Snowflake vitreoretinal degeneration: follow-up of the original family.

PURPOSE: The ocular findings, systemic features, and genetic loci distinguishing known genetic causes of vitreoretinal degenerations were studied in the original Snowflake family. DESIGN: Prospective, comparative study and molecular genetic investigation. PARTICIPANTS: Members of the original snowflake vitreoretinal degeneration family. METHODS: Clinical data were collected on 26 family members by history and examination. Thirteen of the 26 total family members underwent prospective examination. Linkage to known vitreoretinal degeneration loci (COL2A1, COL11A1, and the Wagner disease locus) was evaluated with short tandem repeat markers. MAIN OUTCOME MEASURES: Ocular and systemic features of known vitreoretinal degenerations. RESULTS: Six of the 13 prospectively examined subjects had snowflake vitreoretinal degeneration. Corneal guttae (4/5; 80%), early onset cataract (5/6; 83%), fibrillar vitreous degeneration (6/6; 100%), and peripheral retinal abnormalities (5/6; 83%), including minute crystallinelike deposits called snowflakes (4/6; 67%), were common. Retinal detachment was seen in 1 of 6 of these prospectively examined subjects (17%). A total of 14 affected subjects were identified within the family, and in 3 (21%), retinal detachment developed. Orofacial features, early-onset hearing loss, and arthritis typical of Stickler syndrome were absent. Linkage to known vitreoretinal degeneration loci was excluded. CONCLUSIONS: The absence of vitreous gel in the retrolental space and presence of fibrillar vitreous degeneration were consistent with the vitreous structure reported for collagen 11A1 (COL11A1) but not collagen 2A1 (COL2A1) mutations. The absence of systemic features was characteristic of the vitreoretinopathies linked to chromosome 5q13 (Wagner disease and erosive vitreoretinopathy) and mutations in exon 2 of the COL2A1 gene. Snowflakes in the peripheral retina and the absence of nyctalopia, posterior chorioretinal atrophy, and tractional retinal detachment were inconsistent with the chromosome 5q13 vitreoretinopathies. The association of Fuchs' corneal endothelial dystrophy found in this family has not been reported previously in other vitreoretinal degenerations. These findings and the exclusion of known genetic loci suggest snowflake is a distinct vitreoretinal degeneration.

Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene.

PURPOSE: To report posterior chorioretinal atrophy (PCRA) and correlate the vitreous phenotype with inheritance of the disease mutation in a family with vitreoretinal dystrophy. DESIGN: Prospective observational case series. METHODS: Twenty-four members of a family with 14 affected individuals were examined, and genetic linkage analysis was performed at the COL2A1, COL11A1, and Wagner disease loci. The vitreous phenotype was prospectively graded as optically empty with retrolenticular membrane, fibrillar, or normal. Ocular ultrasonography and optical coherence tomography (OCT) were performed on selected individuals to study the vitreous structure and vitreoretinal interface. RESULTS: The 6-year-old proband had PCRA and optically empty vitreous without systemic features, suggestive of Wagner disease. The family history was negative for systemic disease, except for one cousin with cleft palate. However, when examined, clinical features of the 14 affected subjects included 5 with small chin, 4 with at least submucosal cleft palate, and 9 with a myopic refractive error greater than 5 diopters. Lens opacity or previous cataract extraction was found in 13 family members. All affected individuals in whom the vitreous could be examined had an optically empty vitreous with retrolental membrane. Posterior chorioretinal atrophy was found in eight of the affected subjects. The finding was not limited to highly myopic subjects, nor did all the high myopes have PCRA. Ultrasonography and OCT revealed vitreous adherent to the retina, but without apparent retinal distortion or edema of the macula. Significant linkage was established to the COL2A1 locus; the other loci were excluded. A single nucleotide insertion mutation (c.2012 2013insC) was identified in exon 34, leading to a downstream premature stop codon in the COL2A1 gene. CONCLUSIONS: Although posterior chorioretinal atrophy and vitreoretinal degeneration have been classically associated with Wagner disease, we demonstrate its presence in a family with typical Stickler syndrome. On the basis of clinical, ultrasonographic, and OCT studies, the etiology of PCRA in this family does not seem to be attributable to vitreomacular traction or myopia. The vitreous findings in this large family confirm reports that mutations in the COL2A1 gene lead to the optically empty vitreous with retrolenticular membrane phenotype.