Wagner Vitreoretinopathy

A number sign (#) is used with this entry because of evidence that Wagner syndrome is caused by heterozygous mutation in the gene encoding versican (VCAN; 118661), also known as chondroitin sulfate proteoglycan-2 (CSPG2), on chromosome 5q14.

Description

Wagner vitreoretinopathy is a rare vitreoretinal degeneration inherited as an autosomal dominant trait, first described in a large Swiss pedigree (Wagner, 1938) and subsequently identified in other families. Penetrance in Wagner syndrome is complete, and the disease manifests in childhood or adolescence with a progressive course. Affected individuals usually present with an 'empty' vitreous cavity with fibrillary condensation or avascular strands and veils. Additional features, which are variable and age-dependent, include chorioretinal atrophy with loss of the retinal pigment epithelium (RPE), lattice degeneration of the retina, complicated cataracts, mild myopia, and peripheral traction retinal detachment. Rod and cone electroretinography shows reduced b-wave amplitude and correlates with severe chorioretinal pathology. It is believed that liquefaction of vitreous initiates a degenerative cascade that results in the complex eye phenotype of Wagner syndrome (summary by Kloeckener-Gruissem et al., 2006). Patients with additional ocular features such as progressive nyctalopia (night blindness), visual field constriction, and chorioretinal atrophy, with loss of RPE and choriocapillaries on fluorescein angiography and rod-cone abnormalities on electroretinography, were initially believed to have a distinct clinical entity, which was designated 'erosive vitreoretinopathy' (ERVR). Extraocular abnormalities are not present in patients diagnosed with Wagner or erosive vitreoretinopathy (summary by Mukhopadhyay et al., 2006).

Clinical Features

Wagner (1938) described 13 members of a Canton Zurich family with a peculiar lesion of the vitreous and retina. Ten additional affected members were observed by Boehringer et al. (1960) and 5 more by Ricci (1961). In Holland Jansen (1962) described 2 families with a total of 39 affected persons. In addition to typical changes in the vitreous, retinal detachment occurs in some and cataract is another complication. See hyaloideotapetoretinal degeneration of Favre (268100).

Graemiger et al. (1995) examined 60 members of the Swiss kindred originally studied by Wagner (1938). Twenty-eight members were found to be affected. The most consistent finding was an empty vitreous cavity with avascular strands or veils. Chorioretinal atrophy and cataract increased with age and occurred in all patients older than 45 years. Four patients had a history of a rhegmatogenous retinal detachment in 1 eye, which occurred at a median age of 20 years. Peripheral traction retinal detachments were found in 55% of eyes among patients older than 45 years. Glaucoma was present in 10 eyes (18%), 4 of which showed neovascular glaucoma. Of all patients, 63% showed elevated rod and cone thresholds on dark adaptation, and 87% showed subnormal b-wave amplitudes of the rod and cone systems on electroretinography. Thus, clinical expressivity of the disorder varied from unaffected carriers to bilateral blindness. Progression of the chorioretinal pathology was paralleled by electrophysiologic abnormalities.

Zech et al. (1999) examined 20 affected individuals from a large 4-generation French family with bilateral vitreoretinal degeneration without extraocular abnormalities. Peripheral avascular vitreous veils were seen in all 20 patients, 7 of whom were younger than 15 years. Chorioretinal changes included peripheral alteration of the pigmentary epithelium in 7 patients, lattice degeneration in 6, and chorioretinal atrophy involving the retinal periphery and posterior pole in 2. Rhegmatogenous retinal detachment had occurred in 3 patients, and slight tractional detachment was observed in 3. Presenile cataracts progressed by the third decade and required removal in 11 patients; surgery was bilateral in 8 patients. Refraction was performed in all 20 patients; visual acuity was usually normal in young patients, and severely reduced in older patients.

Miyamoto et al. (2005) studied a large Japanese family with Wagner syndrome. Ocular phenotypes of affected members included an empty vitreous with fibrillary condensations, avascular membrane, perivascular sheathing, and progressive chorioretinal dystrophy and were similar to those of the original Wagner syndrome family. All affected eyes examined exhibited pseudoexotropia with ectopic fovea. No systemic manifestations were observed.

Wagner syndrome is often confused with Stickler syndrome (STL1; 108300) which is caused by mutations in the type II collagen gene (COL2A1; 120140). Like certain mutations in COL2A1 that result in a predominantly ocular or ocular-only phenotype, Wagner syndrome has no systemic features (Richards et al., 2006). However, the vitreoretinal phenotype is different, as neither of the recognized vitreous abnormalities in Stickler syndrome are present in Wagner syndrome and there is a lower incidence of retinal detachment. In addition, patients with Wagner syndrome have poor dark adaptation, which results in night blindness; this can be demonstrated by electrodiagnosis.

Brezin et al. (2011) studied a 4-generation French family with a severe vitreoretinal disorder in which affected individuals exhibited a range of highly variable phenotypes, from exudative vascular abnormalities and diffuse retinal atrophy with pigment clumping to nasally deviated retinal vessels with ectopic foveas. Affected family members manifested retinal detachment at an early age, with variable anterior segment features, including moderate myopia, glaucoma, cataracts, and ectopia lentis. Brezin et al. (2011) noted that visual impairment in this pedigree was highly significant; among 10 affected family members, 3 were totally blind and 5 other patients had completely lost vision in 1 eye.

Mapping

Brown et al. (1994) concluded that erosive vitreoretinopathy (ERVR) is very similar to Wagner disease. Brown et al. (1995) presented linkage evidence that erosive vitreoretinopathy and Wagner disease are allelic disorders, which are distinct from COL2A1-associated Stickler syndrome. Brown et al. (1995) demonstrated that ERVR and Wagner disease map to 5q13-q14.

Black et al. (1999) reported a family in which multiple members through at least 4 generations suffered from a hereditary vitreoretinopathy associated with a variety of ocular developmental abnormalities, including posterior embryotoxon, congenital glaucoma, iris hypoplasia, congenital cataract, ectopia lentis, microphthalmia, and persistent hyperplastic primary vitreous. Genetic linkage studies mapped the disorder to markers from the proximal region of 5q13-q14, specifically to the 5-cM region between markers D5S626 and D5S2103. Both Wagner and erosive vitreoretinopathies had been mapped to the same region, suggesting that the condition in the family studied by Black et al. (1999) is allelic.

In a large 4-generation French family with ERVR, Zech et al. (1999) obtained a maximum 2-point lod score of 5.6 (theta = 0) at marker CRTL1 (HAPLN1; 115435) GT repeat and a maximum multipoint lod score of 5.8 (theta = 0) for markers D5S2029, CRTL1 GT repeat, and D5S459. Recombination events narrowed the disease locus to a 20-cM region between D5S650 and D5S618.

Using 13 microsatellite markers, Mukhopadhyay et al. (2006) determined the 5q14.3 haplotypes in affected individuals from 6 Dutch families with vitreoretinopathy. All patients from 5 of the families, including 4 families diagnosed with Wagner syndrome and 1 diagnosed with ERVR, showed the same haplotype for an 850-kb critical region between D5S626 and D5S107, suggesting a founder allele in the Netherlands.

In a 4-generation French family with a severe vitreoretinal disorder, Brezin et al. (2011) found significant evidence for linkage with markers D5S641 (Z = 3.36; theta = 0) and D5S2103 (Z = 2.89; theta = 0), indicating a critical disease interval for the WGN1 locus on 5q13-q14.

Molecular Genetics

In a large Japanese family with vitreoretinopathy that segregated with the previously identified WGN1 locus on 5q13-q14, Miyamoto et al. (2005) identified a heterozygous splice site mutation in intron 7 of the CSPG2 gene (VCAN; 118661.0001) that cosegregated with the disease.

In the large 5-generation Swiss family with vitreoretinopathy originally described by Wagner (1938), Kloeckener-Gruissem et al. (2006) analyzed 2 positional candidate genes on chromosome 5q13-q14 and identified a heterozygous splice site mutation in intron 8 of the VCAN gene (118661.0002) that segregated with disease.

Mukhopadhyay et al. (2006) studied 8 multigenerational families diagnosed with vitreoretinopathy, 7 of which were of Dutch origin. All affected members of the Dutch families were heterozygous for 1 of 3 splice site mutations in intron 7 of the VCAN gene (118661.0003-118661.0005), including a family diagnosed with erosive vitreoretinopathy. However, no causal variant was identified in the eighth family, which was of Chinese origin. Affected ancestors of 5 of the Dutch families, which shared a common founder haplotype on chromosome 5q14.3, were traced to the same geographic region of the Netherlands; Mukhopadhyay et al. (2006) stated that these 5 families harbored more than 90% of all Dutch patients with Wagner vitreoretinopathy.

In a 4-generation French family with a severe vitreoretinal disorder mapping to 5q13-q14, in which some patients exhibited exudative vascular features (see EVR1, 133780) but in whom no mutations were found in EVR-associated genes, Brezin et al. (2011) identified a heterozygous splice site mutation in intron 7 of the VCAN gene (118661.0006) that segregated with disease and was not found in 100 French controls.

Kloeckener-Gruissem et al. (2013) sequenced the VCAN gene in the British family with Wagner vitreoretinopathy previously studied by Fryer et al. (1990) and in the French family previously described by Zech et al. (1999), and identified 2 heterozygous splice site mutations, in introns 8 and 7 of the VCAN gene, respectively, that segregated with disease in each family (118661.0007 and 118661.0008).

Exclusion Studies

Fryer et al. (1990) studied a large British family with Wagner vitreoretinal degeneration but none of the nonocular features of Stickler syndrome. They demonstrated recombination with the COL2A1 locus (120140), thus excluding that gene as the site of the mutation.

History

Differentiation of the Wagner syndrome and the Stickler syndrome is difficult. Liberfarb et al. (1978, 1981) suggested that the syndromes of Wagner and Stickler are the same. They restudied 3 families reported by Hirose et al. (1973). Blair et al. (1979) reported the clinical and histopathologic findings in 3 severely diseased eyes from 3 patients in 2 families. They concluded that the Stickler and Wagner syndromes are the same disorder. One reason for hesitation in complete acceptance of identity of the Wagner and Stickler syndromes is the fact that retinal detachment was not noted in any of the 28 members of the original Swiss family studied by Wagner (1938) and later by Boehringer et al. (1960) and Ricci (1961).

Korkko et al. (1993) noted phenotypic similarity to the family described by Wagner (1938) in a family in which they found a COL2A1 mutation (120140.0014). The family had early-onset cataracts, lattice degeneration of the retina, and retinal detachment with no involvement of nonocular tissues. Miyamoto et al. (2005) classified the family of Korkko et al. (1993) as an example of Stickler syndrome. Richards et al. (2006) suggested that the family of Korkko et al. (1993) could be an example of predominantly ocular Stickler syndrome or dominantly inherited rhegmatogenous retinal detachment.