Clinical Diagnosis

Clinical diagnostic criteria have not been established for Stickler syndrome. The disorder should be considered in individuals with clinical findings in two or more of the following categories:

Ophthalmologic

• Congenital or early-onset cataract

• Congenital vitreous anomaly, rhegmatogenous retinal detachment

• Myopia greater than −3 diopters
  
  Note: Newborns are typically hyperopic (≥+1 diopter); thus the finding of any degree of myopia in an at-risk newborn (e.g., a newborn who has Pierre-Robin sequence or an affected parent) is suggestive of the diagnosis of Stickler syndrome.

Craniofacial

• Midface hypoplasia, depressed nasal bridge, anteverted nares (characteristic facies typically more pronounced in childhood)

• Bifid uvula, cleft hard palate

• Micrognathia

• Robin sequence (micrognathia, cleft palate, glossoptosis)

Audiologic

• Sensorineural or conductive hearing loss

• Hypermobile middle ear systems (reported in 46% of affected individuals in one cohort [Szymko-Bennett et al 2001])

Joint

• Hypermobility

• Mild spondyloepiphyseal dysplasia

• Precocious osteoarthritis

Molecular Genetic Testing

Genes. Mutations in COL2A1, COL11A1, COL11A2, COL9A1, and COL9A2 have been associated with the Stickler syndrome, termed Stickler syndrome type I, II, III, IV, and V, respectively.

Clinical testing

• Sequence analysis

  • Analysis of exons 1-54 of COL2A1 and exons 14-67 of COL11A1 identified nonsense mutations in COL2A1 and missense, deletion, insertion, and splicing mutations 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].
    
    Note: Analysis of COL11A2 was not included because of the difference in phenotype (i.e., lack of ocular findings).

  • Analysis of the coding region of COL9A1 showed homozygous nonsense mutations in the affected individuals in three families with autosomal recessive Stickler syndrome [Van Camp et al 2006, Nikopoulos et al 2011].

  • 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 carriers of the deletion c.843_846+4del8.

• Deletion/duplication analysis

  • COL2A1. A deletion of the entire gene has been reported [van der Hout et al 2002], but such large rearrangements may be rare.

  • COL11A1. A multiexonic deletion has been reported [Martin et al 1999]; the frequency of such deletions is unknown.

  • COL11A2, COL9A1 and COL9A2. No exonic or whole-gene deletions or duplications of COL11A2 COL9A1, or COL9A2 have been reported to cause Stickler syndrome have been reported. Therefore, the mutation detection rate is unknown and may be very low.

Table 1. Summary of Molecular Genetic Testing Used in Stickler Syndrome

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Gene Symbol	% of Disease Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Test Availability
COL2A1	80%-90%	Sequence analysis	Sequence variants 2	Clinical
		Deletion / duplication analysis 3	Exonic or whole-gene deletions
COL11A1	10%-20%	Sequence analysis	Sequence variants 2	Clinical
		Deletion / duplication analysis 3	Exonic or whole-gene deletions
COL11A2	Rare, unknown	Sequence analysis	Sequence variants 2	Clinical
		Deletion / duplication analysis 3	Exonic or whole-gene deletions 4
COL9A1	Rare, unknown	Sequence analysis	Sequence variants 2	Clinical
		Deletion / duplication analysis 3	Exonic or whole-gene deletions 4
COL9A2	Rare, unknown	Sequence analysis	Sequence variants 2	Clinical
		Deletion / duplication analysis 3	Exonic or whole-gene deletions 4

Test Availability refers to availability in the GeneTests™ Laboratory Directory. 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.

1. Individuals with diagnosis of either Stickler syndrome or Marshall syndrome

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

4. No exonic or whole-gene deletions or duplications of COL11A2, COL9A1, or COL9A2 have been reported to cause Stickler syndrome. Therefore, the mutation detection frequency is unknown and may be very low.

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

Information on specific allelic variants may be available in Molecular Genetics (see Table A and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. The order in which the four genes are tested may be influenced by the clinical findings; 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 may be tested for in individuals with possible autosomal recessive inheritance

• COL9A2 may be tested for in individuals with possible autosomal recessive inheritance

Carrier testing for at-risk relatives requires prior identification of the disease-causing COL9A1 or COL9A2 mutations in the family.

Note: Carriers are heterozygotes for autosomal recessive Stickler syndrome and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Other phenotypes inherited in an autosomal dominant manner associated with mutations in COL2A1:

• Achondrogenesis type II (OMIM 200610). This disorder is characterized by virtual absence of ossification in the vertebral column, sacrum, and pubic bones. There is marked shortening of the limbs and trunk, with a prominent abdomen and hydropic appearance. Death occurs in utero or in the early neonatal period. Vissing et al [1989] identified a COL2A1 mutation in affected individuals. All cases represent de novo mutations.

• Hypochondrogenesis. This term has been used to describe a more mild variant of achondrogenesis (as, for example, hypochondroplasia is to achondroplasia).

• Spondyloepiphyseal dysplasia congenita (SED congenita) (OMIM 183900). Although the skeletal changes in SED congenita are similar to those seen in Stickler syndrome, they are more severe and result in significant short stature. In addition, individuals manifest flat facial profile, myopia, and vitreoretinal degeneration.

• Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type (OMIM 184250). The common clinical manifestations of this COL2A1-related skeletal disorder include severe short stature with severe pectus carinatum and scoliosis, cleft palate, and retinal detachment. A distinctive radiographic finding is irregular sclerotic changes (described as "dappled") in the metaphyses of the long bones. This mottled appearance is created by alternating zones of osteosclerosis and osteopenia. Radiologically, the disorder is indistinguishable from SED congenita during infancy. Tiller et al [1995] identified a heterozygous COL2A1 mutation, confirming that this is an autosomal dominant disorder.

• Kneist dysplasia (OMIM 156550). Affected individuals manifest disproportionate short stature, flat facial profile, myopia and vitreoretinal degeneration, cleft palate, kyphoscoliosis, and a variety of radiographic changes.

• Spondyloperipheral dysplasia (OMIM 271700). Zabel et al [1996] reported on an individual with short stature, radiographic changes consistent with a spondyloepiphyseal dysplasia, and brachydactyly E. A heterozygous COL2A1 mutation was identified in the C-terminus, resulting in a truncated C-propeptide region.

• Platyspondylic lethal skeletal dysplasia, Torrance type (PLSDT) (OMIM 151210). This disorder is characterized by platyspondyly, brachydactyly, and metaphyseal changes. It is generally a perinatal lethal disease. PLSDT is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain [Zankl et al 2005].

• Osteoarthritis with mild chondrodysplasia (OMIM 604864). Ala-Kokko et al [1990] were the first to identify a COL2A1 mutation in a kindred with an arginine-to-cysteine substitution at position 519 of the alpha-1(II) chain.

• Autosomal dominant rhegmatogenous retinal detachment (ARDD) is associated with pathologic myopia and vitreoretinal degeneration. Go et al [2003] described two large families with ARDD with linkage to COL2A1. Most had mild or absent systemic features of Stickler syndrome. In one family, a p.Arg653X mutation was found in the helical domain of COL2A1 resulting in protein truncation.

• Avascular necrosis of femoral head, primary (ANFH) (OMIM 608805). The disorder is characterized by progressive pain in the groin, mechanical failure of the subchondral bone, and degeneration of the hip joint. Nearly one-half of patients require hip replacement before age 40 years. ANFH represents a specific form of the broader disease category of osteonecrosis. Liu et al [2005] identified three families with COL2A1 mutations. Two of the families had a glycine 1170 to serine substitution and the third family had a glycine 717 to serine substitution.

Other phenotypes inherited in an autosomal dominant manner associated with mutations in COL11A1:

• Marshall syndrome (OMIM 154780). Individuals with Marshall syndrome manifest ocular hypertelorism, hypoplasia of the maxilla and nasal bones, flat nasal bridge, and small upturned nasal tip. In contrast to Stickler syndrome, the flat facial profile of Marshall syndrome is usually evident into adulthood. Radiographs demonstrate hypoplasia of the nasal sinuses and a thickened calvarium. Ocular manifestations include high myopia, fluid vitreous humor, and early-onset cataracts (subcapsular, cortical, nuclear, zonular, or anterior axial embryonic sites). Sensorineural hearing loss is common and can be progressive. Cleft palate, both as part of the Pierre Robin sequence and as an isolated anomaly, is seen. Other manifestations include short stature and early-onset arthritis. Skin manifestations include mild hypotrichosis and hypohidrosis [Griffith et al 1998, Shanske et al 1998]. Splice site mutations in COL11A1 have been identified by Griffith et al [1998], Annunen et al [1999], and Majava et al [2007].

Other phenotypes associated with mutations in COL11A2:

• Autosomal recessive otospondylometaepiphyseal dysplasia (OSMED) (OMIM 215150). This disorder is characterized by flat facial profile, cleft palate, and severe hearing loss [van Steensel et al 1997]. Vikkula et al [1995] and Melkoniemi et al [2000] identified homozygous loss-of-function mutations of COL11A2 in individuals with OSMED. It has been suggested that anocular Stickler syndrome (caused by heterozygous COL11A2 mutations) is more appropriately considered a type of OSMED because of its closer similarity to OSMED than Stickler syndrome.

• Weissenbach-Zweymuller syndrome (WZS) (OMIM 277610). WZS has been described as "neonatal Stickler syndrome," but is actually a distinct entity. It is characterized by midface hypoplasia with a flat nasal bridge, small upturned nasal tip, micrognathia, sensorineural hearing loss, and rhizomelic limb shortening. Radiographic findings include dumbbell-shaped femora and humeri and vertebral coronal clefts. The skeletal findings become less apparent in later years, and catch-up growth after age two to three years is common. Although myopia has been reported in some individuals, it is not a manifestation of WZS. WZS is inherited in an autosomal dominant manner. Pihlajamaa et al [1998] identified a mutation in COL11A2 in Weissenbacher & Zweymueller [1964] original family.

• Nonsyndromic sensorineural hearing loss (DFNA13) (OMIM 601868). McGuirt et al [1999] reported heterozygous mutations in COL11A2 in two unrelated families with autosomal dominant non-progressive predominantly middle-frequency nonsyndromic deafness. The deafness in these families had previously been mapped to 6p21.3 and designated DFNA13 (see Hereditary Hearing Loss and Deafness Overview).

Other phenotypes associated with mutations in COL9A1 and COL9A2:

• Multiple epiphyseal dysplasia 6 (EDM6) (OMIM 614135) and multiple epiphyseal dysplasia 2 (EDM2) (OMIM 600204). MED is a clinically heterogeneous autosomal dominantly inherited chondrodysplasia. Symptoms first occur in childhood (age 2-14 years) and include waddling gait, restriction of joint mobility, and pain and stiffness in weight-bearing joints [Jackson et al 2010]. See Multiple Epiphyseal Dysplasia, Dominant.

Natural History

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

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”), which is much less common, is characterized by sparse and irregularly thickened bundles throughout the vitreous cavity.

These ocular phenotypes run true within families [Snead & Yates 1999].

Posterior chorioretinal atrophy was described by Vu et al [2003] in a family with vitreoretinal dystrophy, a novel mutation 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 disease.

Craniofacial findings include a flat facial profile 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. The midfacial hypoplasia 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.

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

Some degree of sensorineural hearing impairment is found in 40% of individuals — typically high-tone, often subtle [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 siblings, and radiographic findings consistent with mild spondyloepiphyseal dysplasia. Some individuals have a marfanoid 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 and no individuals in another.

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 mutations. The majority of individuals who have Stickler syndrome as a result of COL2A1 mutations, including the kindred originally reported by Stickler et al [1965], have premature stop (i.e., nonsense, frameshift, or splicing) mutations 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, normal hearing or mild sensorineural hearing loss, and precocious osteoarthritis. The craniofacial features are variable, ranging from mild nasal anteversion to Robin sequence [Faber et al 2000]. A large family with linkage to COL2A1 revealed a unique p.Leu667Phe mutation producing a novel "afibrillar" vitreous gel devoid of all normal lamella structure [Richards et al 2000].
  A COL2A1 missense mutation 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 mutations may also cause Stickler syndrome. Mutations involving exon 2 of COL2A1 are characterized by a predominantly ocular variant, in which individuals are at high risk for retinal detachment.
  In the nine families with exon 2 mutations of COL2A1 reported by Donoso et al [2003], all mutations 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 system findings of Stickler syndrome.

• COL11A1 mutations. Missense, splicing, and deletion mutations 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 mutations. Mutations in COL11A2 have been shown to cause autosomal dominant non-ocular Stickler syndrome.

• COL9A1 mutations. Mutations 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 types.

• COL9A2 mutations. Mutations 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.

Penetrance

Penetrance is complete.

Anticipation

Anticipation is not observed.

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].

Evaluations Following Initial Diagnosis

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

• 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.

• Genetics consultation

Treatment of Manifestations

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.

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.

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 MVP 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 MVP among affected individuals is unclear, all individuals with Stickler syndrome should be screened for MVP through routine physical examination. More advanced testing such as echocardiogram should be reserved for those with suggestive symptoms.

Agents/Circumstances to Avoid

Affected individuals should be advised to avoid activities such as contact sports that may lead to traumatic retinal detachment.

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 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 disease-causing mutation in the family is 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 Clinical Trials.gov 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.

Other

Genetics clinics, staffed by genetics professionals, provide 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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

COL2A1, COL11A1 and COL11A2-related Stickler syndrome are inherited in an autosomal dominant manner.

COL9A1 and COL9A2-related Stickler syndrome is inherited in an autosomal recessive manner.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

• The majority of individuals with Stickler syndrome have inherited the mutation from a parent.

• A proband with Stickler syndrome may have the disorder as the result of a de novo mutation. The prevalence of de novo mutations is not known.

• When the diagnosis of Stickler syndrome is considered in an individual, it is appropriate to evaluate both parents for manifestations of Stickler syndrome (see Management).

Sibs of a proband

• The risk to sibs depends on the genetic status of the parents.

• If a parent has Stickler syndrome, the risk to each sib of a proband is 50%.

• When the parents are clinically unaffected and/or the disease-causing mutation identified in the proband has not been identified in either parent, the risk to the sibs of a proband appears to be low.

• If the disease-causing mutation cannot be detected in the DNA of either parent of the proband, it is presumed that the proband has a de novo gene mutation. No instances of germline mosaicism have been reported, although it remains a possibility.

Offspring of a proband. Each child of an individual with Stickler syndrome has a 50% chance of inheriting the disease-causing mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

• The parents of a child with COL9A1 or COL9A2-related Stickler syndrome 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 COL9A1- or COL9A2-related Stickler syndrome are obligate heterozygotes (carriers) for a disease-causing mutation.

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 family members at risk of having inherited a COL9A1 or COL9A2 mutation is possible on a clinical basis once the mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

High-risk pregnancies

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

• Ultrasound evaluation. Alternatively, or in conjunction with molecular genetic testing, ultrasound examination can be performed at 19 to 20 weeks' gestation to detect cleft palate. Absence of a cleft palate, however, does not exclude the diagnosis of Stickler syndrome.

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

Low-risk pregnancies. For fetuses with no known family history of Stickler syndrome, but in which cleft palate is detected prenatally, it is appropriate to obtain a three-generation pedigree and to evaluate relatives who have findings suggestive of Stickler syndrome. Molecular genetic testing of the fetus is usually not offered in the absence of a known disease-causing mutation in a parent.

Requests for prenatal testing for conditions which (like Stickler syndrome) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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2. Ala-Kokko L, Baldwin CT, Moskowitz RW, Prockop DJ. Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc Natl Acad Sci U S A. 1990;87:6565–8. [PMC free article: PMC54577] [PubMed: 1975693]
3. Annunen S, Korkko J, Czarny M, Warman ML, Brunner HG, Kaariainen H, Mulliken JB, Tranebjaerg L, Brooks DG, Cox GF, Cruysberg JR, Curtis MA, Davenport SL, Friedrich CA, Kaitila I, Krawczynski MR, Latos-Bielenska A, Mukai S, Olsen BR, Shinno N, Somer M, Vikkula M, Zlotogora J, Prockop DJ, Ala-Kokko L. Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. Am J Hum Genet. 1999;65:974–83. [PMC free article: PMC1288268] [PubMed: 10486316]
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Revision History

• 3 November 2011 (me) Comprehensive update posted live

• 21 October 2010 (cd) Revision: deletion/duplication analysis available clinically for COL11A1 and COL11A2

• 20 August 2009 (me) Comprehensive update posted live

• 2 August 2005 (me) Comprehensive update posted to live Web site

• 18 January 2005 (bp/cd) Revision: sequence analysis for Stickler I, II, III

• 16 June 2003 (ca) Comprehensive update posted to live Web site

• 9 June 2000 (me) Review posted to live Web site

• 31 August 1999 (nr) Original submission