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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Stickler Syndrome

Synonym: Arthro-Ophthalmopathy. Includes: COL11A1-Related Stickler Syndrome, COL11A2-Related Stickler Syndrome, COL2A1-Related Stickler Syndrome, COL9A1-Related Stickler Syndrome, COL9A2-Related Stickler Syndrome

, MD, , MD, , MD, and , MD, PhD.

Author Information
, MD
Department of Genetics and Pediatrics
University of Alabama
Birmingham, Alabama
, MD
Genomic Medicine Institute
Cleveland Clinic Foundation
Cleveland, Ohio
, MD
Center for the Study of Genetic Skeletal Disorders
Children’s Hospital Boston
Boston, Massachusetts
, MD, PhD
Connective Tissue Gene Tests
Allentown, Pennsylvania

Initial Posting: ; Last Update: November 3, 2011.

Summary

Disease 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. Mutations affecting one of five genes (COL2A1, COL9A1, COL9A2, COL11A1, and COL11A2) have been associated with Stickler syndrome; because a few families with features of Stickler syndrome are not linked to any of these four loci, mutations 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 mitral valve prolapse in some circumstances.

Surveillance: Annual examination by a vitreoretinal specialist; audiologic evaluations every six months through age five years, then annually thereafter; screening for 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 mutations in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner; Stickler syndrome caused by mutations in COL9A1 or COL9A2 is inherited in an autosomal recessive manner. In families with autosomal dominant inheritance, affected individuals have a 50% chance of passing on the mutation to each 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 disease-causing mutation(s) in the family are known.

Diagnosis

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

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

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

Gene Symbol% of Disease Attributed to Mutations in This Gene 1Test MethodMutations Detected
COL2A180%-90%Sequence analysisSequence variants 2
Deletion / duplication analysis 3Exonic or whole-gene deletions
COL11A110%-20%Sequence analysisSequence variants 2
Deletion / duplication analysis 3Exonic or whole-gene deletions
COL11A2Rare, unknownSequence analysisSequence variants 2
Deletion / duplication analysis 3Exonic or whole-gene deletions 4
COL9A1Rare, unknownSequence analysisSequence variants 2
Deletion / duplication analysis 3Exonic or whole-gene deletions 4
COL9A2Rare, unknownSequence analysisSequence variants 2
Deletion / duplication analysis 3Exonic or whole-gene deletions 4

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.

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. Genes and Databases 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.

Clinical Description

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].

Differential Diagnosis

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

For allelic disorders see Genetically Related Disorders.

Wagner syndrome (OMIM 143200). Described by Wagner [1938], this condition is characterized by the presence of ocular findings similar to those seen in Stickler syndrome and Marshall syndrome but without the other clinical manifestations. The ocular findings, which progress in severity with age, include high myopia, an empty vitreous cavity with avascular strands, chorioretinal atrophy, and cataract. Retinal detachment and glaucoma are also observed. Abnormalities with dark adaptation are evident on electroretinography. The gene in which mutation is responsible for Wagner syndrome is VCAN. Meredith et al [2007] further delineated the ocular manifestations of Wagner syndrome as vitreous syneresis, thickening and incomplete separation of the posterior hyaloid membrane, chorioretinal changes accompanied by subnormal electroretinographic responses, an ectopic fovea, early-onset cataract, and in their family, anterior uveitis without formation of synechiae.

High-grade myopia is a refractive error greater than or equal to −6 diopters. Several loci for myopia have been mapped (Table 2).

Table 2. Mapped Loci for Myopia

Locus NameLocusOMIM
MYP1Xq28310460
MYP218p11.31160700
MYP312q603221
MYP517q21-q22608474
MYP622q12608908
MYP711p13609256
MYP83q26609257
MYP94q12609258
MYP108p23609259
MYP114q22-q27609994
MYP122q37.1609995
MYP13Xq23-q27.2300613
MYP14610320
MYP1517q21-q22608474
MYP165p15.33-p15.2612554
MYP177p15608367
MYP1814q22.1-q24.2255500
MYP195p15.1-p13.3613969

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 maps to 10q21 [Ghiasvand et al 2000].

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].

Binder syndrome (maxillonasal dysplasia) (OMIM 155050). This condition is characterized by midfacial hypoplasia 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].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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.

Prenatal Testing

High-risk pregnancies

  • Molecular genetic testing. If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).
  • 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 an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Stickler Involved People (SIP)
    15 Angelina
    Augusta KS 67010
    Phone: 316-259-5194
    Email: sip@sticklers.org
  • Stickler Syndrome Support Group (SSSG)
    PO Box 3351
    Littlehampton West Sussex BN16 9GB
    United Kingdom
    Phone: 01903 785771
    Email: info@stickler.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Stickler Syndrome (View All in OMIM)

108300STICKLER SYNDROME, TYPE I; STL1
120140COLLAGEN, TYPE II, ALPHA-1; COL2A1
120210COLLAGEN, TYPE IX, ALPHA-1; COL9A1
120260COLLAGEN, TYPE IX, ALPHA-2; COL9A2
120280COLLAGEN, TYPE XI, ALPHA-1; COL11A1
120290COLLAGEN, TYPE XI, ALPHA-2; COL11A2
184840STICKLER SYNDROME, TYPE III; STL3
604841STICKLER SYNDROME, TYPE II; STL2
614134STICKLER SYNDROME, TYPE IV; STL4
614284STICKLER SYNDROME, TYPE V; STL5

COL2A1

Normal allelic variants. COL2A1 comprises 54 exons.

Pathologic allelic variants. Over 17 different mutations resulting in (or predictive of) premature termination of translation, either by single base substitution or by insertion or deletion of a small number of nucleotides, have been reported to cause Stickler syndrome.

Table 3. Selected COL2A1 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.1957C>Tp.Arg653X
(p.Arg453X)
NM_001844​.4
NP_001835​.3
c.1999C>Tp.Leu667Phe
(p.Leu467Phe)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions. In this instance, the amino acid residues are numbered from the beginning of the mature protein.

Normal gene product. COL2A1 encodes the chains of type II collagen, a major structural component of cartilaginous tissues.

Abnormal gene product. Mutations of COL2A1 typically result in premature termination of translation and decreased synthesis of type II.

COL11A1

Normal allelic variants. COL11A1 comprises 68 exons.

Pathologic allelic variants. Several mutations resulting in aberrant splicing, missense mutations, and in-frame deletions have been described.

Normal gene product. COL11A1 encodes for the alpha 1 chain of type XI collagen. It is presumed to play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.

Abnormal gene product. Mutations in COL11A1 generally lead to disruption of the Gly-X-Y collagen sequence and impaired synthesis or function of type XI collagen.

COL11A2

Normal allelic variants. COL11A2 comprises 66 exons.

Pathologic allelic variants. Mutations resulting in aberrant splicing, exon skipping, and in-frame deletions have been described in individuals with non-ocular Stickler syndrome.

Normal gene product. COL11A2 encodes for the alpha 2 chain of type XI collagen expressed in cartilage but not in adult liver, skin, tendon, or vitreous.

Abnormal gene product. Mutations of COL11A2 are speculated to result in abnormal synthesis or function of type XI collagen.

COL9A1

Normal allelic variants. COL9A1 comprises 38 exons.

Pathologic allelic variants. Mutation analysis of the coding region of COL9A1 showed a homozygous p.Arg295X mutation in the four affected children in the consanguineous family reported by Van Camp et al [2006]. The parents and four unaffected sibs were heterozygous carriers and two unaffected sibs were homozygous for the wildtype allele.

Table 4. Selected COL9A1 Pathologic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.885C>Tp.Arg295XNM_001851​.3
NP_001842​.3

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. COL9A1 codes for the alpha 1 chain of type IX collagen, a minor component of cartilaginous tissues.

Abnormal gene product. Homozygous mutations are predicted to result in loss of function.

COL9A2

Normal allelic variants. COL9A2 comprises 32 exons.

Pathogenic allelic variants. Mutation analysis of the coding region of COL9A2 showed a homozygous mutation, c.843_846+4del8, in the two affected children in the consanguineous family reported by Baker et al [2011]. The parents and an unaffected sib were heterozygous carriers of the mutation.

Table 5. Selected COL9A2 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.843_846+4del8p.(Asp281Glnfs*70) 1NM_001852​.3
NP_001843​.1

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Parenthesis indicates predicted change; experimental proof from mRNA analysis has not been determined (www​.hgvs.org ).

Normal gene product. COL9A2 codes for alpha 2 chain of type IX collagen, a minor component of cartilaginous tissues.

Abnormal gene product. Homozygous mutations are predicted to result in loss of function.

References

Literature Cited

  1. Admiraal RJ, Brunner HG, Dijkstra TL, Huygen PL, Cremers CW. Hearing loss in the nonocular Stickler syndrome caused by a COL11A2 mutation. Laryngoscope. 2000;110:457–61. [PubMed: 10718438]
  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]
  4. Baker S, Booth C, Fillman C, Shapiro M, Blair MP, Hyland JC, Ala-Kokko L. A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome. Am J Med Genet A. 2011;155A:1668–72. [PubMed: 21671392]
  5. Donoso LA, Edwards AO, Frost AT, Ritter R, Ahmad N, Vrabec T, Rogers J, Meyer D, Parma S. Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene. Surv Ophthalmol. 2003;48:191–203. [PubMed: 12686304]
  6. Evans AK, Rahbar R, Rogers GF, Mulliken JB, Volk MS. Robin sequence: a retrospective review of 115 patients. Int J Pediatr Otorhinolaryngol. 2006;70:973–80. [PubMed: 16443284]
  7. Faber J, Winterpacht A, Zabel B, Gnoinski W, Schinzel A, Steinmann B, Superti-Furga A. Clinical variability of Stickler syndrome with a COL2A1 haploinsufficiency mutation: implications for genetic counselling. J Med Genet. 2000;37:318–20. [PMC free article: PMC1734568] [PubMed: 10819645]
  8. Ghiasvand NM, Kanis AB, Helms C, Sheffield VC, Stone EM, Donis-Keller H. Nonsyndromic congenital retinal nonattachment gene maps to human chromosome band 10q21. Am J Med Genet. 2000;90:165–8. [PubMed: 10607958]
  9. Go SL, Maugeri A, Mulder JJ, van Driel MA, Cremers FP, Hoyng CB. Autosomal dominant rhegmatogenous retinal detachment associated with an Arg453Ter mutation in the COL2A1 gene. Invest Ophthalmol Vis Sci. 2003;44:4035–43. [PubMed: 12939326]
  10. Griffith AJ, Sprunger LK, Sirko-Osadsa DA, Tiller GE, Meisler MH, Warman ML. Marshall syndrome associated with a splicing defect at the COL11A1 locus. Am J Hum Genet. 1998;62:816–23. [PMC free article: PMC1377029] [PubMed: 9529347]
  11. Jackson GC, Marcus-Soekarman D, Stolte-Dijkstra I, Verrips A, Taylor JA, Briggs MD. Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy. Am J Med Genet. 2010;152A:863–9. [PMC free article: PMC3557369] [PubMed: 20358595]
  12. Lee MM, Ritter R, Hirose T, Vu CD, Edwards AO. Snowflake vitreoretinal degeneration: follow-up of the original family. Ophthalmology. 2003;110:2418–26. [PubMed: 14644728]
  13. Liberfarb RM, Levy HP, Rose PS, Wilkin DJ, Davis J, Balog JZ, Griffith AJ, Szymko-Bennett YM, Johnston JJ, Francomano CA, Tsilou E, Rubin BI. The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med. 2003;5:21–7. [PubMed: 12544472]
  14. Liu Y-F, Chen W-M, Lin Y-F, Yang R-C, Lin M-W, Li L-H, Chang Y-H, Jou Y-S, Lin P-Y, Su J-S, Huang S-F, Hsaio K-J, Fann CSJ, Hwang H-W, Chen Y-T, Tsai S-F. Type II collagen variants and inherited osteonecrosis of the femoral head. New Eng J Med. 2005;352:2294–301. [PubMed: 15930420]
  15. Majava M, Hoornaert KP, Bartholdi D, Bouma MC, Bouman K, Carrera M, Devriendt K, Hurst J, Kitsos G, Niedrist D, Petersen MB, Shears D, Stolte-Dijkstra I, Van Hagen JM, Ala-Kokko L, Männikkö M, Mortier G. A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies. Am J Med Genet A. 2007;143:258–64. [PubMed: 17236192]
  16. Martin S, Richards AJ, Yates JR, Scott JD, Pope M, Snead MP. Stickler syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity. Eur J Hum Genet. 1999;7:807–14. [PubMed: 10573014]
  17. McGuirt WT, Prasad SD, Griffith AJ, Kunst HP, Green GE, Shpargel KB, Runge C, Huybrechts C, Mueller RF, Lynch E, King MC, Brunner HG, Cremers CW, Takanosu M, Li SW, Arita M, Mayne R, Prockop DJ, Van Camp G, Smith RJ. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat Genet. 1999;23:413–9. [PubMed: 10581026]
  18. Melkoniemi M, Brunner HG, Manouvrier S, Hennekam R, Superti-Furga A, Kaariainen H, Pauli RM, van Essen T, Warman ML, Bonaventure J, Miny P, Ala-Kokko L. Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. Am J Hum Genet. 2000;66:368–77. [PMC free article: PMC1288089] [PubMed: 10677296]
  19. Meredith SP, Richards AJ, Flanagan DW, Scott JD, Poulson AV, Snead MP. Clinical characterisation and molecular analysis of Wagner syndrome. Br J Ophthalmol. 2007;91:655–9. [PMC free article: PMC1954774] [PubMed: 17035272]
  20. Nikopoulos K, Schrauwen I, Simon M, Collin RW, Veckeneer M, Keymolen K, Van Camp G, Cremers FP, van den Born LI. Autosomal recessive Stickler syndrome in two families is caused by mutations in the COL9A1 gene. Invest Ophthalmol Vis Sci. 2011;52:4774–9. [PubMed: 21421862]
  21. Parentin F, Sangalli A, Mottes M, Perissutti P. Stickler syndrome and vitreoretinal degeneration: correlation between locus mutation and vitreous phenotype. Apropos of a case. Graefes Arch Clin Exp Ophthalmol. 2001;239:316–9. [PubMed: 11450497]
  22. Pihlajamaa T, Prockop DJ, Faber J, Winterpacht A, Zabel B, Giedion A, Wiesbauer P, Spranger J, Ala-Kokko L. Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymuller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome). Am J Med Genet. 1998;80:115–20. [PubMed: 9805126]
  23. Printzlau A, Andersen M. Pierre Robin sequence in Denmark: a retrospective population-based epidemiological study. Cleft Palate Craniofac J. 2004;41:47–52. [PubMed: 14697070]
  24. Richards AJ, Baguley DM, Yates JR, Lane C, Nicol M, Harper PS, Scott JD, Snead MP. Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix. Am J Hum Genet. 2000;67:1083–94. [PMC free article: PMC1288550] [PubMed: 11007540]
  25. Rose PS, Ahn NU, Levy HP, Ahn UM, Davis J, Liberfarb RM, Nallamshetty L, Sponseller PD, Francomano CA. Thoracolumbar spinal abnormalities in Stickler syndrome. Spine. 2001;26:403–9. [PubMed: 11224888]
  26. Roy-Doray B, Geraudel A, Alembik Y, Stoll C. Binder syndrome in a mother and her son. Genet Couns. 1997;8:227–33. [PubMed: 9327267]
  27. Shanske A, Bogdanow A, Shprintzen RJ, Marion RW. Marshall syndrome and a defect at the COL11A1 locus. Am J Hum Genet. 1998;63:1558–61. [PMC free article: PMC1377567] [PubMed: 9792885]
  28. Snead MP, Yates JR. Clinical and Molecular genetics of Stickler syndrome. J Med Genet. 1999;36:353–9. [PMC free article: PMC1734362] [PubMed: 10353778]
  29. Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG, Steinberg AG, Ward LE. Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc. 1965;40:433–55. [PubMed: 14299791]
  30. Szymko-Bennett YM, Mastroianni MA, Shotland LI, Davis J, Ondrey FG, Balog JZ, Rudy SF, McCullagh L, Levy HP, Liberfarb RM, Francomano CA, Griffith AJ. Auditory dysfunction in Stickler syndrome. Arch Otolaryngol Head Neck Surg. 2001;127:1061–8. [PubMed: 11556853]
  31. Tiller GE, Polumbo PA, Weis MA, Bogaert R, Lachman RS, Cohn DH, Rimoin DL, Eyre DR. Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepimetaphyseal dysplasia, Strudwick type. Nat Genet. 1995;11:87–9. [PubMed: 7550321]
  32. Van Camp G, Snoeckx RL, Hilgert N, van den Ende J, Fukuoka H, Wagatsuma M, Suzuki H, Smets RM, Vanhoenacker F, Declau F, Van de Heyning P, Usami S. A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am J Hum Genet. 2006;79:449–57. [PMC free article: PMC1559536] [PubMed: 16909383]
  33. van den Elzen AP, Semmekrot BA, Bongers EM, Huygen PL, Marres HA. Diagnosis and treatment of the Pierre Robin sequence: results of a retrospective clinical study and review of the literature. Eur J Pediatr. 2001;160:47–53. [PubMed: 11195018]
  34. Van Der Hout AH, Verlind E, Beemer FA, Buys CH, Hofstra RM, Scheffer H. Occurrence of deletion of a COL2A1 allele as the mutation in Stickler syndrome shows that a collagen type II dosage effect underlies this syndrome. Hum Mutat. 2002;20(3):236. [PubMed: 12204008]
  35. van Steensel MA, Buma P, de Waal Malefijt MC, van den Hoogen FH, Brunner HG. Oto-spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am J Med Genet. 1997;70:315–23. [PubMed: 9188673]
  36. Vikkula M, Mariman EC, Lui VC, Zhidkova NI, Tiller GE, Goldring MB, van Beersum SE, de Waal Malefijt MC, van den Hoogen FH, Ropers HH. et al. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell. 1995;80:431–7. [PubMed: 7859284]
  37. Vissing H, D'Alessio M, Lee B, Ramirez F, Godfrey M, Hollister DW. Glycine to serine substitution in the triple helical domain of pro-alpha 1 (II) collagen results in a lethal perinatal form of short-limbed dwarfism. J Biol Chem. 1989;264:18265–7. [PubMed: 2572591]
  38. Vu CD, Brown J, Korkko J, Ritter R, Edwards AO. Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene. Ophthalmology. 2003;110:70–7. [PubMed: 12511349]
  39. Wagner H. Ein bisher unbeknantes Erbleiden des Auges (degeneratiohyaloideo-retinalis hereditaria), beobachtet im Kanton, Zurich. Klin Mbl Augenheilk. 1938;100:840–57.
  40. Weissenbacher G, Zweymueller E. Simultaneous occurrance of the pierre robin syndrome and fetal chondrodysplasia. Monatsschr Kinderheilkd. 1964;112:315–7. [PubMed: 14234962]
  41. Zabel B, Hilbert K, Stoss H, Superti-Furga A, Spranger J, Winterpacht A. A specific collagen type II gene (COL2A1) mutation presenting as spondyloperipheral dysplasia. Am J Med Genet. 1996;63:123–8. [PubMed: 8723097]
  42. Zankl A, Neumann L, Ignatius J, Nikkels P, Schrander-Stumpel C, Mortier G, Omran H, Wright M, Hilbert K, Bonafe L, Spranger J, Zabel B, Superti-Furga A. Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, Torrance type, and define a novel subfamily within the type 2 collagenopathies. Am J Med Genet. 2005;133A:61–7. [PubMed: 15643621]

Chapter Notes

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
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