Wagner syndrome is a hereditary retinal degenerative disease characterized by vitreous liquefaction. It was first reported by Wagner in 1938. The cause is mutations in the VCAN gene (CSPG2), which encodes versican, a chondroitin sulfate proteoglycan. It shows autosomal dominant inheritance with complete penetrance, meaning all individuals with a VCAN mutation develop the disease to some degree.
The estimated prevalence is less than 1 in 1,000,000, making it an extremely rare disease, with only about 100 familial and sporadic cases reported in the literature. There is no predilection for any specific ethnic group; cases have been reported in diverse populations including European, Asian, and African descent. There are no extraocular manifestations or systemic complications.
Erosive vitreoretinopathy (ERVR), reported by Brown et al. in 1994 as an autosomal dominant condition, has been found to arise from the same genetic cause as Wagner syndrome. Additionally, because it presents with clinical findings similar to the ocular-limited form of Stickler syndrome, it was sometimes considered the same disease before the gene was identified.
Due to autosomal dominant inheritance, the probability of inheriting a VCAN mutation from an affected parent is 50%. If no mutation is found in either parent (de novo mutation), the risk to siblings is low but slightly higher than the general population due to the possibility of germline mosaicism. The risk for a child of an affected individual to develop the condition is 50%.
Ocular findings in Wagner syndrome are diverse. They can be broadly divided into the following two groups.
Vitreous Findings
Optically empty vitreous: A defining finding confirmed by slit-lamp microscopy. The vitreous is markedly liquefied, and the Tyndall phenomenon is absent.
Avascular vitreous strands and veils: Membranous or strand-like opacities within the liquefied vitreous adhere to the equatorial retina.
Peripheral avascular annular vitreous degeneration: A ring-like pattern of vitreous degeneration near the equator.
Fundus and Retinal Findings
Inverted optic disc vascular pattern: Also called inverted papilla, a characteristic finding in Wagner syndrome.
Progressive chorioretinal atrophy: Presents with various changes including pigment aggregation, vascular sheathing, pigmentary lattice degeneration, and peripheral atrophy.
Epiretinal membrane and tractional changes: OCT shows a membranous hyperreflective structure persistently attached around the fovea (different pattern from age-related PVD).
Retinal detachment: Both rhegmatogenous (RRD) and tractional types occur. Some cases present with Coats-like exudative plaques.
Frequency of retinal detachment: In a follow-up study of a Swiss family, RRD occurred in 14% (mean onset age 20 years), and peripheral tractional retinal detachment was found in 25% of all eyes (55% in those over 45). In a French family study, retinal detachment was found in 9 of 12 individuals, with a median onset age of 8 years.
Rare findings include spherophakia, ectopic fovea, synchysis scintillans, optic atrophy, exudative vitreoretinopathy, and uveitis.
Significantly higher than in the general population. In a Swiss family follow-up, 55% of patients over 45 had peripheral tractional retinal detachment. In a French family, 9 of 12 individuals had retinal detachment, with a median onset age of 8 years. Frequency varies greatly by family.
The cause of Wagner syndrome is solely genetic predisposition; no other known risk factors exist.
The VCAN gene is located on chromosome 5q13-15 and encodes versican, an extracellular matrix proteoglycan. Versican has four subtypes (V0–V3) depending on the presence of exon 7 or 8 sequences. Wagner syndrome is characterized by a reduction in subtypes containing exon 8 (V0 and V1).
All reported VCAN pathogenic mutations are in the splice acceptor or donor sites of introns 7 and 8, causing abnormal alternative splicing.
Many patients undergoing evaluation for Wagner syndrome present with an established family history. Clinical diagnosis is possible when there is a positive family history and corresponding clinical findings; in the absence of family history, genetic testing can aid in confirming the diagnosis.
The following tests are used for diagnosis and evaluation:
| Test | Findings/Purpose |
|---|---|
| Full-field electroretinogram | Reduced amplitudes of a- and b-waves (both rod and cone systems) |
| Fluorescein angiography | RPE atrophy and choriocapillaris dropout |
| OCT / OCTA | Membranous structures, retinal thinning, perivascular disappearance |
For a definitive diagnosis, sequence analysis of the splice acceptor and donor sites of introns 7 and 8 of the VCAN gene is the best first step. PCR is used to amplify the intron 7-exon 8 boundary or the exon 8-intron 8 boundary, and heterozygous changes (splice abnormalities) in the base sequence are diagnosed. Since versican is also expressed in peripheral blood leukocytes, RNA can be extracted from blood and a decrease in exon 8 expression can be diagnosed by real-time PCR. If targeted testing is not available, sequence analysis of the entire VCAN gene is performed. Multigene panels including VCAN and genes for other syndromes in the differential diagnosis are also available.
Vitreous degeneration with a veiled appearance resembles familial exudative vitreoretinopathy (FEVR), Stickler syndrome, and Goldmann-Favre syndrome. As retinal degeneration progresses, differentiation from retinitis pigmentosa and choroideremia becomes difficult. The main differential diagnoses are as follows:
A clinical diagnosis is possible if there is a positive family history and characteristic clinical findings (optically empty vitreous, chorioretinal atrophy, etc.). For confirmation, genetic testing is performed to identify mutations in the splice sites of introns 7 and 8 of the VCAN gene. Since the ocular-limited type of Stickler syndrome has similar clinical findings, differentiation by genetic testing is essential.
No fundamental (disease-modifying) treatment has been established for Wagner syndrome. Treatment is based on symptomatic therapy according to the associated conditions, and regular ophthalmic examinations by a vitreoretinal specialist at least once a year are necessary. Referral to a clinical geneticist and genetic counselor should also be made.
Management of Cataract
Cataract surgery (IOL implantation): Performed for cataracts causing significant visual impairment. Extracapsular extraction is recommended to prevent iris neovascularization and neovascular glaucoma.
Posterior capsule opacification (PCO): If it occurs postoperatively, treat with YAG laser posterior capsulotomy.
Management of Retinal Diseases
Retinal tear (without detachment): Treat with laser photocoagulation or cryotherapy.
Retinal detachment, macular traction, epiretinal membrane: Vitrectomy (PPV) or pneumopexy is indicated. For tractional retinal detachment, removal of membranes and vitreoretinal adhesions is necessary, and retinotomy may be required.
Glaucoma: May require surgery.
Main complications of PPV for retinal detachment repair include new retinal tears, proliferative vitreoretinopathy (PVR), and macular hole. Patients with recurrent tears often require silicone oil or gas tamponade.
The core pathology of Wagner syndrome is that splicing abnormalities in the VCAN gene alter the structure of versican, leading to early liquefaction of the vitreous.
The VCAN gene is located on chromosome 5q13-15 and encodes versican, a large proteoglycan of the extracellular matrix. Versican has four subtypes (V0 to V3) depending on the presence or absence of exon 7 or 8. Normally, the glycosaminoglycan (GAG) region of versican inhibits adhesion of collagen fibrils, maintaining the gel-like nature of the vitreous.
In Wagner syndrome, mutations in the splice acceptor or donor sites of intron 7 or 8 cause abnormal alternative splicing, reducing subtypes containing exon 8 (V0 and V1). As a result, the amount of glycosaminoglycan in versican is greatly reduced, leading to aggregation of collagen fibrils and early liquefaction of the vitreous. Membranous and cord-like opacities remain in the liquefied vitreous cavity, which adhere to the equatorial retina or degenerated retina, causing traction.
This series of changes underlies the pathology leading to vitreous liquefaction, veil formation, retinal traction, and further progression to chorioretinal atrophy. Since it shows complete penetrance, all individuals with VCAN mutations exhibit some degree of vitreous degeneration.
Kloeckener-Gruissem B, Amstutz C. VCAN-Related Vitreoretinopathy. GeneReviews® [Internet]. Seattle (WA): University of Washington; 2009 (updated 2016). PMID: 20301747. https://pubmed.ncbi.nlm.nih.gov/20301747/
Mukhopadhyay A, Nikopoulos K, Maugeri A, et al. Erosive vitreoretinopathy and Wagner disease are caused by intronic mutations in CSPG2/Versican that result in an imbalance of splice variants. Invest Ophthalmol Vis Sci. 2006;47(8):3565-72. PMID: 16877430. https://pubmed.ncbi.nlm.nih.gov/16877430/
Kloeckener-Gruissem B, Bartholdi D, Abdou MT, Zimmermann DR, Berger W. Identification of the genetic defect in the original Wagner syndrome family. Mol Vis. 2006;12:350-5. PMID: 16636652. https://pubmed.ncbi.nlm.nih.gov/16636652/
Kloeckener-Gruissem B, Neidhardt J, Magyar I, et al. Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome. Eur J Hum Genet. 2013;21(3):352-6. PMID: 22739342. https://pubmed.ncbi.nlm.nih.gov/22739342/
Brown DM, Kimura AE, Weingeist TA, Stone EM. Erosive vitreoretinopathy. A new clinical entity. Ophthalmology. 1994;101(4):694-704. PMID: 8152765. https://pubmed.ncbi.nlm.nih.gov/8152765/
