What is Wagner syndrome?

Wagner Syndrome

Wagner syndrome is a rare autosomal dominant hereditary vitreoretinopathy caused by mutations in the VCAN gene, characterized by an optically empty vitreous cavity with avascular veils, progressive chorioretinal atrophy, early-onset cataracts, and high risk of retinal detachment leading to significant visual impairment in young adults. 1, 2

Genetic Basis and Inheritance

• Wagner syndrome results from mutations in canonical splice sites of the VCAN gene (chromosome 5q14.2-q14.3), which encodes versican, a large chondroitin sulfate proteoglycan critical for vitreous structure 3
• The condition follows autosomal dominant inheritance with variable expressivity, ranging from asymptomatic carriers to bilateral blindness 2
• Most reported mutations affect splice acceptor and donor sites in introns 7 and 8 (such as c.4004-1G>C, c.9265+2T>A, and c.9265+1G>A), resulting in altered balance of VCAN transcript variants 3
• Novel variants continue to be identified, including a recently reported c.4004-12_4004-6delins17 variant in intron 7 with high pathogenicity predictions 1

Clinical Features and Natural History

Vitreous Abnormalities

• The hallmark finding is an optically empty vitreous cavity with avascular strands or veils, present in virtually all affected individuals 2, 4
• This represents the most consistent diagnostic feature across all age groups 2

Progressive Chorioretinal Changes

• Chorioretinal atrophy increases with age and is present in all patients older than 45 years 2
• Fundus autofluorescence imaging reveals a characteristic perivascular pattern to the chorioretinal atrophy 4
• Spectral-domain optical coherence tomography demonstrates outer retinal disruption 4

Retinal Detachment Risk

• Rhegmatogenous retinal detachment occurs infrequently (approximately 14% of affected individuals) at a median age of 20 years 2
• Peripheral tractional retinal detachments are far more common, occurring in 55% of eyes among patients older than 45 years 2
• This represents a critical management consideration as tractional detachments follow a different natural history than rhegmatogenous detachments 2

Cataract Development

• Cataracts develop progressively with age and are present in all affected individuals older than 45 years 2
• Cataract formation contributes significantly to visual impairment in young adults 5

Other Ocular Complications

• Glaucoma develops in approximately 18% of eyes, with neovascular glaucoma accounting for a subset of these cases 2
• Cystoid macular edema may occur, sometimes in association with uveitis 4
• Constricted central visual fields with smaller isopter testing are characteristic 4

Diagnostic Evaluation

Electrophysiologic Testing

• Dark adaptation studies show elevated rod and cone thresholds in 63% of patients 2
• Electroretinography demonstrates subnormal b-wave amplitudes of both rod and cone systems in 87% of affected individuals, with depressed function in both photoreceptor systems 2, 4
• These findings parallel the progression of chorioretinal pathology 2

Genetic Confirmation

• Molecular genetic testing for VCAN mutations confirms the diagnosis in most cases 4, 3
• Testing should focus on splice site mutations in introns 7 and 8, though novel variants continue to be identified 1, 3
• Variations of unknown significance may be encountered and require careful clinical correlation 4

Multimodal Imaging

• Spectral-domain optical coherence tomography reveals outer retinal disruption and can identify cystoid macular edema 4
• Fundus autofluorescence highlights the perivascular pattern of chorioretinal atrophy 4
• Fluorescein angiography may be performed in selected cases to evaluate vascular changes 2

Management Approach

Prophylactic Intervention

• For patients at high risk of retinal detachment (those with significant vitreoretinal traction or zones of retinal delamination), prophylactic encircling band with retinopexy should be considered 1
• The encircling band supports zones of retinal delamination, releases vitreoretinal tractions, and additional laser photocoagulation can secure areas of dehiscence 1
• This represents a shift from purely observational management to preventive surgical intervention in selected high-risk cases 1

Monitoring Protocol

• Regular ophthalmologic surveillance is essential given the progressive nature of the disease 2
• Particular attention should be paid to peripheral retinal examination for early detection of tractional changes, especially in patients approaching or exceeding 45 years of age 2
• Intraocular pressure monitoring is necessary given the 18% risk of glaucoma development 2

Management of Complications

• Cataract extraction when visually significant, recognizing the universal occurrence in older affected individuals 2
• Prompt treatment of retinal detachments when they occur, though the high rate of peripheral tractional detachments may complicate surgical management 2
• Management of neovascular glaucoma when present, which may require aggressive intervention 2

Prognosis

• Clinical expressivity varies widely from unaffected carriers to bilateral blindness 2
• Visual impairment typically progresses with age, with severe visual incapacitation common in young adults due to cataracts and retinal complications 5
• The combination of chorioretinal atrophy, cataracts, and peripheral tractional retinal detachments in elderly affected individuals represents the typical end-stage phenotype 2