Wagner syndrome (WS) is a rare vitreoretinopathy with no other systemic manifestations that was first described in 1938 in 13 members of a Swiss family.1 To date, only 13 families with WS have been characterized at a molecular level worldwide.2 Estimated prevalence is less than 1:1,000,000,4 and the pattern of inheritance is known to be autosomal dominant (AD) with near complete penetrance.4 At least nine different AD inherited mutations in the VCAN gene have been reported to date in families with WS.1
In 1995, Brown et al. were the first to show the condition could be mapped to chromosome 5q13–14.6 In 2005, Miyamoto et al. associated the pathology to the extracellular matrix component gene versican (VCAN), alternatively called CSPG2 (chondroitin sulfate proteoglycan 2 gene).
Clinically, WS is characterized by an optically empty vitreous cavity with avascular vitreous veils and strands at the equatorial vitreoretinal interface. Patients may also present with mild myopia, presenile cataracts, progressive chorioretinal atrophy, retinal pigment epithelium (RPE) clumping, ectopic foveae, inverted optic disc, uveitis, glaucoma, and nyctalopia.1,2 The course of the disease is progressive, and the chorioretinal pathology causes gradual visual loss, usually in the absence of retinal detachment (RD). However, some reports suggest that approximately 55% of WS cases can have tractional RDs by the age of 45 years, and electrophysiologic abnormalities are found in 87% of the cases.4,5 Due to the variation of clinical presentation, expressivity and severity among patients, WS is often overlooked or misdiagnosed.
A 23-year-old male from Ukraine was evaluated for flashes, floaters, and progressive visual loss in the left eye. He was otherwise healthy and had a history of RD repair in the right eye (OD) 4 months prior presentation to our department. In addition, it was disclosed that he had previously undergone laser barricade to regions around vitreoretinal traction in the left eye (OS), as an attempt to prevent further progression four months prior to our evaluation. Family history was negative for ocular diseases.
At first examination, best-corrected visual acuity (BCVA) was 20/200 OD and 20/70 OS. Intraocular pressure was normal. Slit-lamp examination disclosed conjunctival injection with a posterior subcapsular cataract in the right eye and a normal left eye. Posterior examination showed a detached retina under silicone oil with laser scars and pigment clumping in the right eye (Figure 1A), and a combined tractional and rhegmatogenous RD in the left eye (Figure 1C). The tractional component in the left eye compromised the macula and the mid-periphery, and operculated holes were located inferiorly. Clumps of pigment outside the arcades in an annular configuration were also noticed in the left eye, very similar in appearance to the contralateral eye. Fluorescein angiography showed hyperfluorescence secondary to pooling in the areas of detached retina with hypofluorescence in the areas of pigment clumping (Figures 1B and 1D). Optical coherence tomography (OCT) in the right eye revealed atrophy of the outer retinal layers and subretinal fluid (SRF) in the macula, and the left eye showed tractional detachment (Figures 2A–2C). As the presentation was atypical for a specific condition, we performed a full field electroretinogram (ERG) that reported cone-rod dysfunction worse in the right eye (Figure 3). Genetic testing was performed by direct testing in the gene of the MVL Vision Panel (v2; Molecular Vision Lab, Hillsboro, OR) by target enrichment and next-generation sequencing. Testing results reported a novel hetero missense variant in the VCAN gene, namely NM_004385.5:c.9265G>C (p.Gly3089Arg), which was consistent with a diagnosis of WS.
Color fundus photographs showing retinal detachment and pigmentary changes both eyes (A, C). Fluorescein angiography images demonstrating pooling and staining both eyes without leakage (B, D).
Preoperative optical coherence tomography (OCT) of the left eye showing presence of subretinal fluid and tractional component (A, B, C). Postoperative OCT of the same eye showing attachment of the retina (D, E, F).
Full-field electroretinogram of the patient demonstrating cone-rod dysfunction (A).
The patient was managed surgically with a standard three-port pars plana vitrectomy (PPV) in the left eye with C3F8 18% tamponade. During follow-up, the retina remained attached and without SRF in the OCT (Figures 2C–2E).
Pathology results from the membranous tissue extracted from surgery revealed internal limiting membrane (Periodic Acid Schiff stain positive), fibrocellular tissue, and glial tissue. Three months after his RD repair, the patient had cataract surgery. At last follow-up, his BCVA in the left eye had improved to 20/40, and the right eye is scheduled for surgery to repair the persistent RD.
Bilateral RD is rarely observed in the setting of WS.3–5 This patient presented with combined tractional and rhegmatogenous components and electro-physiologic findings consistent with a possibly dystrophic component to his disease.
There are several potential secondary diagnoses. One possibility is annular choroidal dystrophy, a rare disorder characterized by peripapillary atrophy of the RPE and choriocapillaris, that extends along the arcades sparing the macula.9 Another potential diagnosis is Goldmann-Favre syndrome, also known as enhanced S-cone syndrome, which is an autosomal recessive condition caused by mutations in NR2E3 and characterized by increased sensitivity to blue light, night blindness from an early age, and decreased vision. A final possibility is an atypical presentation of X linked retinoschisis. ERG was helpful in ruling out this condition, despite the fact the study's validity was limited by the patient's RD. Stickler Syndrome was also considered due to its presence of similar ocular abnormalities. We considered these differential diagnoses for the case because of the way it presented (bilateral combined RD), but chorioretinal atrophy has been well-described as a finding in patients with WS.
Stickler syndrome is another hereditary progressive arthro-ophthalmopathy that can overlap with the WS phenotype, though it is caused by mutations in different types of collagen.7 The characteristics of the vitreous can help to distinguish subtypes of Stickler syndrome and WS. Stickler syndrome demonstrates a membranous anterior vitreous (type 1 vitreous) or a fibrillar vitreous (type 2 vitreous.) In WS, the vitreous is described as an “optically empty vitreous” with avascular veils or fibrillary condensations. A variant of Stickler syndrome, the so-called “ocular only Stickler syndrome,” which lacks systemic findings, can be particularly difficult to distinguish from WS.
In an era where genetic testing is becoming increasingly available, there are three main objectives that justify obtaining this information. First, it is very useful to confirm a diagnosis when there is uncertainty. Additionally, genetic testing can guide the discussion regarding prognosis and progression of the disorder. Finally, genetic counseling allows the patient to be more knowledgeable about the inheritance patterns and its potential impact on future generations of offspring.
In summary, this case represents a rare presentation of WS with combined tractional and rhegmatogenous RD and the possibility of a concomitant retinal dystrophy. Genetic testing played a key role in confirming the diagnosis and revealed a unique variant in the VCAN gene.
- Thomas AS, Branham K, Van Gelder RN, et al. Multimodal Imaging in Wagner Syndrome. Ophthalmic Surg Lasers Imaging Retina. 2016;47(6):574–579. doi:10.3928/23258160-20160601-10 [CrossRef] PMID:27327288
- Pierre-Raphaël Rothschild, Brézin Antoine P, Brigitte Nedelec, Cyril Burin des Roziers, Tiffany Ghiotti, Lucie Orhant. A Family With Wagner Syndrome With Uveitis and a New Versican Mutation. Mol Vis. 2013;19:2040–2049. PMID: 24174867
- Meredith SP, Richards AJ, Flanagan DW, Scott JD, Poulson AV, Snead MP. Clinical characterisation and molecular analysis of Wagner syndrome. Br J Ophthalmol. 2007;91(5):655–659. doi:10.1136/bjo.2006.104406 [CrossRef] PMID:17035272
- Ronan SM, Tran-Viet KN, Burner EL, Metlapally R, Toth CA, Young TL. Mutational hot spot potential of a novel base pair mutation of the CSPG2 gene in a family with Wagner syndrome. Arch Ophthalmol. 2009;127(11):1511–1519. doi:10.1001/archophthalmol.2009.273 [CrossRef] PMID:19901218
- Graemiger RA, Niemeyer G, Schneeberger SA, Messmer EP. Wagner vitreoretinal degeneration. Follow-up of the original pedigree. Ophthalmology. 1995;102(12):1830–1839. doi:10.1016/S0161-6420(95)30787-7 [CrossRef] PMID:9098284
- Brown MB, Graemiger RA, Hergersberg M, et al. Genetic linkage of Wagner disease and erosive vitreoretinopathy to chromosome 5q13-14. Arch Ophthalmol. 1995;113(5):671–675. doi:10.1001/archopht.1995.01100050139045 [CrossRef] PMID: 7748141
- Tran-Viet KN, Soler V, Quiette V, et al. Mutation in collagen II alpha 1 isoforms delineates Stickler and Wagner syndrome phenotypes. Mol Vis. 2013;19:759–766. PMID:23592912
- Donoso LA, Edwards AO, Frost AT, et al. Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene. Surv Ophthalmol. 2003;48(2):191–203. doi:10.1016/S0039-6257(02)00460-5 [CrossRef] PMID:12686304
- Lenis TL, Klufas MA, Randhawa S, Sharma M, Sarraf D. Posterior polar annular choroidal dystrophy. Retin Cases Brief Rep. 2017;11(suppl 1):S24–S27. doi:10.1097/ICB.0000000000000392 [CrossRef] PMID:27571427
- Littink KW, Stappers PTY, Riemslag FCC, et al. Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome. Genes (Basel). 2018;9(2):68. doi:10.3390/genes9020068 [CrossRef] PMID:29385733