The approximate incidence of Stickler syndrome among newborns is 1:9,000. It is a connective tissue disorder characterized by sensorineural and/or conductive hearing loss, facial dysmorphism (▶ Fig. 1.2), cleft palate, spondyloepiphyseal dysplasia, and arthropathy. Ocular findings include high myopia, cataract (▶ Fig. 14.1), characteristic vitreous changes, lattice degeneration (▶ Fig. 14.2), and a high risk for retinal detachment. Focal and circumferential laser treatment, as well as 360-degree cryotherapy have been evaluated as prophylactic treatment to prevent retinal detachment in type 1 Stickler syndrome. Although the methodology was retrospective and perhaps with high-risk bias, recommendations for prophylactic treatment are widely accepted. Myopia is usually greater than –3 diopters at the time of diagnosis. Vitreous abnormalities include “membranous” (type 1), “beaded” (type 2), syneretic, “afibrillar,” and “optically empty” vitreous. The types may coexist and may show some genotype–phenotype correlations.

The facial appearance includes midface hypoplasia, broad or flat nasal bridge, possible telecanthus, and epicanthal folds. The myopic eyes often look exophthalmic. There is also small and upturned nasal tip, and long philtrum. Micro/retrognathia is usual and can be associated with cleft palate as part of the Pierre Robin sequence (micrognathia, cleft palate, glossoptosis). About 50% of patients with Pierre Robin sequence have an underlying syndrome, of which Stickler syndrome is the most frequent (up to 30%). Craniofacial findings characteristic of Stickler syndrome may become less distinctive with age.

The sensorineural hearing impairment mechanism is unknown, although it has been proposed that it is related to the expression of type II and IX collagen in the inner ear. Conductive hearing loss may also occur secondary to recurrent ear infections associated with craniofacial structure and middle ear anomalies. Mitral valve prolapse has been reported in up to 50% of patients with Stickler syndrome. Early-onset arthritis is common and may be severe, but frequently the arthropathy is mild.

14.2 Molecular Genetics

Mutations have been described in COL2A1 (12q13.11), COL11A1 (1p21.1), COL11A2 (6p21.32), COL9A1 (6q13), COL9A2 (1p34.2), and COL9A3 (20q13.33), although there are patients with the typical phenotype but without a mutation in those genes. COL2A1, COL11A1, or COL11A2 mutations are autosomal dominant (AD). Penetrance is complete, with variable expression. COL9A1, COL9A2, or COL9A3 mutations are typically autosomal recessive (AR). The majority of patients with Stickler syndrome have a COL2A1 nonsense mutation resulting in haploinsufficiency. A specific COL2A1 variant (p.Leu667Phe) has been associated with “afibrillar” vitreous gel. Mutations involving exon 2 of COL2A1 affect predominantly the eye, with mild or no systemic findings as this exon is not expressed in nonocular tissues. These patients have optically empty vitreous, perivascular pigmentary changes, and early-onset retinal detachment.

Sequence variants and deletions in the COL11A1 gene lead to Stickler syndrome with significant hearing loss and type 2 vitreous anomaly (“beaded”). Pathogenic variants of COL11A2 are associated with nonocular Stickler syndrome.

Biallelic pathogenic variants in COL9A1 are associated with AR Stickler syndrome. Affected patients have moderate to severe hearing loss, myopia with vitreoretinopathy, cortical cataracts, and epiphyseal dysplasia. Biallelic mutations in COL9A2 are associated with mild to moderate hearing loss, high myopia, and vitreoretinopathy. Biallelic pathogenic variants in COL9A3 are also associated with AR Stickler syndrome. These patients may have intellectual disability.

14.3 Differential Diagnosis

14.3.1 Knobloch Syndrome (OMIM 267750)

Knobloch syndrome (OMIM 267750) is a developmental disorder characterized by typical eye abnormalities, including high myopia, ectopia lentis, vitreoretinal anomalies, and retinal detachment, associated with occipital skull defects, which can range from occipital encephalocele to occipital cutis aplasia. It is due to biallelic mutation in the COL18A1 gene.

14.3.2 Spondyloepiphyseal Dysplasia Congenita (OMIM 183900)

Phenotypically very similar to Stickler syndrome, although patients also have short stature. Retinal findings are usually severe. Myopia is frequently present. It is caused by COL2A1 mutation.

14.3.3 Kniest Dysplasia (OMIM 156550)

Kniest dysplasia is characterized by severe short stature, flat facial profile, myopia, vitreoretinal degeneration, cleft palate, and kyphoscoliosis. It is due to COL2A1 mutations, which are frequently de novo.

14.3.4 Marshall Syndrome (OMIM 154780)

This is an AD disorder associated with COL11A1 mutations, particularly splice site changes. These patients have hypertelorism, hypoplasia of the nasal bones and maxilla, flat nasal bridge, and upturned nasal tip. The flat facial appearance of Marshall syndrome is usually more obvious in adulthood, as opposed to the Stickler facies, which is seen from infancy. Patients with Marshall syndrome also have high myopia, vitreous syneresis, and early-onset cataracts. Sensorineural hearing loss is frequent. Other findings include cleft palate, Pierre Robin sequence, short stature, arthropathy, and hypotrichosis. There is also a Marshall/Stickler overlap due to mutations in COL11A1.

14.3.5 Weissenbacher–Zweymuller Syndrome (OMIM 277610)

This AD disorder is due to COL11A2 mutations. It has been reported as “neonatal” Stickler syndrome because of the similar facial appearance. In contrast, myopia is not a manifestation of this syndrome, although there are reports in some patients. The characteristic finding is short stature and “dumbbell”-shaped femurs.

14.3.6 Wagner Syndrome (OMIM 143200)

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