Stickler Syndrome

Synonym: Arthroophthalmopathy

Robin NH, Moran RT, Ala-Kokko L.

Publication Details

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 multi-gene panel, and more comprehensive genomic testing:

  • 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 multi-gene 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 varies by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.
    For more information on multi-gene panels click 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 more information on comprehensive genome sequencing click here.
Table 1.

Table 1.

Molecular Genetic Testing Used in Stickler Syndrome

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. [Sirko-Osadsa et al 1998, Vikkula et al 1995, 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 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

Stickler syndrome caused by heterozygous pathogenic variants in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner.

Stickler syndrome caused by biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • The majority of individuals with autosomal dominant Stickler syndrome inherited a COL2A1, COL11A1, or COL11A2 pathogenic variant from a parent.
  • A proband with Stickler syndrome may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is not known.
  • It is appropriate to evaluate both parents of a proband for manifestations of Stickler syndrome (see Management) and, if a pathogenic variant has been identified in the proband, offer molecular genetic testing.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.

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 pathogenic variant identified in the proband has not been identified in the leukocyte DNA of either parent, it is presumed that the variant occurred de novo and risk to sibs is low. No instances of germline mosaicism have been reported, although it remains a theoretic possibility.

Offspring of a proband. Each child of an individual with Stickler syndrome has a 50% chance of inheriting the pathogenic variant.

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 Stickler syndrome caused by biallelic pathogenic variants COL9A1, COL9A2, or COL9A3 are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with autosomal recessive Stickler syndrome are obligate heterozygotes (carriers) for a COL9A1, COL9A2, or COL9A3 pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a COL9A1, COL9A2, or COL9A3 pathogenic variant.

Carrier (heterozygote) detection. Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Related Genetic Counseling Issues

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

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

High-risk pregnancies

  • Molecular genetic testing. Once the pathogenic variant(s) in a family with Stickler syndrome have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
  • 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.

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 pathogenic variant in a parent.

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.

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.

  • My46 Trait Profile
  • 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 A.

Table A.

Stickler Syndrome: Genes and Databases

Table B.

Table B.

OMIM Entries for Stickler Syndrome (View All in OMIM)

COL2A1

Gene structure. COL2A1 comprises 54 exons. COL2A1 has one alternatively spliced exon and two different isoforms. NM_001844.4 is the longer transcript and it encodes for 1487 amino acids in 54 exons. This variant is mainly expressed in the vitreous humor of the eye. Variants in the alternatively spliced exon typically result in a predominantly ocular variant of Stickler syndrome. NM_033150.2 is the shorter transcript encoding 1418 amino acids in 53 exons. By convention, the longest transcript variant is used as the reference sequence (Table 3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 17 different pathogenic variants 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.

Table 3.

Selected COL2A1 Pathogenic Variants

Normal gene product. COL2A1 encodes the chains of type II collagen, a major structural component of cartilaginous tissues. See COL2A1, Gene structure for different protein isoforms.

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

COL11A1

Gene structure. COL11A1 comprises 68 exons. COL11A1 has alternative splice variants, which encode different isoforms. NM_080629.2 is the longest transcript encoding 1818 amino acids in 67 exons. The three other transcript variants are known to encode protein isoforms of varying lengths. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Splice site variants, missense variants, 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. Pathogenic variants in COL11A1 generally lead to disruption of the Gly-X-Y collagen sequence and impaired synthesis or function of type XI collagen.

COL11A2

Gene structure. COL11A2 comprises 66 exons. COL11A1 has alternative splice variants, which encode different isoforms. NM_080680.2 is the longest transcript encoding 1736 amino acids in 66 exons. The three other transcript variants are known to encode protein isoforms of varying lengths For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. In-frame deletions and variants resulting in aberrant splicing and exon skipping 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. Pathogenic variants of COL11A2 are speculated to result in abnormal synthesis or function of type XI collagen.

COL9A1

Gene structure. COL9A1 comprises 38 exons. COL9A1 had two transcript variants, NM_001851.4 and NM_078485.3. They encode 921 and 678 amino acids in 38 and 32 exons, respectively. The shorter isoform results from the use of an alternative downstream transcription initiation site. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Sequence analysis of the coding region of COL9A1 showed homozygosity for the p.Arg295Ter pathogenic variant 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.

Table 4.

Selected COL9A1 Pathogenic Variants

Normal gene product. COL9A1 codes for the alpha 1 chain of type IX collagen. Type IX collagen is a structural component of hyaline cartilage, vitreous of the eye and intervertebral disc.

Abnormal gene product. Biallelic pathogenic variants are predicted to result in loss of function.

COL9A2

Gene structure. COL9A2 NM_001852.3 comprises 32 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Sequence analysis of the coding region of COL9A2 showed homozygosity for the pathogenic variant, 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 pathogenic variant.

Table 5.

Table 5.

Selected COL9A2 Pathogenic Variants

Normal gene product. COL9A2 codes for a 689-amino acid alpha 2 chain of type IX collagen. Type IX collagen is a structural component of hyaline cartilage, vitreous of the eye, and intervertebral disc.

Abnormal gene product. Biallelic pathogenic variants are predicted to result in loss of function.

COL9A3

Gene structure. COL9A3 transcript NM_001853.3 comprises 32 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Three sibs affected with autosomal recessive Stickler syndrome were homozygous for a COL9A3 loss-of-function variant [Faletra et al 2014].

Normal gene product. COL9A3 codes for the 680-amino acid alpha 3 chain of type IX collagen. Type IX collagen is a structural component of hyaline cartilage, vitreous of the eye, and intervertebral disc.

Abnormal gene product. Biallelic pathogenic variants are predicted to result in loss of function.

References

Literature Cited

  • Acke FR, Malfait F, Vanakker OM, Steyaert W, De Leeneer K, Mortier G, Dhooge I, De Paepe A, De Leenheer EM, Coucke PJ. Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing. Mol Genet Metab. 2014;113:230–5. [PubMed: 25240749]

  • 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]

  • Ahmad N, Richards AJ, Murfett HC, Shapiro L, Scott JD, Yates JR, Norton J, Snead MP. Prevalence of mitral valve prolapse in Stickler syndrome. Am J Med Genet. 2003;116A:234–7. [PubMed: 12503098]

  • Annunen S, Körkkö J, Czarny M, Warman ML, Brunner HG, Kääriäinen 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]

  • 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]

  • Donoso LA, Edwards AO, Frost AT, Ritter R 3rd, 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]

  • 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]

  • 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. [letter] [PMC free article: PMC1734568] [PubMed: 10819645]

  • Faletra F, D'Adamo AP, Bruno I, Athanasakis E, Biskup S, Esposito L, Gasparini P. Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene. Am J Med Genet A. 2014;164A:42–7. [PubMed: 24273071]

  • Lee MM, Ritter R 3rd, Hirose T, Vu CD, Edwards AO. Snowflake vitreoretinal degeneration: follow-up of the original family. Ophthalmology. 2003;110:2418–26. [PubMed: 14644728]

  • Liberfarb RM, Goldblatt A. Prevalence of mitral-valve prolapse in the Stickler syndrome. Am J Med Genet. 1986;24:387–92. [PubMed: 3728560]

  • 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]

  • 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;143A:258–64. [PubMed: 17236192]

  • 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]

  • 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]

  • 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]

  • 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]

  • 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]

  • Richards AJ, McNinch A, Martin H, Oakhill K, Rai H, Waller S, Treacy B, Whittaker J, Meredith S, Poulson A, Snead MP. Stickler syndrome and the vitreous phenotype: mutations in COL2A1 and COL11A1. Hum Mutat. 2010;31:E1461–71. [PubMed: 20513134]

  • 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]

  • Rose PS, Levy HP, Liberfarb RM, Davis J, Szymko-Bennett Y, Rubin BI, Tsilou E, Griffith AJ, Francomano CA. Stickler syndrome: clinical characteristics and diagnostic criteria. Am J Med Genet Part A. 2005;138A:199–207. [PubMed: 16152640]

  • 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]

  • Sirko-Osadsa DA, Murray MA, Scott JA, Lavery MA, Warman ML, Robin NH. Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha2(XI) chain of type XI collagen. J Pediatr. 1998;132:368–71. [PubMed: 9506662]

  • Snead MP, Yates JR. Clinical and Molecular genetics of Stickler syndrome. J Med Genet. 1999;36:353–9. [PMC free article: PMC1734362] [PubMed: 10353778]

  • 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]

  • 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]

  • 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]

  • 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;20:236. [PubMed: 12204008]

  • Vijzelaar R, Waller S, Errami A, Donaldson A, Lourenco T, Rodrigues M, McConnell V, Fincham G, Snead M, Richards A. Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA). BMC Med Genet. 2013;14:48. [PMC free article: PMC3652776] [PubMed: 23621912]

  • 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, Mayne R, Cheah KSE, Olsen BR, Warman ML, Brunner HG. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell. 1995;80:431–7. [PubMed: 7859284]

  • Vu CD, Brown J Jr, Korkko J, Ritter R 3rd, 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]

  • Vuoristo MM, Pappas JG, Jansen V, Ala-Kokko L. A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome. Am J Med Genet A. 2004;130A:160–4. [PubMed: 15372529]

Chapter Notes

Author History

Leena Ala-Kokko, MD, PhD (2000-present)
Rocio T Moran, MD (2000-present)
Nathaniel H Robin, MD (2000-present)
Matthew Warman, MD; Children’s Hospital Boston (2000-2011)

Revision History

  • 16 March 2017 (ha) Comprehensive update posted live
  • 26 November 2014 (aa) Revision: additions to Genetically Related Disorders
  • 11 September 2014 (me) Comprehensive update posted live
  • 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