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Wagner syndrome is a rare vitreoretinopathy described in a limited number of families. Here the authors describe four cases of suspected Wagner syndrome. All four cases had depressed rod and cone function on electroretinography, outer retinal disruption on spectral-domain optical coherence tomography, and constricted central visual fields with smaller isopter testing. Fundus autofluorescence performed in one patient highlighted a perivascular pattern to chorioretinal atrophy. Two patients had a history of uveitis with active cystoid macular edema. The diagnosis of Wagner syndrome was supported in three cases with genetic testing for VCAN mutations, whereas the other case harbored a variation of unknown significance in VCAN that may have been nonpathogenic.
Wagner syndrome (WS) (OMIM 143200) is a rare autosomal dominant, ocular-only syndrome initially described in 1938 in 13 members of a Swiss family. It is characterized by an optically empty vitreous cavity with avascular vitreous veils, moderate myopia, presenile cataracts, and chorioretinal atrophy.1–3 Follow-up of 60 family members from this cohort in 1995 found additional clinical features such as depressed electroretinography (ERG) and tractional retinal detachment.4 The disease was originally linked to a mutation in chromosome 5q13–145 and was subsequently isolated to the versican (VCAN) gene.6 VCAN encodes a large chondroitin sulfate proteoglycan, which is a major component of the extracellular matrix of the vitreous gel. The central portion of VCAN is encoded by two exons — exons 7 and 8. At least nine different dominantly inherited mutations in the VCAN gene reported to date in families with WS that either affect the acceptor splice site of intron 7 or the donor splice site of intron 8.6–13 These novel mutations have on occasion been linked to new phenotypic variants not identified in the original Swiss cohort. In this observational case series, we describe the clinical and multimodal imaging findings in four members of three families with suspected WS. Three of the reported cases harbored mutations in VCAN predicted to be pathogenic, whereas one patient harbored a variant of undetermined significance (VUS) in VCAN.
A 33-year-old black woman was referred to the University of Michigan Kellogg Eye Institute for a possible diagnosis of retinitis pigmentosa (RP). She reported decreased visual acuity for approximately the past 3 years and difficulty with night vision. Cataracts were removed at the age of 33. Family history revealed that the proband’s father was diagnosed with RP at the age of 35 and her full brother had been diagnosed with RP at the age of 32. The proband’s paternal half-brother (age 31) reported night vision problems; however, he did not carry a definitive diagnosis. The proband had four daughters, of whom one reported difficulty with night vision. Visual acuity was 20/60 in both eyes (OU). Anterior segment examination identified trace flare in the right eye (OD). Fundus examination (Figure 1A) showed generalized retinal pigment epithelial (RPE) atrophy with peripheral pigmentary changes OU. Retinal vessels were attenuated and optic discs were full with mild pallor OU. A vitreous veil was noted on examination OU (arrows, Figure 1A). Goldmann visual field (GVF) testing (Figure 1B) showed a markedly constricted central visual field OU. Spectral-domain optical coherence tomography (SD-OCT) showed cystoid macular edema (CME) OD and outer retinal disruption OU (Figure 1C). Both the scotopic and photopic full-field ERG were markedly abnormal OU. Genetic testing revealed a mutation in VCAN (NM_004385.4), c.4004-1G>T, p.?, confirming the diagnosis of WS.
This patient was the 10-year-old daughter (Figure 1D) of the patient presented in Case 1. The patient reported difficulty with night vision for the year prior and was subsequently referred for a possible diagnosis of RP. Her visual acuity was 20/125 OD and 20/160 in the left eye (OS). On fundus examination, her vessels were slightly attenuated and there was a generalized mottling of the RPE. A vitreous veil was noted OD (Figure 1E). GVF was markedly abnormal OU (Figure 1F). SD-OCT through the macula revealed outer retinal thinning OU (Figure 1G). Both rod and cone full-field ERGs were abnormal OU. Genetic testing identified a VCAN mutation, c.4004-1G>T, p.?, identical to that of her mother.
A 45-year-old white male was referred to Oregon Health & Science University, Casey Eye Institute, for a possible diagnosis of RP. The patient reported a 5-year history of reduced vision and difficulty with dark-adaptation. The patient had a history of treatment for intermediate uveitis with CME OU with a negative workup. He subsequently developed a cataract OS, which was extracted. He had also undergone vitrectomy OU in an attempt to relieve the macular edema. Family ocular history was unremarkable except for the proband’s maternal grandmother having a history of an unspecified retinal degeneration and retinal detachment (Figure 1H). The patient had moderate myopia with a visual acuity of 20/60 OU. Fundus examination revealed vascular attenuation with perivascular chorioretinal atrophy (Figures 2A and 2B) accentuated on fundus autofluorescence (Figures 2C and 2D), as well as perivascular pigment deposition. SD-OCT through the macula revealed segmental outer retinal disruption OU and nasal CME OS (Figures 2E and 2F). Kinetic perimetry (Figure 3A) was markedly abnormal OU. Full-field ERG (Figure 3B) showed severely depressed scotopic and photopic responses. Multifocal ERG (Figure 3C) showed subnormal amplitude of the macular cone responses. Genetic testing revealed an exon 8 change in VCAN, c.4882G>A, p.Val1628ILe.
A 32-year-old black woman was referred to the University of Michigan Kellogg Eye Institute for a diagnosis of WS versus pericentral RP. She reported a history of poor vision since the age of 18 and a history of night vision difficulties of unknown duration. Cataracts were removed at the age of 32. At the time of referral, she was only aware of a maternal uncle with decreased vision. Subsequently, her daughter was diagnosed with early RP at the age of 6.
Visual acuity was 20/100 OD and 20/80 OS. Scattered pigment deposits, retinal scarring, diffuse atrophy, and peripheral veils were present in both eyes (Figure 1). GVF showed a ring scotoma OU. Both the scotopic and photopic full-field ERG were markedly abnormal OU with reduced photopic and scotopic ERGs. Genetic testing revealed a mutation of VCAN (NM_004385.4), (c.4004-1G>T, p.?,) confirming the diagnosis of WS.
WS is a rare vitreoretinopathy which was historically diagnosed strictly based on clinical features and pedigree analysis. Among patients with WS, ERG shows progressive generalized rod and cone dysfunction, visual fields show ring scotomas with progressive loss of central vision, and fundus autofluorescence highlights progressive peripheral and perivascular chorioretinal atrophy. These features are typical findings in several other retinal dystrophies such as RP, thus making the diagnosis of WS challenging. Based on this phenotypic overlap, genetic analysis has emerged as a necessary ancillary for the definitive diagnosis of this condition. In all four cases presented in this report, changes in VCAN were uncovered through testing for a larger retinal dystrophy gene panel. No variants were found in other genes in this panel, and confirmatory Sanger sequencing for VCAN was performed in all four patients.
With identification of the causative gene mutation, diagnosis of WS has risen in the last decade. Alternative splicing of VCAN leads to four different isoforms (V0 – V3) of the translated protein based on the presence or absence of exon 7 and/or exon 8. This alternative splicing appears to cause phenotypic variations in WS. Three patients in this case series had a mutation (c.4004-1G>T) in the acceptor splice site on intron 7 of the VCAN gene. This mutation has been previously described7,14 and is reported to result in upregulation of the V2 and V3 protein isoforms, which is predicted to be disease-causing.14 The third patient in the case series had a missense mutation in VCAN (c.4882G>A); this variant has been reported in the Exome Aggregation Consortium (ExAC) database in 4/122,258 alleles all in the heterozygous state for a frequency of 0.0033%. This relatively high frequency and lack of functional data makes this change a VUS. It is therefore possible that this variant is not pathogenic. However, it has been well-established in the original Wagner cohort that the disease is characterized by variable expressivity and ocular pleiotropy. It is thus unclear if other carriers of this allelic variant may have had subtle ocular pathology. Genetic testing for genes that cause RP did not reveal any mutations, although an alternative diagnosis of pigmented paravenous chorioretinopathy remains possible. More information as to significance of this change in VCAN in this patient will be needed before a conclusive diagnosis can be made.
In this series, we describe two adult patients who had prominent spontaneous uveitis as part of their clinical presentation. Three other families with WS have been reported to have uveitis with the first report of this association in 2007.11–13 Although VCAN is known to play a pivotal role as an inflammatory mediator,15 its role in uveitis in WS is poorly understood. However, with uveitis now having been described in five families with WS diagnosed at a molecular level, it is evident that the presence of uveitis may help separate this condition from other retinal and vitreoretinal degenerations.
With a limited dataset available worldwide to describe this condition, our knowledge of the phenotypic characteristics and variations of WS is likely incomplete. Judicious genetic testing in cases of atypical retinal and vitreoretinal degenerations could lead to improved diagnosis and understanding of this complex condition.
Dr. Pennesi is a consultant for Sucampo Pharmaceuticals. Dr. Van Gelder receives grant support from the National Institutes of Health and Theravance. Dr. Daiger receives honoraria for service on the scientific boards of Foundation Fighting Blindness and AGTC. Drs. Bowne and Sullivan receive grant support from the Foundation Fighting Blindness, the National Institute of Health (NIH), and eyeGene fee-for-service genetic testing from the NIH.
The remaining authors report no relevant financial disclosures.