Stickler syndrome

The prevalence of Stickler syndrome is estimated at approximately 1 in 7,500–9,000 individuals; however, the true prevalence may be higher due to underdiagnosis of milder phenotypes.

Six genes carrying germline pathogenic variants are currently known to be associated with Stickler syndrome, the most frequent being COL2A1 and COL11A1. COL2A1 accounts for approximately 80% of cases and COL11A1 for approximately 20%; COL11A2, COL9A1, COL9A2, and COL9A3 each account for fewer than 1%. COL2A1 is typically associated with autosomal dominant disease, with pathogenic variants leading to either haploinsufficiency or, in rarer cases, dominant-negative effects, whereas COL11A1 and COL11A2 are associated with autosomal dominant disease predominantly through dominant-negative mechanisms. The type IX collagen genes (COL9A1, COL9A2, COL9A3) are associated with autosomal recessive disease and typically act through biallelic loss-of-function. All mechanisms disrupt fibrillogenesis of hyaline cartilage and the vitreous.

In the majority of cases, Stickler syndrome is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Only the considerably rarer forms associated with biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 follow autosomal recessive inheritance, with a 25% recurrence risk per pregnancy for parents who are heterozygous carriers.

No consensus clinical diagnostic criteria for Stickler syndrome have been published. Supportive findings include mild spondyloepiphyseal involvement on radiographs and characteristic vitreous abnormalities on slit-lamp examination. The diagnosis can be established by the identification of a heterozygous pathogenic variant in COL2A1, COL11A1, or COL11A2, or biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 in an individual with consistent clinical findings.

Main differential diagnoses include:

• Isolated Pierre Robin sequence: triad of micrognathia, glossoptosis, and cleft palate; non-syndromic forms lack ocular and skeletal involvement.
• Other type II, IX and XI collagen disorders: Variants in the above-mentioned genes are associated with a phenotypic spectrum ranging from classical Stickler syndrome to more severe skeletal dysplasias (e.g. spondyloepiphyseal dysplasia congenita, Kniest dysplasia, Marshall syndrome, etc,.)
• Hereditary vitreoretinopathies without systemic manifestations represent an important differential diagnosis, particularly in individuals with predominant ocular findings; examples include VCAN-related vitreoretinopathy () and other disorders characterised by vitreous abnormalities and an increased risk of retinal detachment.
• Additional syndromic conditions with combined ocular and craniofacial manifestations may also be considered, including entities associated with high myopia, vitreoretinal degeneration, with or without additional developmental anomalies (e.g. BMP4-, LRP2-, LOXL3-related disorders)

• Establishing the molecular diagnosis confirms the clinical suspicion, identifies the underlying genetic cause, and enables accurate assessment of inheritance patterns, including predictive testing of at-risk relatives and informed reproductive counselling.
• A confirmed molecular diagnosis supports individualised surveillance and clinical management; specific evaluations addressing the ocular, auditory, craniofacial, and musculoskeletal manifestations are summarised in current guidance and are coordinated by the treating physicians in consultation with the affected individual.

• Mortier G. Stickler Syndrome. 2023 Sep 7. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301479. Available from:
• Hoornaert KP, Vereecke I, Dewinter C, Rosenberg T, Beemer FA, Leroy JG, et al. Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients. European journal of human genetics : EJHG. 2010;18(8):872–880. doi: 10.1038/ejhg.2010.23. PMID:.
• Barat-Houari M, Sarrabay G, Gatinois V, Fabre A, Dumont B, Geneviève D, et al. Mutation update for COL2A1 gene variants associated with type II collagenopathies. Human mutation. 2016;37(1):7–15. doi: 10.1002/humu.22915. PMID: .