Stickler syndrome
General Information (adopted from Orphanet):
Synonyms, Signs: |
Hereditary progressive arthroophthalmopathy |
Number of Symptoms | 78 |
OrphanetNr: | 828 |
OMIM Id: |
108300
604841 609508 614134 614284 |
ICD-10: |
Q87.5 |
UMLs: |
C0265253 |
MeSH: |
C537492 |
MedDRA: |
10063402 |
Snomed: |
78675000 |
Prevalence, inheritance and age of onset:
Prevalence: | 0.5 of 100 000 [Orphanet] |
Inheritance: |
Autosomal dominant Autosomal recessive [Orphanet] |
Age of onset: |
Childhood [Orphanet] |
Disease classification (adopted from Orphanet):
Parent Diseases: |
Musculoskeletal disease with cataract
-Rare eye disease -Rare genetic disease Pierre Robin syndrome associated with collagen disease -Rare developmental defect during embryogenesis -Rare genetic disease -Rare maxillo-facial surgical disease -Rare otorhinolaryngologic disease Rare disease with glaucoma as a major feature -Rare eye disease -Rare genetic disease Spondyloepiphyseal dysplasia and spondyloepimetaphyseal dysplasia -Rare bone disease -Rare developmental defect during embryogenesis -Rare genetic disease Syndromic developmental defect of the eye -Rare developmental defect during embryogenesis -Rare eye disease -Rare genetic disease Syndromic genetic deafness -Rare developmental defect during embryogenesis -Rare genetic disease -Rare otorhinolaryngologic disease Syndromic myopia -Rare eye disease -Rare genetic disease Vitreoretinal degeneration -Rare eye disease -Rare genetic disease |
Symptom Information:
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(HPO:0003196) | Short nose | Very frequent [Orphanet] | 264 / 7739 | |||
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(HPO:0000682) | Abnormality of dental enamel | Occasional [Orphanet] | 102 / 7739 | |||
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(HPO:0000695) | Natal tooth | Occasional [Orphanet] | 42 / 7739 | |||
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(HPO:0000327) | Hypoplasia of the maxilla | Very frequent [Orphanet] | 129 / 7739 | |||
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(HPO:0000201) | Pierre-Robin sequence | 20 / 7739 | ||||
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(HPO:0000204) | Cleft upper lip | Frequent [Orphanet] | 193 / 7739 | |||
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(HPO:0009804) | Reduced number of teeth | Occasional [Orphanet] | 137 / 7739 | |||
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(HPO:0000158) | Macroglossia | Frequent [Orphanet] | 119 / 7739 | |||
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(HPO:0000272) | Malar flattening | Very frequent [Orphanet] | 277 / 7739 | |||
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(HPO:0000174) | Abnormality of the palate | Frequent [Orphanet] | 298 / 7739 | |||
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(HPO:0000457) | Depressed nasal ridge | Frequent [Orphanet] | 85 / 7739 | |||
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(HPO:0000520) | Proptosis | Frequent [Orphanet] | 192 / 7739 | |||
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(HPO:0000463) | Anteverted nares | Frequent [Orphanet] | 305 / 7739 | |||
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(HPO:0000343) | Long philtrum | Very frequent [Orphanet] | 262 / 7739 | |||
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(HPO:0000162) | Glossoptosis | Frequent [Orphanet] | 26 / 7739 | |||
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(HPO:0000506) | Telecanthus | Very frequent [Orphanet] | 156 / 7739 | |||
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(HPO:0000175) | Cleft palate | 349 / 7739 | ||||
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(HPO:0000277) | Abnormality of the mandible | Frequent [Orphanet] | 394 / 7739 | |||
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(HPO:0005280) | Depressed nasal bridge | Very frequent [Orphanet] | 381 / 7739 | |||
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(HPO:0000689) | Dental malocclusion | Occasional [Orphanet] | 114 / 7739 | |||
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(HPO:0010290) | Short hard palate | Occasional [Orphanet] | 5 / 7739 | |||
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(HPO:0010650) | Hypoplasia of the premaxilla | Very frequent [Orphanet] | 39 / 7739 | |||
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(HPO:0000316) | Hypertelorism | Occasional [Orphanet] | 644 / 7739 | |||
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(HPO:0000286) | Epicanthus | Very frequent [Orphanet] | 371 / 7739 | |||
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(HPO:0000486) | Strabismus | Occasional [Orphanet] | 576 / 7739 | |||
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(HPO:0000618) | Blindness | 124 / 7739 | ||||
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(HPO:0004327) | Abnormality of the vitreous humor | Very frequent [Orphanet] | 14 / 7739 | |||
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(HPO:0000518) | Cataract | Very frequent [Orphanet] occasional [HPO:skoehler] | 454 / 7739 | |||
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(HPO:0000483) | Astigmatism | Frequent [Orphanet] | 67 / 7739 | |||
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(HPO:0000541) | Retinal detachment | Very frequent [Orphanet] | 87 / 7739 | |||
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(HPO:0000545) | Myopia | Very frequent [Orphanet] | 286 / 7739 | |||
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(HPO:0000572) | Visual loss | Occasional [Orphanet] | 272 / 7739 | |||
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(HPO:0001083) | Ectopia lentis | Occasional [Orphanet] | 45 / 7739 | |||
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(HPO:0000501) | Glaucoma | Occasional [Orphanet] | 180 / 7739 | |||
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(HPO:0100533) | Inflammatory abnormality of the eye | Occasional [Orphanet] | 70 / 7739 | |||
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(HPO:0000407) | Sensorineural hearing impairment | Frequent [Orphanet] | 524 / 7739 | |||
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(HPO:0000389) | Chronic otitis media | Frequent [Orphanet] | 64 / 7739 | |||
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(HPO:0000405) | Conductive hearing impairment | occasional [HPO:skoehler] | 164 / 7739 | |||
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(HPO:0000365) | Hearing impairment | Frequent [Orphanet] | 539 / 7739 | |||
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(HPO:0004374) | Hemiplegia/hemiparesis | Occasional [Orphanet] | 158 / 7739 | |||
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(HPO:0000926) | Platyspondyly | Frequent [Orphanet] | 150 / 7739 | |||
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(HPO:0005930) | Abnormality of epiphysis morphology | Very frequent [Orphanet] | 119 / 7739 | |||
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(HPO:0004349) | Reduced bone mineral density | Occasional [Orphanet] | 165 / 7739 | |||
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(HPO:0003179) | Protrusio acetabuli | Occasional [Orphanet] | 37 / 7739 | |||
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(HPO:0001385) | Hip dysplasia | Occasional [Orphanet] | 242 / 7739 | |||
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(HPO:0001382) | Joint hypermobility | Frequent [Orphanet] | 231 / 7739 | |||
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(HPO:0003312) | Abnormal form of the vertebral bodies | Very frequent [Orphanet] | 172 / 7739 | |||
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(HPO:0002857) | Genu valgum | Frequent [Orphanet] | 144 / 7739 | |||
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(HPO:0002650) | Scoliosis | Frequent [Orphanet] | 705 / 7739 | |||
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(HPO:0011302) | Long palm | Frequent [Orphanet] | 70 / 7739 | |||
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(HPO:0001166) | Arachnodactyly | 62 / 7739 | ||||
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(HPO:0002758) | Osteoarthritis | Frequent [Orphanet] | 78 / 7739 | |||
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(HPO:0000767) | Pectus excavatum | 244 / 7739 | ||||
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(HPO:0002655) | Spondyloepiphyseal dysplasia | 21 / 7739 | ||||
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(HPO:0003416) | Spinal canal stenosis | Occasional [Orphanet] | 28 / 7739 | |||
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(HPO:0006361) | Irregular femoral epiphysis | 3 / 7739 | ||||
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(HPO:0000940) | Abnormal diaphysis morphology | Occasional [Orphanet] | 41 / 7739 | |||
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(HPO:0005059) | Arthralgia/arthritis | Very frequent [Orphanet] | 141 / 7739 | |||
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(HPO:0002808) | Kyphosis | Frequent [Orphanet] | 289 / 7739 | |||
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(HPO:0002652) | Skeletal dysplasia | Very frequent [Orphanet] | 113 / 7739 | |||
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(HPO:0000768) | Pectus carinatum | Frequent [Orphanet] | 136 / 7739 | |||
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(HPO:0004568) | Beaking of vertebral bodies | 19 / 7739 | ||||
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(HPO:0001373) | Joint dislocation | Frequent [Orphanet] | 59 / 7739 | |||
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(HPO:0003040) | Arthropathy | 19 / 7739 | ||||
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(HPO:0002653) | Bone pain | Frequent [Orphanet] | 75 / 7739 | |||
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(HPO:0002577) | Abnormality of the stomach | Frequent [Orphanet] | 84 / 7739 | |||
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(HPO:0004322) | Short stature | Occasional [Orphanet] | 1232 / 7739 | |||
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(HPO:0001519) | Disproportionate tall stature | Frequent [Orphanet] | 39 / 7739 | |||
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(HPO:0004326) | Cachexia | Occasional [Orphanet] | 71 / 7739 | |||
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(HPO:0004325) | Decreased body weight | Occasional [Orphanet] | 492 / 7739 | |||
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(HPO:0001633) | Abnormality of the mitral valve | Frequent [Orphanet] | 69 / 7739 | |||
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(HPO:0011675) | Arrhythmia | Frequent [Orphanet] | 226 / 7739 | |||
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(HPO:0001634) | Mitral valve prolapse | 69 / 7739 | ||||
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(HPO:0002205) | Recurrent respiratory infections | Frequent [Orphanet] | 254 / 7739 | |||
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(HPO:0001252) | Muscular hypotonia | Frequent [Orphanet] | 990 / 7739 | |||
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(HPO:0003202) | Skeletal muscle atrophy | Occasional [Orphanet] | 281 / 7739 | |||
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(HPO:0000006) | Autosomal dominant inheritance | 2518 / 7739 | ||||
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(HPO:0011800) | Midface retrusion | 221 / 7739 |
Associated genes:
ClinVar (via SNiPA)
Gene symbol | Variation | Clinical significance | Reference |
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Additional Information:
Diagnosis GeneReviews | 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:... Gene Symbol% of Disease Attributed to Mutations in This Gene 1Test MethodMutations DetectedTest AvailabilityCOL2A180%-90% | Sequence analysisSequence variants 2Clinical Deletion / duplication analysis 3Exonic or whole-gene deletionsCOL11A110%-20%Sequence analysisSequence variants 2Clinical Deletion / duplication analysis 3Exonic or whole-gene deletionsCOL11A2Rare, unknownSequence analysisSequence variants 2Clinical Deletion / duplication analysis 3Exonic or whole-gene deletions 4COL9A1Rare, unknownSequence analysisSequence variants 2ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletions 4COL9A2Rare, unknownSequence analysisSequence variants 2ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletions 41. 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. Genetically Related (Allelic) DisordersOther phenotypes inherited in an autosomal dominant manner associated with mutations in COL2A1: Achondrogenesis type II (OMIM 200610). This disorder is characterized by virtual absence of ossification in the vertebral column, sacrum, and pubic bones. There is marked shortening of the limbs and trunk, with a prominent abdomen and hydropic appearance. Death occurs in utero or in the early neonatal period. Vissing et al [1989] identified a COL2A1 mutation in affected individuals. All cases represent de novo mutations. Hypochondrogenesis. This term has been used to describe a more mild variant of achondrogenesis (as, for example, hypochondroplasia is to achondroplasia). Spondyloepiphyseal dysplasia congenita (SED congenita) (OMIM 183900). Although the skeletal changes in SED congenita are similar to those seen in Stickler syndrome, they are more severe and result in significant short stature. In addition, individuals manifest flat facial profile, myopia, and vitreoretinal degeneration. Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type (OMIM 184250). The common clinical manifestations of this COL2A1-related skeletal disorder include severe short stature with severe pectus carinatum and scoliosis, cleft palate, and retinal detachment. A distinctive radiographic finding is irregular sclerotic changes (described as "dappled") in the metaphyses of the long bones. This mottled appearance is created by alternating zones of osteosclerosis and osteopenia. Radiologically, the disorder is indistinguishable from SED congenita during infancy. Tiller et al [1995] identified a heterozygous COL2A1 mutation, confirming that this is an autosomal dominant disorder. Kneist dysplasia (OMIM 156550). Affected individuals manifest disproportionate short stature, flat facial profile, myopia and vitreoretinal degeneration, cleft palate, kyphoscoliosis, and a variety of radiographic changes. Spondyloperipheral dysplasia (OMIM 271700). Zabel et al [1996] reported on an individual with short stature, radiographic changes consistent with a spondyloepiphyseal dysplasia, and brachydactyly E. A heterozygous COL2A1 mutation was identified in the C-terminus, resulting in a truncated C-propeptide region.Platyspondylic lethal skeletal dysplasia, Torrance type (PLSDT) (OMIM 151210). This disorder is characterized by platyspondyly, brachydactyly, and metaphyseal changes. It is generally a perinatal lethal disease. PLSDT is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain [Zankl et al 2005].Osteoarthritis with mild chondrodysplasia (OMIM 604864). Ala-Kokko et al [1990] were the first to identify a COL2A1 mutation in a kindred with an arginine-to-cysteine substitution at position 519 of the alpha-1(II) chain. Autosomal dominant rhegmatogenous retinal detachment (ARDD) is associated with pathologic myopia and vitreoretinal degeneration. Go et al [2003] described two large families with ARDD with linkage to COL2A1. Most had mild or absent systemic features of Stickler syndrome. In one family, a p.Arg653X mutation was found in the helical domain of COL2A1 resulting in protein truncation. Avascular necrosis of femoral head, primary (ANFH) (OMIM 608805). The disorder is characterized by progressive pain in the groin, mechanical failure of the subchondral bone, and degeneration of the hip joint. Nearly one-half of patients require hip replacement before age 40 years. ANFH represents a specific form of the broader disease category of osteonecrosis. Liu et al [2005] identified three families with COL2A1 mutations. Two of the families had a glycine 1170 to serine substitution and the third family had a glycine 717 to serine substitution. Other phenotypes inherited in an autosomal dominant manner associated with mutations in COL11A1: Marshall syndrome (OMIM 154780). Individuals with Marshall syndrome manifest ocular hypertelorism, hypoplasia of the maxilla and nasal bones, flat nasal bridge, and small upturned nasal tip. In contrast to Stickler syndrome, the flat facial profile of Marshall syndrome is usually evident into adulthood. Radiographs demonstrate hypoplasia of the nasal sinuses and a thickened calvarium. Ocular manifestations include high myopia, fluid vitreous humor, and early-onset cataracts (subcapsular, cortical, nuclear, zonular, or anterior axial embryonic sites). Sensorineural hearing loss is common and can be progressive. Cleft palate, both as part of the Pierre Robin sequence and as an isolated anomaly, is seen. Other manifestations include short stature and early-onset arthritis. Skin manifestations include mild hypotrichosis and hypohidrosis [Griffith et al 1998, Shanske et al 1998]. Splice site mutations in COL11A1 have been identified by Griffith et al [1998], Annunen et al [1999], and Majava et al [2007]. Other phenotypes associated with mutations in COL11A2:Autosomal recessive otospondylometaepiphyseal dysplasia (OSMED) (OMIM 215150). This disorder is characterized by flat facial profile, cleft palate, and severe hearing loss [van Steensel et al 1997]. Vikkula et al [1995] and Melkoniemi et al [2000] identified homozygous loss-of-function mutations of COL11A2 in individuals with OSMED. It has been suggested that anocular Stickler syndrome (caused by heterozygous COL11A2 mutations) is more appropriately considered a type of OSMED because of its closer similarity to OSMED than Stickler syndrome. Weissenbach-Zweymuller syndrome (WZS) (OMIM 277610). WZS has been described as "neonatal Stickler syndrome," but is actually a distinct entity. It is characterized by midface hypoplasia with a flat nasal bridge, small upturned nasal tip, micrognathia, sensorineural hearing loss, and rhizomelic limb shortening. Radiographic findings include dumbbell-shaped femora and humeri and vertebral coronal clefts. The skeletal findings become less apparent in later years, and catch-up growth after age two to three years is common. Although myopia has been reported in some individuals, it is not a manifestation of WZS. WZS is inherited in an autosomal dominant manner. Pihlajamaa et al [1998] identified a mutation in COL11A2 in Weissenbacher & Zweymueller [1964] original family. Nonsyndromic sensorineural hearing loss (DFNA13) (OMIM 601868). McGuirt et al [1999] reported heterozygous mutations in COL11A2 in two unrelated families with autosomal dominant non-progressive predominantly middle-frequency nonsyndromic deafness. The deafness in these families had previously been mapped to 6p21.3 and designated DFNA13 (see Hereditary Hearing Loss and Deafness Overview). Other phenotypes associated with mutations in COL9A1 and COL9A2:Multiple epiphyseal dysplasia 6 (EDM6) (OMIM 614135) and multiple epiphyseal dysplasia 2 (EDM2) (OMIM 600204). MED is a clinically heterogeneous autosomal dominantly inherited chondrodysplasia. Symptoms first occur in childhood (age 2-14 years) and include waddling gait, restriction of joint mobility, and pain and stiffness in weight-bearing joints [Jackson et al 2010]. See Multiple Epiphyseal Dysplasia, Dominant.
Clinical Description GeneReviews | Stickler syndrome is a multisystem connective tissue disorder that can affect the eye, craniofacies, inner ear, skeleton, and joints. ... |
Genotype-Phenotype Correlations GeneReviews | 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.... |
Differential Diagnosis GeneReviews | A number of disorders have features that overlap with those of Stickler syndrome. ... Locus NameLocusOMIMMYP1 | Xq28310460MYP218p11.31160700MYP312q603221MYP517q21-q22608474MYP622q12608908MYP711p13609256MYP83q26609257MYP94q12609258MYP108p23609259MYP114q22-q27609994MYP122q37.1609995MYP13Xq23-q27.2300613MYP14610320MYP1517q21-q22608474MYP165p15.33-p15.2612554MYP177p15608367MYP1814q22.1-q24.2255500MYP195p15.1-p13.3613969Nonsyndromic 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Management GeneReviews | To establish the extent of disease in an individual diagnosed with Stickler syndrome, the following evaluations are recommended:... |
Molecular genetics GeneReviews |
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.... Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCOL2A112q13 | Collagen alpha-1(II) chainDeafness Gene Mutation Database