Wagner syndrome type 1

Progressive vitreous degeneration is the primary abnormality. Vitreous syneresis may progress to extensive liquefaction, causing the vitreous cavity to appear optically empty on slit-lamp examination, with residual avascular strands and veils. The first ocular manifestations usually become apparent in childhood or adolescence, although onset may occur earlier. Myopia is common and ranges from mild to high degrees. Presenile cataract frequently develops and may contribute to progressive visual impairment. Over time, chorioretinal degeneration can occur, leading to night blindness, peripheral visual field loss and reduced visual acuity. Retinal detachment, either tractional or rhegmatogenous, represents a major vision-threatening complication. In some affected individuals, chorioretinal atrophy predominates, a phenotype historically referred to as erosive vitreoretinopathy and now considered part of the same disease spectrum. Clinical manifestations may vary considerably within and between families, and the disorder is typically limited to the eye.

Wagner syndrome is a very rare inherited vitreoretinopathy. The prevalence is unknown, and only a limited number of affected families have been reported worldwide.

Wagner syndrome is caused by heterozygous pathogenic variants in VCAN, which encodes versican, a major extracellular matrix proteoglycan of the vitreous. Versican is essential for maintaining the structural organisation and transparency of the vitreous body. Most pathogenic variants affect splice donor or acceptor sites of exons 7 and 8, resulting in abnormal splicing and an altered ratio of versican isoforms. This disrupts vitreous homeostasis and leads to progressive vitreous degeneration and liquefaction. Both sequence variants and copy number variants have been reported.

Wagner syndrome is inherited in an autosomal dominant manner. Most affected individuals have an affected parent, although de novo pathogenic variants have also been reported. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant.

No consensus clinical diagnostic criteria have been established. The diagnosis is based on characteristic clinical findings and/or the identification of a heterozygous pathogenic or likely pathogenic variant in VCAN. Characteristic ocular findings include an optically empty vitreous with avascular strands and veils, as well as a circumferential equatorial vitreous condensation or veil on slit-lamp examination. Additional supportive findings may include abnormalities on optical coherence tomography (OCT) and reduced full-field electroretinographic (ERG) responses.

Main differential diagnoses include:

• : vitreoretinal degeneration associated with sensorineural hearing loss, craniofacial abnormalities and early-onset arthropathy; retinal detachment is common. Associated genes include COL2A1, COL11A1 and others.
• Familial exudative vitreoretinopathy (FEVR): characterised by incomplete peripheral retinal vascularisation, retinal neovascularisation and exudation. Associated genes include FZD4, LRP5, TSPAN12, NDP and others.
• Goldmann-Favre syndrome: retinal degeneration with night blindness, vitreous abnormalities and retinoschisis, typically caused by biallelic NR2E3 variants.
• Snowflake vitreoretinal degeneration: vitreous degeneration associated with characteristic crystalline “snowflake” deposits in the peripheral retina; associated with KCNJ13.
• Autosomal dominant vitreoretinochoroidopathy (ADVIRC): characterised by peripheral circumferential chorioretinal pigmentation with a sharp posterior border, frequently accompanied by microcornea and ocular developmental anomalies; associated with BEST1.

• Establishing the diagnosis: Identification of the underlying pathogenic or likely pathogenic variant confirms the clinical diagnosis and distinguishes the condition from clinically overlapping inherited vitreoretinopathies. A molecular diagnosis supports condition-specific monitoring and management decisions made by the treating physicians in consultation with the affected individual.
• Familial risk assessment: Identification of the underlying disease-causing variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Rothschild PR. VCAN-related vitreoretinopathy. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .
• Ghoraba HH, Sears J, Traboulsi EI. Hereditary vitreoretinopathies: molecular diagnosis, clinical presentation and management. Clin Exp Ophthalmol. 2025;53(3):281-291. PMID: .