population [Kolehmainen et al 2003], with more than 35 individuals diagnosed in Finland to date. The Finnish phenotype is comparable to that seen in individuals of non-Finnish descent [Chandler, Kidd et al 2003].

Cohen syndrome is overrepresented in the Amish population. Of the more than 60 individuals with Cohen syndrome from around the US currently registered in the National Cohen Syndrome Support Center, approximately 50% are Amish. Since the first report of Cohen syndrome in the Ohio Geauga Old Order Amish settlement in 2004 [Falk et al 2004], more than 30 affected individuals have been identified in this highly consanguineous, isolated population of approximately 15,000 — indicating a prevalence as high as 1 in 500 and providing evidence for a founder effect.

The concept of a Jewish type of Cohen syndrome, first reported in a cohort of individuals from Israel [Sack & Friedman 1986] has since been challenged [Chandler & Clayton-Smith 2002]. The originally reported 39 individuals of Jewish descent in 32 families appeared macrocephalic and tall with generalized obesity, as opposed to being microcephalic and short with truncal obesity as seen in classic Cohen syndrome. Furthermore, the individuals reported with "Jewish-type" Cohen syndrome did not have neutropenia or chorioretinal dysplasia — manifestations found in all affected individuals of Finnish ancestry [Norio et al 1984]. The likelihood that these individuals belong to a completely different clinical entity is supported by the fact that no COH1 mutations have been found in individuals with Jewish-type Cohen or Cohen-like syndrome [Kolehmainen et al 2004]. Thus, the incidence of classic Cohen syndrome may not be increased in the Ashkenazi Jewish ethnic group.

Evaluations at Initial Diagnosis to Establish the Extent of Disease

• Ophthalmologic evaluation to assess visual acuity and pigmentary retinopathy

• Hematologic evaluation including a white blood cell count with differential to identify neutropenia

Treatment of Manifestations

Ophthalmologic issues are among the most concerning for families of individuals with Cohen syndrome registered in the National Cohen Syndrome Database. Management includes the following:

• Spectacle correction of refractive errors

• Training as needed for the visually impaired

• Psychosocial support for affected individuals and their families

If neutropenia is documented, consideration should be given to the use of granulocyte-colony stimulating factor (G-CSF). In a study reported by Kivitie-Kallio et al (1997) response to adrenaline stimulation was subnormal in 12 of 14 individuals, and to hydrocortisone in eight of 16 individuals, but administration of recombinant G-CSF caused granulocytosis in all three individuals studied.

Recurrent infections should be treated per standard therapy; full immunologic evaluation should be considered.

Early intervention and physical, occupational, and speech therapyare appropriate to address gross developmental delay, hypotonia, joint hyperextensibility, and motor clumsiness.

Surveillance

Annual ophthalmologic evaluation should assess visual acuity, refractive error, and/or retinal dystrophy.

Repeat testing of white blood cell count with differential over time to identify intermittent neutropenia is indicated.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Anecdotal reports notwithstanding, pycnogenol, a standard French maritime pine bark extract effective in improving visual acuity in retinal vascular leakage conditions [Schonlau & Rohdewald 2001, Spadea & Balestrazzi 2001], has not been proven an effective treatment for the pigmentary retinopathy observe in Cohen syndrome.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

Cohen syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband.  The offspring of an individual with Cohen syndrome are obligate heterozygotes (carriers) for a disease-causing mutation in the COH1 gene.

Other family members of a proband.  Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is clinically available once the disease-causing mutations have been identified in the proband.

Related Genetic Counseling Issues

Family planning.  The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

Author Notes

Web site for Dr Wang: www.ddcclinic.org

Revision History

• 24 October 2006 (cd) Revision: sequence analysis of the entire coding region clinically available

• 29 August 2006 (me) Review posted to live Web site

• 18 April 2006 (mjf) Original submission