Clinical Description
Stickler syndrome is characterized by typical craniofacial features, ocular manifestations, hearing impairment, and osteoarticular problems. To date, more than 1,000 individuals have been identified with Stickler syndrome due to a pathogenic variant(s) in one of the genes listed in Table 1 [Wang et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Stickler Syndrome: Frequency of Select Features by Related Gene
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Feature | % of Persons w/Feature 1 |
---|
COL2A1-SS | COL11A1-SS | COL11A2-SS | COL9A1-, COL9A2-, & COL9A3-SS |
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Cleft palate
| 30%-60% | 60% | 35% | -- |
Myopia
| 80%-90% | 80%-85% | -- | 90%-95% |
Retinal detachment
| 40%-70% | <40% | -- | 13%-18% |
Hearing impairment
| 20%-50% (SNHL ± conductive HL) | 75%-80% | 60% | 90%-95% (SNHL) |
Skeletal manifestations 2
| 35%-40% | 25% | 50% | 25% |
-- = not reported; HL = hearing loss; SNHL = sensorineural hearing loss; SS = Stickler syndrome
- 1.
- 2.
Includes mainly early-onset degenerative joint disease
Craniofacial findings include a flat face or midface retrusion with underdevelopment of the maxilla and nasal bridge. Midface retrusion is most pronounced in infants and young children; older individuals may have a normal facial profile.
Micrognathia is common and may be associated with cleft palate as part of the Pierre Robin sequence (micrognathia, glossoptosis, cleft palate). The degree of micrognathia may compromise the upper airway, necessitating tracheostomy in the neonatal period.
Cleft palate may be seen in the absence of micrognathia. Cleft palate may range from open cleft to submucous cleft or just bifid uvula.
Ocular manifestations include myopia, vitreous abnormalities, spontaneous retinal detachments, cataracts, and glaucoma. The ocular phenotype is often consistent between affected family members.
High myopia (greater than −3 diopters) is common; myopia may be progressive and is detectable in the newborn period.
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 development of a retinal tear and subsequent retinal detachment is increased in individuals with Stickler syndrome. Prophylactic retinopexy is recommended, as surgical repair of retinal detachment in individuals with Stickler syndrome is often not successful [Alexander & Snead 2022], and recurrent detachment is reported to be common [Lee et al 2020]. Comparison of prophylactic treatment options to prevent retinal detachment have been reported in some recent retrospective studies [Khanna et al 2022, Ripandelli et al 2022].
Posterior chorioretinal atrophy was described in a family with vitreoretinal dystrophy, systemic features of Stickler syndrome, and a novel pathogenic variant in COL2A1 [Vu et al 2003], suggesting that individuals with Stickler syndrome may have posterior pole chorioretinal changes in addition to the vitreous abnormalities.
Cataracts were reported to be more common in individuals with COL11A1-related Stickler syndrome (59%) compared to individuals with COL2A1-related Stickler syndrome (36%) [Boysen et al 2020]. Glaucoma has been reported in 10% of individuals with Stickler syndrome [Wubben et al 2018, Boysen et al 2020, Walters et al 2020].
Hearing impairment is common. The degree of hearing impairment is variable and may be progressive. Sensorineural hearing loss in individuals with COL2A1-related Stickler syndrome is typically mild, usually involves the higher frequencies, and is not significantly progressive; it is less severe than that reported for COL11A1-related Stickler syndrome [Acke & De Leenheer 2022].
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 include mainly early-onset degenerative joint disease with radiographic findings consistent with mild spondyloepiphyseal dysplasia. Stature is within normal limits, but affected individuals may be relatively short in comparison to their unaffected first-degree relatives.
Early-onset osteoarthrosis 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 with mild joint pain and nonspecific joint stiffness.
Spinal abnormalities sometimes observed in Stickler syndrome that result in chronic back pain are scoliosis and kyphosis [Rose et al 2001]. There is no good documentation in the literature of the presence/occurrence of odontoid hypoplasia, resulting in clinically significant atlantoaxial instability, in individuals with Stickler syndrome. This is in contrast to other, more severe type II collagen disorders such as COL2A1-related spondyloepiphyseal dysplasia congenita (see Genetically Related Disorders).
Phenotype Correlations by Gene
COL11A1. Individuals with COL11A1-related Stickler syndrome typically have more pronounced midface hypoplasia (flat face), more severe hearing loss, and type 2 congenital vitreous anomaly or "beaded" vitreous phenotype; however, individuals or families with a "membranous" vitreous (type 1) phenotype have been reported [Parentin et al 2001, Majava et al 2007]. The risk for retinal detachments may be lower (<40%) than in COL2A1-related Stickler syndrome [Boothe et al 2020].
COL11A2. Pathogenic variants in COL11A2 cause autosomal dominant non-ocular Stickler syndrome [Vikkula et al 1995, Sirko-Osadsa et al 1998, Vuoristo et al 2004, Acke et al 2014].
COL9A1, COL9A2, COL9A3. Biallelic pathogenic variants in the type IX collagen genes cause autosomal recessive Stickler syndrome. Almost all affected individuals have sensorineural hearing loss (usually moderate to severe) and moderate-to-high myopia with vitreoretinopathy. Retinal detachments are not as frequent, with a rate of 13%-18%. Interestingly, cleft palate has not yet been reported in this group of individuals [Nixon et al 2022].
Genotype-Phenotype Correlations
Although inter- and intrafamilial variation is common, some generalities can be made regarding genotype-phenotype correlations.
COL2A1-related Stickler syndrome. Pathogenic variants in COL2A1 that cause Stickler syndrome are typically loss-of-functions variants associated with haploinsufficiency of type II collagen (e.g., nonsense variants, small deletions/duplications, splicing variants that cause a frameshift). COL2A1 pathogenic variants that do not result in a premature stop codon and/or nonsense-mediated RNA decay but have a dominant-negative effect are causative for the more severe type II collagenopathies such as spondyloepiphyseal dysplasia congenita (see Table 3). These are usually missense variants causing a glycine substitution in the triple helical domain. However, glycine substitutions have been reported in individuals with Stickler syndrome, and these tend to cluster at the N-terminal end of the protein.
COL2A1 pathogenic variants involving exon 2 are characterized by a predominantly ocular variant phenotype in which individuals are at high risk for retinal detachment. Affected individuals from nine families with an exon 2 variant resulting in a premature stop codon had optically empty vitreous, typical perivascular pigmentary changes, and/or early-onset retinal detachment with minimal or absent systemic findings of Stickler syndrome [Donoso et al 2003].
COL11A1-related Stickler syndrome. Heterozygous pathogenic COL11A1 variants are predominantly splice site alterations and missense variants including glycine substitutions. The splice site alterations usually result in in-frame deletions (exon skipping) and therefore most likely have a dominant-negative effect. Intron 50 (donor splice site) is a mutational hot spot. Rarely, biallelic COL11A1 pathogenic variants have been reported in individuals with Stickler syndrome; in these instances, at least one pathogenic variant affects the alternatively spliced exon 9. Pathogenic variants of COL11A1 resulting in haploinsufficiency (e.g., nonsense variants) are rare and cause a milder and less obvious phenotype such as nonsyndromic hearing loss.
COL11A2-related Stickler syndrome. Heterozygous pathogenic COL11A2 variants are rare and usually have a dominant-negative effect. They include missense variants in the helical domain, in-frame deletions, or splice site alterations.
COL9A1-, COL9A2-, and COL9A3-related Stickler syndrome. Pathogenic variants in COL9A1, COL9A2, and COL9A3 associated with Stickler syndrome are biallelic and have a loss-of-function effect, resulting in complete absence of the protein.