Stickler Syndrome

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Retrieved

2021-01-18

Source

Gene_reviews

Trials

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Genes

COL9A2, COL9A1, COL9A3, COL2A1, COL11A1, COL11A2, LOXL3, BMP4, TECTA, ZAP70, WRN, LRP2, SULT2A1, RPS6KA3, PLXNA2, CGA, MYP10

Drugs

Adeno-associated virus serotype 8 containing the human RdCVF sequence and the human RdCVFL sequence, Combination of three adeno-associated viral vectors of serotype 8 containing the 5'-, the body- and the 3'- coding sequences of human CEP290 fused to inteins, Methotrexate ( LEDERTREXATE, NORDIMET, METHOTREXATE WYETH LEDERLE )

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Summary

Clinical characteristics.

Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity.

Diagnosis/testing.

The diagnosis of Stickler syndrome is clinically based. At present, no consensus minimal clinical diagnostic criteria exist. Pathogenic variants in one of six genes (COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) have been associated with Stickler syndrome; because a few families with features of Stickler syndrome are not linked to any of these six loci, pathogenic variants in other genes may also cause the disorder.

Management.

Treatment of manifestations: Management in a comprehensive craniofacial clinic when possible; tracheostomy as needed in infants with Robin sequence; mandibular advancement procedure to correct malocclusion for those with persistent micrognathia; correction of refractive errors with spectacles; standard treatment of retinal detachment and sensorineural and conductive hearing loss; symptomatic treatment for arthropathy.

Prevention of secondary complications: Antibiotic prophylaxis for certain surgical procedures if mitral valve prolapse is present.

Surveillance: Annual examination by a vitreoretinal specialist; audiologic evaluations every six months through age five years, then annually thereafter; screening for mitral valve prolapse (MVP) on routine physical examination.

Agents/circumstances to avoid: Activities such as contact sports that may lead to traumatic retinal detachment.

Evaluation of relatives at risk: It is appropriate to determine which family members at risk have Stickler syndrome and thus warrant ongoing surveillance.

Genetic counseling.

Stickler syndrome caused by pathogenic variants COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner; Stickler syndrome caused by pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner. In families with autosomal dominant inheritance, affected individuals have a 50% chance of passing on the pathogenic variant to offspring. In families with autosomal recessive inheritance, 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. Prenatal testing is possible in pregnancies at increased risk if the pathogenic variant(s) in the family are known.

Diagnosis

Suggestive Findings

Stickler syndrome should be suspected in individuals with a combination of the following findings:

Cleft palate (open cleft, submucous cleft, or bifid uvula)
Characteristic facial features including malar hypoplasia, broad or flat nasal bridge, and micro/retrognathia
Vitreous changes or retinal abnormalities (lattice degeneration, retinal hole, retinal detachment, or retinal tear)
High-frequency sensorineural hearing loss
Skeletal findings including:
- Slipped epiphysis or Legg-Perthes-like disease
- Scoliosis, spondylolisthesis, or Scheuermann-like kyphotic deformity
- Osteoarthritis before age 40
An independently affected first-degree relative

Establishing the Diagnosis

The diagnosis of Stickler syndrome is established in a proband who meets the proposed clinical diagnostic criteria and/or has a heterozygous pathogenic variant in COL2A1, COL11A1, or COL11A2 or biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 (see Table 1).

Clinical Diagnostic Criteria

Clinical diagnostic criteria have been proposed for type 1 Stickler syndrome (in which individuals have the membranous type of vitreous abnormality; see Clinical Description) but not validated [Rose et al 2005]. The proposed criteria are based on assigning points for clinical features, family history data, and molecular data.

Stickler syndrome should be considered in individuals with ≥5 points and absence of features suggestive of an alternative diagnosis. At least one finding should be a major (2-point) manifestation (denoted by *).

Abnormalities (2-pt maximum per category)

Orofacial
- Cleft palate* (open cleft, submucous cleft, or bifid uvula): 2 points
- Characteristic facial features (malar hypoplasia, broad or flat nasal bridge, and micro/retrognathia): 1 point
Ocular. Characteristic vitreous changes or retinal abnormalities* (lattice degeneration, retinal hole, retinal detachment, or retinal tear): 2 points
Auditory
- High-frequency sensorineural hearing loss*: 2 points
  - Age <20 years: threshold ≥20 dB at 4-8 Hz
  - Age 20-40 years: threshold ≥30 dB at 4-8 Hz
  - Age >40 years: threshold ≥40 dB at 4-8 Hz
- Hypermobile tympanic membranes: 1 point
Skeletal
- Femoral head failure (slipped epiphysis or Legg-Perthes-like disease): 1 point
- Radiographically demonstrated osteoarthritis before age 40: 1 point
- Scoliosis, spondylolisthesis, or Scheuermann-like kyphotic deformity: 1 point

Family history/molecular data

Independently affected first-degree relative in a pattern consistent with autosomal dominant inheritance or presence of a COL2A1, COL11A1, or COL11A2 pathogenic variant associated with Stickler syndrome**: 1 point

* Denotes major manifestation

** Does not account for families with autosomal recessive Stickler syndrome

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

Serial single-gene testing can be considered based on the individual's clinical findings and family history; however, findings should not be used to exclude specific testing:
- COL2A1 may be tested first in individuals with ocular findings including type 1 "membranous" congenital vitreous anomaly and milder hearing loss.
- COL11A1 may be tested first in individuals with typical ocular findings including type 2 "beaded" congenital vitreous anomaly and significant hearing loss.
- COL11A2 may be tested for in individuals with craniofacial and joint manifestations and hearing loss but without ocular findings.
- COL9A1, COL9A2, and COL9A3 may be tested for in individuals with possible autosomal recessive inheritance.
Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
A multigene panel that includes COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3, and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Stickler Syndrome

Gene ¹	Proportion of Stickler Syndrome Attributed to Pathogenic Variants in This Gene	Proportion of Pathogenic Variants ² Detectable by Method
Gene ¹		Sequence analysis ³	Gene-targeted deletion/duplication analysis ⁴
COL2A1	80%-90% ⁵	~99%	Unknown ^6, 7
COL11A1	10%-20% ⁵	~99%	Unknown ^6, 8
COL11A2	Rare; unknown ⁹	~100%	Unknown ⁶
COL9A1	Rare; unknown ¹⁰	~100%	Unknown ⁶
COL9A2	Rare; unknown ¹¹	~100%	Unknown ⁶
COL9A3	Rare; unknown ¹²	~100%	Unknown ⁶
Unknown ¹³		NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.: Sequence analysis of exons 1-54 of COL2A1 and exons 14-67 of COL11A1 identified nonsense variants in COL2A1 and missense, deletion, insertion, and splicing variants in both COL2A1 and COL11A1 in approximately 90% of individuals who had clinical diagnoses consistent with both Stickler syndrome and Marshall syndrome (see Genetically Related Disorders) [Annunen et al 1999; Acke et al 2014; Author, unpublished data].
6.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
7.: Deletions of COL2A1 have been reported [Van Der Hout et al 2002; Richards et al 2010; Author, unpublished data]; however, such large rearrangements may be rare.
8.: Multiexon deletions of COL11A1 have been reported [Martin et al 1999, Vijzelaar et al 2013]; the frequency of such deletions is unknown.
9.: Vikkula et al [1995], Sirko-Osadsa et al [1998], Vuoristo et al [2004], Acke et al [2014]
10.: Analysis of the coding region of COL9A1 showed homozygous nonsense variants in the affected individuals in three families with autosomal recessive Stickler syndrome [Van Camp et al 2006, Nikopoulos et al 2011].
11.: Analysis of the coding region of COL9A2 identified a homozygous 8-bp deletion in the two affected children of a family with autosomal recessive Stickler syndrome [Baker et al 2011]. The parents and an unaffected sib were heterozygous for the deletion c.843_846+4del8.
12.: Biallelic loss-of-function variants of COL9A3 were reported in three affected children of a family with autosomal recessive Stickler syndrome [Faletra et al 2014].
13.: Because a few families with features of Stickler syndrome are not linked to any of these six loci, pathogenic variants in other genes may also cause the disorder.

Clinical Characteristics

Clinical Description

Stickler syndrome is a multisystem connective tissue disorder that can affect the craniofacies, eyes, inner ear, skeleton, and joints.

Craniofacial findings include a flat facial profile or an appearance that is often referred to as a "scooped out" face. This profile is caused by underdevelopment of the maxilla and nasal bridge, which can cause telecanthus and epicanthal folds. Midface retrusion is most pronounced in infants and young children; older individuals may have a normal facial profile. Often the nasal tip is small and upturned, making the philtrum appear long.

Micrognathia is common and may be associated with cleft palate as part of the Pierre Robin sequence (micrognathia, cleft palate, glossoptosis). The degree of micrognathia may compromise the upper airway, necessitating tracheostomy.

Cleft palate may be seen in the absence of micrognathia.

Eye findings include high myopia (>−3 diopters) that is non-progressive and detectable in the newborn period [Snead & Yates 1999] and vitreous abnormalities. Two types of vitreous abnormalities are observed:

Type 1 ("membranous"), which is much more common, is characterized by a persistence of vestigial vitreous gel in the retrolental space that is bordered by a folded membrane.
Type 2 ("beaded"), much less common, is characterized by sparse and irregularly thickened bundles throughout the vitreous cavity.

The ocular phenotype runs true within families [Snead & Yates 1999].

Posterior chorioretinal atrophy was described by Vu et al [2003] in a family with vitreoretinal dystrophy, a novel pathogenic variant in COL2A1, and systemic features of Stickler syndrome, suggesting that individuals with Stickler syndrome may have posterior pole chorioretinal changes in addition to the vitreous abnormalities.

Note: Previously, families with posterior chorioretinal atrophy were thought to have Wagner syndrome.

Hearing impairment is common. The degree of hearing impairment is variable and may be progressive.

Some degree of sensorineural hearing impairment (typically high-tone, often subtle) is found in 40% of individuals [Snead & Yates 1999]. The exact mechanism is unclear, although it is related to the expression of type II and IX collagen in the inner ear [Admiraal et al 2000]. Overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive; it is less severe than that reported for types II and III Stickler syndrome.

Conductive hearing loss can also be seen. This may be secondary to recurrent ear infections that are often associated with cleft palate and/or may be secondary to a defect of the ossicles of the middle ear.

Skeletal manifestations are early-onset arthritis, short stature relative to unaffected sibs, and radiographic findings consistent with mild spondyloepiphyseal dysplasia. Some individuals have a slender body habitus, but without tall stature.

Joint laxity, sometimes seen in young individuals, becomes less prominent (or resolves completely) with age [Snead & Yates 1999].

Early-onset arthritis is common and may be severe, leading to the need for surgical joint replacement even as early as the third or fourth decade. More commonly, the arthropathy is mild, and affected individuals often do not complain of joint pain unless specifically asked. However, nonspecific complaints of joint stiffness can be elicited even from young children.

Spinal abnormalities commonly observed in Stickler syndrome that result in chronic back pain are scoliosis, endplate abnormalities, kyphosis, and platyspondylia [Rose et al 2001].

Mitral valve prolapse (MVP) has been reported in nearly 50% of individuals with Stickler syndrome in one series [Liberfarb & Goldblatt 1986]; diagnosis of Stickler syndrome was made on clinical features prior to the identification of the involved genes. A later study [Liberfarb et al 2003] reported MVP on echocardiogram in only one of 25 individuals with Stickler syndrome and a COL2A1 pathogenic variant. Ahmad et al [2003] screened a group of 75 individuals with molecularly confirmed Stickler syndrome and found no individuals with clinical or echocardiographic evidence of significant mitral valve or other valve abnormality. It was suggested that among those with Stickler syndrome, the prevalence of MVP may be similar to that in the general population. No additional studies reviewing cardiac findings in Stickler syndrome have been reported.

Genotype-Phenotype Correlations

Although inter- and intrafamilial variation was observed among 25 individuals from six families with the same molecular diagnosis [Liberfarb et al 2003], some generalities can be made regarding genotype-phenotype correlation:

COL2A1 pathogenic variants. The majority of individuals who have Stickler syndrome as a result of a COL2A1 pathogenic variant – including the kindred originally reported by Stickler et al [1965] – have premature stop (i.e., nonsense, frameshift, or splicing) variants that result in functional haploinsufficiency of the COL2A1 product. Most affected individuals have type 1 congenital vitreous abnormalities and are at high risk for retinal detachment and precocious osteoarthritis. Most have normal hearing or mild sensorineural hearing loss. The craniofacial features are variable, ranging from mild nasal anteversion to Robin sequence [Faber et al 2000]. A large family with a unique p.Leu667Phe pathogenic variant had a novel "afibrillar" vitreous gel devoid of all normal lamella structure [Richards et al 2000].
A COL2A1 missense variant has been described in some families with characteristic ophthalmologic and craniofacial findings, as well as a mild multiple epiphyseal dysplasia with brachydactyly, suggesting that mild heterozygous pathogenic variants may also cause Stickler syndrome. Pathogenic variants involving exon 2 of COL2A1 are characterized by a predominantly ocular variant phenotype, in which individuals are at high risk for retinal detachment.
In the nine families with an exon 2 pathogenic variant of COL2A1 reported by Donoso et al [2003], all pathogenic variants resulted in stop codons. The phenotype was characterized by optically empty vitreous, typical perivascular pigmentary changes, and/or early-onset retinal detachment with minimal or absent systemic findings of Stickler syndrome.
COL11A1 pathogenic variants. Missense and splicing variants and deletions within COL11A1 have been observed in individuals with the typical Stickler syndrome phenotype. Typically these individuals have more severe hearing loss and type 2 congenital vitreous anomaly or "beaded" vitreous phenotype; however, three individuals or families with a "membranous" vitreous (type 1) phenotype have been reported [Parentin et al 2001, Majava et al 2007].
COL11A2 pathogenic variants. Pathogenic variants in COL11A2 have been shown to cause autosomal dominant non-ocular Stickler syndrome [Vikkula et al 1995, Sirko-Osadsa et al 1998, Vuoristo et al 2004, Acke et al 2014].
COL9A1 pathogenic variants. Biallelic pathogenic variants in COL9A1 have been shown to cause autosomal recessive Stickler syndrome (Stickler syndrome, type IV). Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, cataracts, and epiphyseal dysplasia [Van Camp et al 2006, Nikopoulos et al 2011]. Of note, the vitreous abnormality resembled an aged vitreous rather than the typical membranous, beaded, or nonfibrillar type.
COL9A2 pathogenic variants. Biallelic pathogenic variants in COL9A2 have been shown to cause autosomal recessive Stickler syndrome (Stickler syndrome, type V). In the family of Asian Indian origin described by Baker et al [2011] two children had Stickler syndrome manifest as mild-to-moderate hearing loss, high myopia, and vitreoretinopathy.
COL9A3 pathogenic variants. Biallelic pathogenic variants in COL9A3 have been shown to cause autosomal recessive Stickler syndrome. Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia, midface retrusion, and intellectual disability [Faletra et al 2014]. In the consanguineous family reported by Faletra et al [2014], the intellectual disability is likely unrelated to pathogenic variants in COL9A3.

Penetrance

Penetrance is complete.

Prevalence

No studies to determine the prevalence of Stickler syndrome have been undertaken. However, an approximate incidence of Stickler syndrome among newborns can be estimated from data regarding the incidence of Robin sequence in newborns (1:10,000-1:14,000) and the percent of these newborns who subsequently develop signs or symptoms of Stickler syndrome (35%). These data suggest that the incidence of Stickler syndrome among neonates is approximately 1:7,500-1:9,000 [Printzlau & Andersen 2004].

Differential Diagnosis

A number of disorders have features that overlap with those of Stickler syndrome.

For allelic disorders see Genetically Related Disorders.

VCAN-related vitreoretinopathy, which includes Wagner syndrome and erosive vitreoretinopathy, is characterized by "optically empty vitreous" on slit lamp examination and avascular vitreous strands and veils, mild or occasionally moderate to severe myopia, presenile cataract, night blindness of variable degree associated with progressive chorioretinal atrophy, retinal traction and retinal detachment at advanced stages of the disease, and reduced visual acuity. Optic nerve inversion has also been described. Systemic abnormalities are not observed. The first signs usually become apparent during early adolescence, but onset can be as early as age two years. VCAN-related vitreoretinopathy is inherited in an autosomal dominant manner.

High-grade myopia is a refractive error greater than or equal to −6 diopters. More than 20 loci for myopia have been mapped (see Myopia: OMIM Phenotypic Series to view loci/genes associated with this phenotype in OMIM).

Nonsyndromic congenital retinal nonattachment (NCRNA) (OMIM 221900) comprises congenital insensitivity to light, massive retrolental mass, shallow anterior chamber, microphthalmia, and nystagmus in otherwise normal individuals. NCRNA is caused by pathogenic variants in ATOH7 and is inherited in an autosomal recessive manner.

Snowflake vitreoretinal degeneration (OMIM 193230) is characterized by cataract, fibrillar degeneration of the vitreous, and peripheral retinal abnormalities including minute, shiny crystalline-like deposits resembling snowflakes. Individuals show a low rate of retinal detachment [Lee et al 2003]. Snowflake vitreoretinal degeneration is caused by pathogenic variants in KCNJ13 and inherited in an autosomal dominant manner.

Binder syndrome (maxillonasal dysplasia) (OMIM 155050) is characterized by midface retrusion and absence of the anterior nasal spine on radiographs. While some families with vertical transmission have been reported [Roy-Doray et al 1997], Binder syndrome is not considered a genetic syndrome, but rather a nonspecific abnormality of the nasomaxillary complex.

Robin sequence. Approximately half of all individuals with Robin sequence have an underlying syndrome, of which Stickler syndrome is the most common. In one study, 34 of 100 individuals with Robin sequence had Stickler syndrome. A retrospective study of 74 individuals with Robin sequence also found that more than 30% of these individuals had Stickler syndrome [van den Elzen et al 2001]. In a more recent study of 115 individuals with Robin sequence, 18% had Stickler syndrome [Evans et al 2006].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Stickler syndrome, the following evaluations are recommended:

Evaluation of palate by a craniofacial specialist
Baseline ophthalmologic examination
Baseline audiogram
Directed history to elicit complaints suggestive of mitral valve prolapse (MVP), such as episodic tachycardia and chest pain. If symptoms are present, referral to a cardiologist should be made.
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Craniofacial. Infants with Robin sequence need immediate attention from specialists in otolaryngology and pediatric critical care, as they may require tracheostomy to ensure a competent airway. It is recommended that evaluation and management occur in a comprehensive craniofacial clinic that provides all the necessary services, including otolaryngology, plastic surgery, oral and maxillofacial surgery, pediatric dentistry, orthodontics, and medical genetics.

In most individuals, micrognathia tends to become less prominent over time, allowing for removal of the tracheostomy. However, in some individuals, significant micrognathia persists, causing orthodontic problems. In these individuals, a mandibular advancement procedure is often required to correct the malocclusion.

Ophthalmologic. Refractive errors should be corrected with spectacles.

Individuals with Stickler syndrome should be advised of the symptoms associated with retinal detachment and the need for immediate evaluation and treatment when such symptoms occur.

Audiologic. See Hereditary Hearing Loss and Deafness Overview. Otitis media may be a recurrent problem secondary to palatal abnormalities. Myringotomy tubes are often required.

Joints. Treatment of arthropathy is symptomatic and includes using over-the-counter anti-inflammatory medications before and after physical activity.

Prevention of Secondary Complications

Individuals with mitral valve prolapse may need antibiotic prophylaxis for certain surgical procedures.

Surveillance

Annual examination by a vitreoretinal specialist is appropriate.

Follow-up audiologic evaluations are appropriate every six months through age five years, and annually thereafter.

While the prevalence of mitral valve prolapse (MVP) among affected individuals is unclear, all individuals with Stickler syndrome should be screened for MVP through routine physical examination. More advanced testing (e.g., echocardiogram) should be reserved for those with suggestive symptoms.

Agents/Circumstances to Avoid

Affected individuals should be advised to avoid activities that may lead to traumatic retinal detachment (e.g., contact sports).

At present, no prophylactic therapies to minimize joint damage in affected individuals exist. Some physicians recommend avoiding physical activities that involve high impact to the joints in an effort to delay the onset of the arthropathy. While this recommendation seems logical, there are no data to support it.

Evaluation of Relatives at Risk

Because of the variable expression of Stickler syndrome [Faber et al 2000], it is appropriate to evaluate the older and younger sibs of a proband as well as other at-risk relatives in order to identify those who warrant ongoing evaluation (see Surveillance). Evaluation can be done in one of two ways:

By documenting medical history and performing physical examination and ophthalmologic, audiologic, and radiographic assessments. The examination of childhood photographs may be helpful in the assessment of craniofacial findings of adults, since the craniofacial findings characteristic of Stickler syndrome may become less distinctive with age.
By molecular genetic testing if the pathogenic variant(s) in the family are known

It is recommended that relatives at risk in whom the diagnosis of Stickler syndrome cannot be excluded with certainty be followed for potential complications.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.