Mutational hot spot potential of a novel base pair mutation of the CSPG2 gene in a family with Wagner syndrome.

OBJECTIVE: To report a 3-generation white family clinically diagnosed variably with Wagner, Stickler, and Jansen syndromes and screened for sequence variants in the COL2A1 and CSPG2 genes. Wagner syndrome is an autosomal dominant vitreoretinopathy with a predisposition to retinal detachment and cataracts. It has significant phenotypic overlap with allelic Jansen syndrome and ocular Stickler syndrome type 1. Sticker syndrome type 1 maps to chromosome 12q13.11-q13.2, with associated COL2A1 gene mutations. Wagner syndrome maps to chromosome 5q13-q14 and is associated with mutations in CSPG2 encoding versican, a proteoglycan present in human vitreous. METHODS: Genomic DNA samples derived from venous blood were collected from all family members. Complete sequencing of COL2A1 was performed on a proband. Primers for polymerase chain reaction and sequencing were designed to cover all exon and intron-exon boundaries. Direct sequencing of CSPG2 was performed on all family member samples. RESULTS: No detectable COL2A1 mutations were noted, making the diagnosis of ocular Stickler syndrome highly unlikely for this family. A unique base pair substitution (c.9265 + 1G>T) in intron 8 of the CSPG2 gene cosegregating with disease status was identified. This mutation occurred in a highly conserved previously reported splice site with a similar base pair substitution (G>A). Direct sequencing of this splice site mutation in 107 unrelated external controls revealed no variants, supporting the rarity of this base pair change and its causation in Wagner syndrome. This novel base pair substitution is thought to cause the deletion of exon 8 and formation of a truncated protein product. CONCLUSION: Mutation screening of CSPG2 in autosomal dominant vitreoretinopathy families is important for accurate diagnosis. CLINICAL RELEVANCE: This study underscores the importance of obtaining extensive pedigree information and comparative ophthalmologic clinical information, as the phenotypic findings may vary greatly among independent family members. The study also affirms the paradigm shift from diagnosis assignment based on eponyms to that based on gene mutation type.

Multiple intracranial meningiomas causing papilledema and visual loss in a patient with nevoid Basal cell carcinoma syndrome.

A 27-year-old man with nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) who had undergone craniospinal irradiation for a childhood brain stem medulloblastoma complained of progressive binocular visual loss. Ophthalmologic examination disclosed subnormal visual acuity and visual fields in both eyes attributed to chronic papilledema. Brain MRI demonstrated mass effect from multiple large meningiomas. After embolization and surgical resection of the largest meningioma, papilledema disappeared and visual dysfunction resolved partially. This is the sixth reported patient with NBCCS, medulloblastoma, and craniospinal radiation who has developed intracranial meningioma, further documenting the fact that such patients have a relatively high likelihood of developing meningiomas, especially multiple meningiomas. Because patients with NBCCS are often mentally impaired and because papilledema can progress silently before causing irreversible visual loss, periodic ophthalmologic examination is advisable after craniospinal radiation.

Retinal pigment epithelium tears after intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration.

BACKGROUND: Intravitreal bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) treatment of neovascular age-related macular degeneration (AMD) has become an important part of clinical retinal practice. We describe retinal pigment epithelium (RPE) tears that were noted after intravitreal injection of bevacizumab. METHODS: In this multimember, retrospective case series, data on eyes that developed RPE tears after intravitreal bevacizumab injection were collected and analyzed. Previous treatments, type of lesion, time to tear, and preinjection and final visual acuities were all compared. The total numbers of bevacizumab injections were available from all four institutions and compiled to estimate the incidence rate. RESULTS: Four retina centers administered a total of 1,455 intravitreal 1.25-mg bevacizumab injections for neovascular AMD during the 9-month study period. Twelve patients presented with RPE tears within 4 days to 8 weeks of injection (mean +/- SD, 24.3 +/- 15.2 days from injection to tear). In each case, the RPE tear was preceded by an RPE detachment, and all had a component of serous sub-RPE fluid. On the basis of our collective data, we estimate an incidence rate of approximately 0.8%. CONCLUSIONS: RPE tears can occur after intravitreal injection of bevacizumab. The low incidence of this adverse event should not preclude anti-vascular endothelial growth factor therapy counseling for patients with neovascular AMD, but eyes with serous RPE detachments appear to be most vulnerable to this adverse event.

X-linked high myopia associated with cone dysfunction.

OBJECTIVE: Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia. METHODS: X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds. RESULTS: Significant maximum logarithm of odds scores of 3.38 and 3.11 at theta = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease-affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia. CONCLUSIONS: Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families. CLINICAL RELEVANCE: X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin.

New locus for autosomal dominant high myopia maps to the long arm of chromosome 17.

PURPOSE: To map the gene(s) associated with autosomal dominant (AD) high-grade myopia. METHODS: A multigeneration English/Canadian family with AD severe myopia was ascertained. Myopes were healthy, with no clinical evidence of syndromic disease, anterior segment abnormalities, or glaucoma. The family contained 22 participating members (12 affected). The average age of diagnosis of myopia was 8.9 years (range, birth to 11 years). The average refractive error for affected adults was -13.925 D (range, -5.50 to -50.00). Microsatellite markers for genotyping were used to assess linkage to several candidate loci, including three previously identified AD high-myopia loci on 18p11.31, 12q22-q23, and 7q36. Syndromic myopia linkage was excluded by using intragenic or flanking markers for Stickler syndrome types 1, 2, and 2B; Marfan syndrome; Ehlers-Danlos syndrome type 4; and juvenile glaucoma. A full genome screening was performed, with 327 microsatellite markers spaced by 5 to 10 cM. Two-point linkage was analyzed using the FASTLINK program run at 90% penetrance and a myopia gene frequency of 0.0133. RESULTS: Linkage to all candidate loci was excluded. The genome screening yielded a maximum two-point lod score of 3.17 at theta = 0 with microsatellite marker D17S1604. Fine mapping and haplotype analysis defined the critical interval of 7.71 cM at 17q21-22. CONCLUSIONS: A novel putative disease locus for AD high-grade myopia has been identified and provides additional support for genetic heterogeneity for this disorder.