A number sign (#) is used with this entry because of evidence that Stickler syndrome type VI (STL6) is caused by homozygous or compound heterozygous mutation in the COL9A3 gene (120270) on chromosome 20q13.

Stickler syndrome type VI (STL6) is characterized by early-onset progressive hearing loss and progressive myopia, with variable manifestation of facial dysmorphism and skeletal anomalies (Nixon et al., 2019; Rad et al., 2022).

For a general phenotypic description and discussion of genetic heterogeneity of Stickler syndrome, see STL1 (108300).

Faletra et al. (2014) reported 3 Moroccan sibs with hearing loss, visual defects, and bone abnormalities, and mutation in the COL9A3 gene. The 2 younger sibs, an 11-year-old boy and a 4-year-old girl, exhibited midface hypoplasia and depressed nasal bridge. The oldest sib, a 16-year-old boy, had ptosis, and both boys showed downslanting palpebral fissures. All 3 children had moderate to high myopia, astigmatism, and amblyopia due to impairment of ocular motility. No vitreous or retinal abnormalities were detected. All 3 had symmetric moderate to severe sensorineural hearing loss, with a mildly downsloping form on audiography and an age-dependent correlation. Skeletal abnormalities shared by the 3 affected children included squared metacarpal epiphyses, squared femoral epiphyses, internal tibial rotation, and severe bilateral flat feet with valgus hindfoot. All 3 children also exhibited moderate to severe intellectual disability. The first-cousin parents were unaffected.

Hanson-Kahn et al. (2018) described a 12-year-old Indian boy (ISDR R08-308A) with midface hypoplasia, myopia, hearing loss, and epiphyseal changes, and mutation in the COL9A3 gene. The proband failed the newborn hearing exam and was diagnosed with moderate to severe sensorineural hearing loss at age 5 months. By age 2 years, he had developed myopia, which was progressive and had worsened by age 12. No vitreous abnormalities were observed. Femoral and tibial bowing were noted at birth, and x-rays at age 6 years demonstrated slightly flattened proximal femoral epiphyses and mild platyspondyly. Autoimmune hypothyroidism was identified at age 10 years. Speech was delayed due to hearing loss, but intelligence was normal. The proband's third-cousin parents and an older sister were unaffected. The authors noted that the clinical features of this patient were similar to those of the sibs reported by Faletra et al. (2014).

Nixon et al. (2019) studied 2 sibs (patients E and F) with myopia, hypoplastic vitreous, and high-frequency sensorineural hearing loss, and mutation in the COL9A3 gene. Neither sib exhibited midface hypoplasia. The older sib (patient E), age 20 years, had a very myopic-appearing retina, and also had severe joint involvement, with thoracolumbar scoliosis requiring surgery at age 13 years, and severe joint pain in the hips and knees requiring a wheelchair for mobility and pain clinic involvement. The younger sib (patient F), age 18 years, had a normal-appearing retina and no joint symptoms, with normal x-rays. Their father had mild high-frequency sensorineural hearing loss without auditory symptoms, as well as moderately severe degenerative changes of the left hip and minor changes in the mid-thoracic spine. His ocular examination was normal, including normal vitreous gel architecture. Their mother had arthritis of the hip requiring steroid injections, back pain due to facet joint arthritis, and moderate myopia with normal vitreous and retina. The authors noted that the parents' findings were nonspecific and quite common in the general population.

Markova et al. (2021) reported a 3-year-old Russian boy with early-onset arthropathy, vitreoretinal degeneration, and sensorineural hearing loss, and mutation in the COL9A3 gene. At 1 month of age, he exhibited adductor spasm and evaluation revealed hip dysplasia with bilateral absence of ossification centers. At age 3 months, he was diagnosed with congenital bilateral high myopia, and at 11 months, audiologic evaluation due to speech delay showed bilateral sensorineural hearing loss that required hearing aids. By age 2.5 years, he had valgus knee deformity, waddling gait, rapid fatigability, and pain in the lower limb joints. Radiographs at age 3 years showed mild spondyloepiphyseal dysplasia with enlarged joint spaces, flattened and irregular femoral heads, broad and short femoral necks, coxa valga, and flattened distal femoral epiphyses and intercondylar eminences of proximal tibiae. Ocular assessment revealed peripheral pigment rearrangement with whitish dystrophic foci at the periphery, multiple vitreous floaters, and preretinal membrane growth in the posterior chamber. Facial dysmorphisms included mild midface hypoplasia, flattened nasal bridge, small nose, and high palate. Skeletal abnormalities included lumbar lordosis, limited hip abduction, internal rotation of hip joints, long fingers, deformed prominent knee joints with genu valgum, and planovalgus foot deformity. The authors noted that the proband expanded the STL6 phenotype with this more severe clinical presentation.

Rad et al. (2022) reported 5 patients from 3 unrelated consanguineous Iranian families with high myopia, progressive moderate to profound sensorineural hearing loss, and variable skeletal changes, and mutation in the COL9A3 gene. The proband in family 1 was a 28-year-old woman who had high myopia as well as vitreoretinal degeneration with empty vitreous, multiple lattice degenerations, and retinal pigmentary changes. She had severe and progressive sensorineural hearing loss, and also experienced knee pain, although x-rays and clinical examination did not detect osteoarthritis. She did not show midface hypoplasia or other craniofacial anomalies. The 2 brothers in family 2, who were 65 and 57 years old, had a history of multiple vitreoretinal surgeries for recurrent rhegmatogenous retinal detachments due to advanced vitreoretinal degeneration. The older brother had no light perception in either eye, whereas the younger had counting-fingers vision in 1 eye. Both had severe progressive sensorineural hearing loss, and both had a herniated cervical disc. No x-rays were available for review. In family 3, an 11-year-old brother and 3-year-old sister had myopia and congenital progressive moderate to severe sensorineural hearing loss. The brother reported knee pain, and x-rays in both children revealed spondyloepiphyseal dysplasia. In addition, both sibs showed midface hypoplasia, downslanting palpebral fissures, depressed nasal bridge, anteverted nares, and pes planus.

The transmission pattern of STL6 in the family reported by Faletra et al. (2014) was consistent with autosomal recessive inheritance.

In 3 Moroccan sibs with hearing loss, visual defects, and skeletal abnormalities, Faletra et al. (2014) analyzed putative causative genes located within 9 shared homozygous regions and identified homozygosity for a 23-bp deletion in the COL9A3 gene (120270.0005). Their unaffected first-cousin parents were heterozygous for the deletion. The authors suggested that the intellectual disability exhibited by the sibs was likely due to variation in another gene in this consanguineous family.

By whole-exome sequencing in a 12-year-old Indian boy (ISDR R08-308A) with hearing loss, myopia, and epiphyseal abnormalities, Hanson-Kahn et al. (2018) identified homozygosity for a 1-bp duplication in the COL9A3 gene (120270.0006). His unaffected third-cousin parents and older sister were heterozygous for the duplication, which was not found in public SNP databases.

In 2 sibs with myopia, hypoplastic vitreous, and high-frequency sensorineural hearing loss, 1 of whom also had severe joint involvement, Nixon et al. (2019) analyzed a panel of Stickler syndrome-associated genes and identified homozygosity for a nonsense mutation in the COL9A3 gene (R471X; 120270.0007). Their parents, who were heterozygous for the mutation, exhibited some features of Stickler syndrome, including arthritis and myopia in the mother, and arthritis and sensorineural hearing loss in the father. However, because these symptoms are not very specific and occur in the general population with considerable frequency, the authors concluded that there was no solid evidence for carrier manifestation of heterozygous COL9A3 null alleles. Nixon et al. (2019) also compared reported cases of dominant and recessive Stickler syndrome, noting that hearing loss and myopia were more common in recessive cases, whereas face, palate, and joint problems were less common.

In a 3-year-old Russian boy with severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs, Markova et al. (2021) performed targeted sequencing of 166 genes associated with congenital skeletal disorders and identified compound heterozygosity for 2 nonsense mutations in the COL9A3 gene, R90X (120270.0008) and R577X (120270.0009). Sanger sequencing confirmed that the mutations segregated with disease in the family; his unaffected sibs did not carry either of the COL9A3 variants.

By exome sequencing in 5 patients from 3 unrelated consanguineous Iranian families with high myopia, progressive moderate to profound sensorineural hearing loss, and variable skeletal changes, Rad et al. (2022) identified homozygosity for truncating mutations in the COL9A3 gene: a 10-bp deletion (120270.0010) in the female proband of family 1, a nonsense mutation (R402X; 120270.0011) in the 2 brothers from family 2, and a 1-bp deletion (120270.0012) in a brother and sister (family 3). The authors reviewed previously reported cases of biallelic COL9A3 loss-of-function variants and noted that high myopia and moderate to severe hearing loss appeared to be consistent features among all cases, whereas skeletal findings were more variable.