Wagner vitreoretinopathy is a rare vitreoretinal degeneration inherited as an autosomal dominant trait, first described in a large Swiss pedigree (Wagner, 1938) and subsequently identified in other families. Penetrance in Wagner syndrome is complete, and the disease manifests ... Wagner vitreoretinopathy is a rare vitreoretinal degeneration inherited as an autosomal dominant trait, first described in a large Swiss pedigree (Wagner, 1938) and subsequently identified in other families. Penetrance in Wagner syndrome is complete, and the disease manifests in childhood or adolescence with a progressive course. Affected individuals usually present with an 'empty' vitreous cavity with fibrillary condensation or avascular strands and veils. Additional features, which are variable and age-dependent, include chorioretinal atrophy with loss of the retinal pigment epithelium (RPE), lattice degeneration of the retina, complicated cataracts, mild myopia, and peripheral traction retinal detachment. Rod and cone electroretinography shows reduced b-wave amplitude and correlates with severe chorioretinal pathology. It is believed that liquefaction of vitreous initiates a degenerative cascade that results in the complex eye phenotype of Wagner syndrome (summary by Kloeckener-Gruissem et al., 2006). Patients with additional ocular features such as progressive nyctalopia (night blindness), visual field constriction, and chorioretinal atrophy, with loss of RPE and choriocapillaries on fluorescein angiography and rod-cone abnormalities on electroretinography, were initially believed to have a distinct clinical entity, which was designated 'erosive vitreoretinopathy' (ERVR). Extraocular abnormalities are not present in patients diagnosed with Wagner or erosive vitreoretinopathy (summary by Mukhopadhyay et al., 2006).
Wagner (1938) described 13 members of a Canton Zurich family with a peculiar lesion of the vitreous and retina. Ten additional affected members were observed by Boehringer et al. (1960) and 5 more by Ricci (1961). In Holland ... Wagner (1938) described 13 members of a Canton Zurich family with a peculiar lesion of the vitreous and retina. Ten additional affected members were observed by Boehringer et al. (1960) and 5 more by Ricci (1961). In Holland Jansen (1962) described 2 families with a total of 39 affected persons. In addition to typical changes in the vitreous, retinal detachment occurs in some and cataract is another complication. See hyaloideotapetoretinal degeneration of Favre (268100). Graemiger et al. (1995) examined 60 members of the Swiss kindred originally studied by Wagner (1938). Twenty-eight members were found to be affected. The most consistent finding was an empty vitreous cavity with avascular strands or veils. Chorioretinal atrophy and cataract increased with age and occurred in all patients older than 45 years. Four patients had a history of a rhegmatogenous retinal detachment in 1 eye, which occurred at a median age of 20 years. Peripheral traction retinal detachments were found in 55% of eyes among patients older than 45 years. Glaucoma was present in 10 eyes (18%), 4 of which showed neovascular glaucoma. Of all patients, 63% showed elevated rod and cone thresholds on dark adaptation, and 87% showed subnormal b-wave amplitudes of the rod and cone systems on electroretinography. Thus, clinical expressivity of the disorder varied from unaffected carriers to bilateral blindness. Progression of the chorioretinal pathology was paralleled by electrophysiologic abnormalities. Zech et al. (1999) examined 20 affected individuals from a large 4-generation French family with bilateral vitreoretinal degeneration without extraocular abnormalities. Peripheral avascular vitreous veils were seen in all 20 patients, 7 of whom were younger than 15 years. Chorioretinal changes included peripheral alteration of the pigmentary epithelium in 7 patients, lattice degeneration in 6, and chorioretinal atrophy involving the retinal periphery and posterior pole in 2. Rhegmatogenous retinal detachment had occurred in 3 patients, and slight tractional detachment was observed in 3. Presenile cataracts progressed by the third decade and required removal in 11 patients; surgery was bilateral in 8 patients. Refraction was performed in all 20 patients; visual acuity was usually normal in young patients, and severely reduced in older patients. Miyamoto et al. (2005) studied a large Japanese family with Wagner syndrome. Ocular phenotypes of affected members included an empty vitreous with fibrillary condensations, avascular membrane, perivascular sheathing, and progressive chorioretinal dystrophy and were similar to those of the original Wagner syndrome family. All affected eyes examined exhibited pseudoexotropia with ectopic fovea. No systemic manifestations were observed. Wagner syndrome is often confused with Stickler syndrome (STL1; 108300) which is caused by mutations in the type II collagen gene (COL2A1; 120140). Like certain mutations in COL2A1 that result in a predominantly ocular or ocular-only phenotype, Wagner syndrome has no systemic features (Richards et al., 2006). However, the vitreoretinal phenotype is different, as neither of the recognized vitreous abnormalities in Stickler syndrome are present in Wagner syndrome and there is a lower incidence of retinal detachment. In addition, patients with Wagner syndrome have poor dark adaptation, which results in night blindness; this can be demonstrated by electrodiagnosis. Brezin et al. (2011) studied a 4-generation French family with a severe vitreoretinal disorder in which affected individuals exhibited a range of highly variable phenotypes, from exudative vascular abnormalities and diffuse retinal atrophy with pigment clumping to nasally deviated retinal vessels with ectopic foveas. Affected family members manifested retinal detachment at an early age, with variable anterior segment features, including moderate myopia, glaucoma, cataracts, and ectopia lentis. Brezin et al. (2011) noted that visual impairment in this pedigree was highly significant; among 10 affected family members, 3 were totally blind and 5 other patients had completely lost vision in 1 eye.
In a large Japanese family with vitreoretinopathy that segregated with the previously identified WGN1 locus on 5q13-q14, Miyamoto et al. (2005) identified a heterozygous splice site mutation in intron 7 of the CSPG2 gene (VCAN; 118661.0001) that cosegregated ... In a large Japanese family with vitreoretinopathy that segregated with the previously identified WGN1 locus on 5q13-q14, Miyamoto et al. (2005) identified a heterozygous splice site mutation in intron 7 of the CSPG2 gene (VCAN; 118661.0001) that cosegregated with the disease. In the large 5-generation Swiss family with vitreoretinopathy originally described by Wagner (1938), Kloeckener-Gruissem et al. (2006) analyzed 2 positional candidate genes on chromosome 5q13-q14 and identified a heterozygous splice site mutation in intron 8 of the VCAN gene (118661.0002) that segregated with disease. Mukhopadhyay et al. (2006) studied 8 multigenerational families diagnosed with vitreoretinopathy, 7 of which were of Dutch origin. All affected members of the Dutch families were heterozygous for 1 of 3 splice site mutations in intron 7 of the VCAN gene (118661.0003-118661.0005), including a family diagnosed with erosive vitreoretinopathy. However, no causal variant was identified in the eighth family, which was of Chinese origin. Affected ancestors of 5 of the Dutch families, which shared a common founder haplotype on chromosome 5q14.3, were traced to the same geographic region of the Netherlands; Mukhopadhyay et al. (2006) stated that these 5 families harbored more than 90% of all Dutch patients with Wagner vitreoretinopathy. In a 4-generation French family with a severe vitreoretinal disorder mapping to 5q13-q14, in which some patients exhibited exudative vascular features (see EVR1, 133780) but in whom no mutations were found in EVR-associated genes, Brezin et al. (2011) identified a heterozygous splice site mutation in intron 7 of the VCAN gene (118661.0006) that segregated with disease and was not found in 100 French controls. Kloeckener-Gruissem et al. (2013) sequenced the VCAN gene in the British family with Wagner vitreoretinopathy previously studied by Fryer et al. (1990) and in the French family previously described by Zech et al. (1999), and identified 2 heterozygous splice site mutations, in introns 8 and 7 of the VCAN gene, respectively, that segregated with disease in each family (118661.0007 and 118661.0008).
VCAN-related vitreoretinopathy is characterized by:...
DiagnosisClinical DiagnosisVCAN-related vitreoretinopathy is characterized by:“Optically empty vitreous” on slit-lamp examination and avascular vitreous strands and veilsMild or occasionally moderate to severe myopiaPresenile cataractNight blindness of variable degree associated with progressive chorioretinal atrophyRetinal traction and detachment at advanced stages of the diseaseReduced visual acuity resulting from the above manifestationsAbsence of systemic abnormalities The clinical diagnosis of VCAN-related vitreoretinopathy is established based on typical clinical findings and a family history consistent with autosomal dominant inheritance. Not every clinical finding listed above is observed in every affected individual. The hallmark, however, is the empty vitreous. The presence of several affected family members facilitates diagnosis by identifying the mode of inheritance and spectrum of ocular findings among affected family members at different ages. In general, it is the pattern of ocular findings in an individual or a family rather than a specific ocular finding that helps establish the diagnosis. Establishing the diagnosis may be more difficult in a simplex case (i.e., a single occurrence in a family). Molecular Genetic TestingGene. VCAN (previously known as CSPG2), encoding the large extracellular matrix proteoglycan versican, is the only gene in which mutations are known to cause Wagner syndrome and erosive vitreoretinopathy (ERVR) [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Mukhopadhyay et al 2006, Meredith et al 2007, Brezin et al 2011, Kloeckener-Gruissem et al 2012]. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in VCAN-Related VitreoretinopathyView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityVCANSequence analysisSequence variants 210/12 families with VCAN-related vitreoretinopathy 3ClinicalDeletion / duplication analysis 4Exonic, multiexonic, or whole-gene deletion / duplicationUnknown; none reported 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. In ten of twelve families with VCAN-related vitreoretinopathy, sequence analysis of the entire VCAN coding region and flanking introns identified mutations; in two families no mutation was found [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Mukhopadhyay et al 2006, Meredith et al 2007].4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. No deletions or duplications of VCAN have been reported to cause VCAN-related vitreoretinopathy. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband1.Because all VCAN mutations to date associated with Wagner syndrome and ERVR are found in the splice acceptor or splice donor site of introns 7 and 8, respectively, sequencing of this DNA region is recommended as a first step. 2.If no mutation is found, sequencing of the entire VCAN coding region is recommended.Of note, the presence of characteristic connective tissue abnormalities in the patient or relatives could prompt genetic testing for Stickler syndrome rather than or in addition to testing for VCAN mutations. See Differential Diagnosis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersNo phenotypes other than VCAN-related vitreoretinopathy have been reported to be associated with mutations in VCAN.
VCAN-related vitreoretinopathy comprises the phenotypic continuum of Wagner vitreoretinal degeneration (Wagner syndrome) and erosive vitreoretinopathy (ERVR), two disorders that were previously thought to be distinct entities based on clinical findings. Wagner syndrome, the first reported inherited vitreoretinal degeneration, was described by Wagner [1938]. ERVR was described in 1994 as a new clinical entity with some features that overlapped with Wagner syndrome [Brown et al 1994]. ...
Natural HistoryVCAN-related vitreoretinopathy comprises the phenotypic continuum of Wagner vitreoretinal degeneration (Wagner syndrome) and erosive vitreoretinopathy (ERVR), two disorders that were previously thought to be distinct entities based on clinical findings. Wagner syndrome, the first reported inherited vitreoretinal degeneration, was described by Wagner [1938]. ERVR was described in 1994 as a new clinical entity with some features that overlapped with Wagner syndrome [Brown et al 1994]. Vitreoretinal degeneration. As described by Wagner [1938], the hallmark of VCAN-related vitreoretinopathy is progressive degenerative changes of the vitreous (syneresis) and the vitreoretinal interface beginning at a young age. Syneresis can lead to massive liquefaction of the vitreous such that on slit-lamp examination the vitreous cavity appears optically empty ("empty vitreous") with pockets of liquefied vitreous that are usually lined by avascular strands and veils. Preretinal vitreous membranes that span the whole equator of the eye are characteristic. Ocular changes show considerable inter- and intrafamilial variability.The first signs usually become apparent during early adolescence, but onset can be as early as age two years [Miyamoto et al 2005]. No gender-specific difference in the occurrence or frequency of any particular ocular features has been observed. The vitreous degeneration, which is assumed to be the primary pathology, leads to a number of secondary changes, including presenile cataract, degeneration and atrophy of the retina, and the underlying retinal pigment epithelium (RPE) and choroid, and retinal detachment [Wagner 1938, Jansen 1962, Graemiger et al 1995, Zech et al 1999, Miyamoto et al 2005, Mukhopadhyay et al 2006, Meredith et al 2007].Common Ocular Features (≤60% of Affected Individuals)Myopic refractive error (nearsightedness) results from axial myopia (a developmental mismatch of the refractive power and length of the globe) and/or index myopia (a change in the refractive index of the progressively cataractous lens). Axial myopia is common, although severity varies. In the family reported by Wagner, most affected members had mild myopia and only a few had moderate to severe myopia. In contrast, in the Dutch family all members had high myopia with astigmatism [Jansen 1962]. Presenile cataract (progressive loss of transparency of the ocular lens) is a common finding and a common cause of decline in visual acuity over time. The types of cataract vary. Small spherical opacities and posterior subcapsular cataract affected 43% of eyes in the original family reported by Wagner [Graemiger et al 1995]. In the Dutch families, cataract types included moderate cortical cataract, anterior and posterior cortical cataract, and posterior subcapsular cataract [Mukhopadhyay et al 2006]. Nuclear cataract without any posterior subcapsular opacity was described in a British family [Meredith et al 2007].In a Japanese family, approximately 50% of affected individuals underwent cataract surgery; the oldest was age 35 years [Miyamoto et al 2005]. In a French family, cataract affected 55% of individuals [Zech et al 1999]. Of note, even after cataract extraction and correction of the refractive error, visual acuity was not normal, typically ranging from 6/12 (20/40) to 6/24 (20/80). Nonspecific reactive changes of the retinal pigment epithelium and overlying retina (pigment condensation, vascular sheathing, pigmented lattice degeneration, and later chorioretinal atrophy in the retinal periphery) occur. Affected individuals may experience nyctalopia (night blindness) and visual field constriction that are not as severe as those seen in retinitis pigmentosa. Nyctalopia may or may not progress. In some cases the chorioretinal atrophy is so severe that it resembles choroideremia. Diffuse retinal pigmentary changes and patchy chorioretinal atrophy are observed in some, but not all family members affected by Wagner syndrome [Meredith et al 2007, Ronan et al 2009]. The full-field electroretinogram (ERG) becomes attenuated. Typically both the amplitudes of the a-waves (response of the photoreceptor layer) and the b-waves (response of the bipolar cell layer) are reduced. The rod and cone systems (as measured by the scotopic and photopic response, respectively) are affected to varying degrees but in a family-specific manner, as demonstrated by the Swiss family originally reported by Wagner, the Japanese family, and the British family [Graemiger et al 1995, Miyamoto et al 2005, Meredith et al 2007]. No ERG measurements were reported from the French and Dutch families [Zech et al 1999, Mukhopadhyay et al 2006]. Abnormal retinal vessels or poor vascularization of the peripheral retina were found in approximately 50% of individuals from the family reported by Wagner [Graemiger et al 1995], but only in a few individuals of the Dutch families [Mukhopadhyay et al 2006]. No details about retinal vessel characteristics were given for the other reported families [Zech et al 1999, Miyamoto et al 2005, Meredith et al 2007].Retinal detachment was initially found to be associated with increasing age; however, a recent report indicates that detachments can occur earlier (average of 9.5 years) [Ronan et al 2009]. Caused by shrinkage of the preretinal membranes and the vitreous strands and veils, retinal detachment is either tractional or rhegmatogenous. Tractional retinal detachment is caused by tangential shortening of the adhering membranes. The detached retina is rigid; successful surgical repair requires meticulous removal of the membranes and vitreoretinal adhesions and, most often, extensive retinotomies to relieve the traction. Tractional retinal detachment is not a particularly common feature of Wagner syndrome.Rhegmatogenous retinal detachment is caused by retinal breaks associated with the preretinal membranes. Liquefied vitreous fluid enters the potential subretinal space through one or more retinal tears caused by shrinking membranes. The retinal detachment is typically bullous; surgical repair primarily relies on closure of all retinal breaks. Of note, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration in young individuals in a considerable number of cases presents with only minor changes of the vitreous. Consequently, large retinal tears in young persons should raise the suspicion of a hereditary disease, and should prompt examination of other family members and eventually molecular genetic analysis. In the original publication by Wagner the incidence of retinal detachment at age 20 years was one in four, whereas in the Dutch pedigrees published by Jansen bilateral retinal detachment was a frequent finding at a young age. Of note, follow-up publications of the original Wagner pedigree reported an incidence of retinal detachment more than one in two. Of the few retinal detachments described in the Swiss family reported originally by Wagner and the Dutch families reported by Jansen, some were peripheral tractional [Graemiger et al 1995, Mukhopadhyay et al 2006]. Further tractional effects were observed as situs inversus [Wagner 1938]. Recently, affected individuals were described with inversion of the papilla as a possible consequence of tractional forces [Ronan et al 2009].In the Japanese family reported by Miyamoto et al [2005], most of the retinal detachments were rhegmatogenous. No retinal detachments were observed in the only two affected individuals reported in a British family [Meredith et al 2007]. Occasional Ocular Features The following features have been reported rarely. Some may not be part of VCAN-related vitreoretinopathy but rather occur coincidentally.Spherophakia, a spherical deformation of the ocular lens, has been observed sporadically in persons with VCAN-related vitreoretinopathy [Graemiger et al 1995]. Cataract can induce a change of the refractive index of the lens nucleus, further attenuating the myopic refractive error (index myopia). Posterior vitreous detachment (PVD), detachment of the posterior vitreous membrane from the retinal surface, is caused by shrinkage of the vitreous body and the pathological vitreoretinal interface. In contrast to the usual age-related PVD, the PVD in VCAN-related vitreoretinopathy initially affects the peripheral rather than the central posterior vitreous. None of the individuals from the original family described by Wagner or the French family showed PVD [Graemiger et al 1995, Zech et al 1999].Ectopic fovea, manifesting as an increased angle kappa (the angle between the visual axis and the pupillary axis), has occasionally been reported [Graemiger et al 1995, Miyamoto et al 2005, Meredith et al 2007].Phthisis bulbi (painful shrinking of the ocular globe as a result of loss of intraocular pressure) can occur and may require enucleation of the eye. Retinal detachment that has not been repaired successfully and retinal detachment associated with proliferative retinal vitreoretinopathy (PVR) are risk factors for phthisis bulbi. The decrease in intraocular pressure is caused by decreased aqueous production by the ciliary body epithelium, which becomes compromised by the pathologic vitreoretinal membranes because of the primary vitreal changes, the PVR, or both.Synchysis scintillans (bilateral accumulation of cholesterol crystals in the vitreous, which may or may not be associated with recurrent vitreous hemorrhage), may or may not occur with increased frequency in VCAN-related vitreoretinopathy, as it was only observed in a few older affected individuals [Graemiger et al 1995, Zech et al 1999]. Optic atrophy was found in only a few of the older individuals from the original Wagner family. These individuals had advanced chorioretinal atrophy, suggesting that optic atrophy is secondary to the massive loss in retinal ganglion cells [Graemiger et al 1995]. Glaucoma may not be a common feature of Wagner syndrome, as only a few individuals with VCAN-related vitreoretinopathy have been reported with glaucoma, none of them having primary open-angle glaucoma (one had congenital glaucoma, two had chronic angle-closure glaucoma, and three had neovascular glaucoma).Exudative vitreoretinopathy with vascular abnormalities has only been reported in one French family [Brezin et al 2011]; in fact, familial exudative vitreoretinopathy (FEVR) was the initial diagnosis suspected in this family. Uveitis is also a rare feature observed in individuals with Wagner syndrome. A case was reported in a French [Brezin et al 2011] and a British [Meredith et al 2007] family. Systemic FindingsTo date, no systemic abnormalities associated with VCAN-related vitreoretinopathy have been reported, and consequently VCAN-related vitreoretinopathy is considered an isolated vitreoretinal degeneration. Note: Recording blood pressure in persons with vitreoretinopathy may reveal possible systemic complications.
Because of the highly variable frequency of findings and the low number of mutations identified to date, no definite genotype-phenotype correlations have been established so far. ...
Genotype-Phenotype CorrelationsBecause of the highly variable frequency of findings and the low number of mutations identified to date, no definite genotype-phenotype correlations have been established so far.
Syndromes with overlapping features. A recent review summarizes the clinical features of inherited vitreoretinopathies and points out the importance of consulting an expert ophthalmologist in diagnostic assessment of the disease [Edwards 2008]. ...
Differential DiagnosisSyndromes with overlapping features. A recent review summarizes the clinical features of inherited vitreoretinopathies and points out the importance of consulting an expert ophthalmologist in diagnostic assessment of the disease [Edwards 2008]. Autosomal Dominant VitreoretinopathiesSnowflake vitreoretinal degeneration (SVD) (OMIM 193230). Both SVD and VCAN-related vitreoretinopathy exhibit vitreous abnormalities including fibrillar condensation, gel liquefaction, and marked thickening of the cortical vitreous. In SVD, however, membranous degeneration of the vitreous with avascular strands and veils is not observed. Retinal defects start in the superficial retinal layers, whereas in VCAN-related vitreoretinopathy they start in the deep retinal layers and choroid; retinal detachment is uncommon; and the retinal crystalline snowflake-like deposits that give the disease its name are common. Mutations in KCNJ13 are causative [Hejtmancik et al 2008].Stickler syndrome, or hereditary arthroophthalmopathy, is most often a systemic disorder associated with a skeletal dysplasia (spondyloepiphyseal dysplasia) and craniofacial abnormalities, including cleft palate. Retinal detachment is much more common in Stickler syndrome (50%) than in VCAN-related vitreoretinopathy (15%). Abnormal dark adaptation associated with alterations in the ERG that is common in VCAN-related vitreoretinopathy has not been described in Stickler syndrome. Two different and specific vitreoretinal phenotypes have been described in Stickler syndrome (Stickler syndrome type 1 and type 2). The type 1 vitreoretinal phenotype is caused by mutations in COL2A1 encoding type II procollagen. For certain mutations in COL2A1, a predominantly ocular or nonsyndromic phenotype can result. Usually, however, these patients can be readily distinguished from patients with Wagner syndrome because of the specific vitreous anomaly associated with type 1 Stickler syndrome. However, some authors have referred to this form of Stickler syndrome as Wagner syndrome type II [Gupta et al 2002].Autosomal dominant vitreoretinochoroidopathy (ADVIRC) (OMIM 193220). Only a few families with vitreoretinochoroidopathy (VRCP) have been described. Affected individuals show the following findings that seem to progress more slowly than those of VCAN-related vitreoretinopathy:Fibrillar condensation of the vitreous, but not optically empty vitreous Chorioretinal hyperpigmentation with peripheral pigmentary clumping Macular atrophyBreakdown of the blood retinal barrier (observed in one family) Normal full-field (Ganzfeld) ERG but altered multifocal ERG pattern Cataract High myopia and retinal detachment do not appear to be part of VRCP [Oh & Vallar 2006]. Mutations in VMD2, the gene encoding bestrophin, are causative. It appears that splicing defects may cause VRCP, whereas mutations in the coding region result in Best disease [Yardley et al 2004].Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). Bennett et al [1990] reported a six-generation family with an autosomal dominant vitreoretinopathy in which the prevailing clinical features were severe anterior and posterior segment inflammation; neovascular proliferations and related complications, in particular tractional retinal detachment and neovascular glaucoma; and a selective loss of the b-wave amplitude on the ERG early in the disease. Mutations in VMD2 are causative. ADNIV and ADVIRC may be considered to belong to a disease spectrum of VMD2-related autosomal dominant vitreoretinopathies.Autosomal Recessive VitreoretinopathiesGoldmann-Favre syndrome (included in enhanced S-cone syndrome). Mutations in NR2E3 (nuclear receptor subfamily 2, group E, member 3) have been identified in Goldmann-Favre syndrome, enhanced S-cone syndrome (ESCS), and clumped pigmentary retinal degeneration [Haider et al 2000]. All these clinical entities are usually associated with night blindness and visual field constriction. Electroretinography characteristically reveals a severe reduction in rod function and a relatively enhanced function of the short-wavelength-sensitive cones. The classic Goldmann-Favre phenotype includes progressive vitreous changes (vitreous liquefaction and fibrillar strands and veils); night blindness and severe reduction in the ERG in early childhood; chorioretinal atrophy and pigmentary retinal degeneration later in the disease course resulting in marked visual field loss; retinoschisis in the periphery, macula, or both; presenile cataract; and a hyperopic rather than myopic refractive error. Although ESCS lacks the marked vitreous changes typical of the Goldmann-Favre phenotype, vitreous cells are a very common feature, and more prominent vitreous changes including vitreous opacities, haze, and veils can occur. Peripheral retinal schisis has been observed in ESCS, and foveal schisis, eventually associated with cystoid changes, may even be a common feature. The fundus appearance varies, and features are overlapping with clumped pigmentary retinal degeneration, in which the retinal pigmentary changes are the most prominent feature of the phenotype [Audo et al 2008]. Knobloch syndrome (OMIM 267750). Knobloch syndrome is a syndromic vitreoretinopathy in which ocular changes similar to those of VCAN-related vitreoretinopathy are associated with occipital encephalocele. Mutations in COL18A1, the gene encoding the alpha 1 chain of collagen type 18, are causative [Menzel et al 2004, Keren et al 2007].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with VCAN-related vitreoretinopathy, the following evaluations are recommended: ...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with VCAN-related vitreoretinopathy, the following evaluations are recommended: Baseline ophthalmologic examination including best corrected visual acuity, assessment of intraocular pressure, slit-lamp examination of the anterior segment, and biomicroscopy and indirect ophthalmoscopy of the posterior segmentFamily historyVisual field examinationPhotographic fundus documentationOptical coherence tomography (OCT), if available. While not mandatory, OCT scan is useful assessing the vitreoretinal interface, quantifying atrophic changes of the central retina, and evaluating for cystoid macular edema. ERG examination Orthoptic assessmentTreatment of ManifestationsRefractive error is corrected by spectacles or contact lenses. Visually disabling cataract is treated by cataract surgery. Phacoemulsification and implantation of an intraocular lens in the capsular bag has become the widely adopted standard procedure; however, as emphasized by Edwards, cataract surgery in patients with vitreoretinopathy and possibly preceding vitrectomy can be difficult and should be performed by an experienced surgeon [Miyamoto et al 2005, Edwards 2008]. Posterior capsule opacification after cataract surgery is treated with YAG laser capsulotomy. Retinal breaks are treated with laser retinopexy or cryocoagulation if no retinal detachment is present. Vitreoretinal surgery is indicated for retinal detachment, vitreoretinal traction involving the macula, or epiretinal membranes involving the macula. Surveillance Annual ophthalmologic examination by a vitreoretinal specialist is indicated.Evaluation of Relatives at RiskFamily mutation known. If the disease-causing mutation has been identified in at least one affected family member, it is appropriate to offer molecular genetic testing to at-risk relatives in order to reduce morbidity by early diagnosis and treatment of ophthalmologic complications.Family mutation not known. If the disease-causing mutation in the family is not known, it is appropriate to offer ophthalmologic evaluations to those family members at risk in order to identify individuals who presumably will benefit from regular ophthalmologic examinations and early treatment of ophthalmologic complications. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. VCAN-Related Vitreoretinopathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDVCAN5q14.2-q14.3Versican core proteinVCAN @ LOVDVCANData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for VCAN-Related Vitreoretinopathy (View All in OMIM) View in own window 118661VERSICAN; VCAN 143200WAGNER VITREORETINOPATHY; WGVRPMolecular Genetic PathogenesisSince VCAN is expressed in many human tissues, mutations in VCAN could be expected to interfere with functions in tissues and organs other than the eye; the cardiovascular system in particular would seem a likely candidate, as versican, the protein product of VCAN, is a component of the extracellular matrix of the blood vessels [Yao et al 1994, Lemire et al 1999]. A possible explanation for the absence of consequences of VCAN mutations in non-ocular tissues is that splicing of the VCAN transcripts may be tissue-specific. Normal allelic variants. The genomic region (109,399 nucleotides) of VCAN includes 15 exons (NCBI Genbank accession number NM_004385.3). The two largest exons, 7 (2961 nucleotides) and 8 (5262 nucleotides), are subject to alternative splicing, yielding four naturally occurring splice variants (named V0, 1, 2, and 3) that exhibit a tissue-specific expression pattern. The respective exon-intron boundaries show the consensus sequences for splice acceptor and splice donor sites.Pathologic allelic variants. Five different point mutations, all located in conserved splice sites of introns 7 and 8, are associated with the phenotype [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Mukhopadhyay et al 2006, Meredith et al 2007, Ronan et al 2009, Brezin et al 2011]. In some cases, identical mutations have been found in different, unrelated families (Table 2). No exonic mutations have been found. In several patients, it was shown that the mutations can lead to aberrant splice products and/or to quantitative changes of the naturally occurring splice variants lacking exon 8.Table 2. Selected VCAN Pathologic Allelic VariantsView in own windowDNA Nucleotide Change 1Protein Amino Acid ChangeReference SequencesNumber of Families with Mutation 2Referencec.9265+1G>A/T (IVS 8 splice donor)--NM_004385.4 NP_004376.22 Kloeckener-Gruissem et al [2006], Meredith et al [2007], Ronan et al [2009]c.9265+2T>A--2Kloeckener-Gruissem et al [2012]c.4004-1G>A (IVS 7 splice acceptor)--1 Mukhopadhyay et al [2006]c.4004-1G>C--1Kloeckener-Gruissem et al [2012]c.4004-2A>G/T (IVS 7 splice acceptor)--1 Miyamoto et al [2005], Brezin et al [2011]c.4004-5T>C (IVS 7 splice acceptor)--4 Mukhopadhyay et al [2006]c.4004-5T>A (IVS 7 splice acceptor)--2 Mukhopadhyay et al [2006]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. IVS: Intervening sequence; N>N refers to the respective nucleotide exchange. 2. VCAN mutations were identified in eight of ten families with vitreoretinopathy.Normal gene product. The extracellular matrix proteoglycan (chondroitin sulfate proteoglycan type 2), also named versican, is found in many different tissues in the human body, including the eye [White & Bruzzone 2000]. Four naturally occurring variants accumulate tissue-specifically. They are products of alternative splicing of exons 7 and 8 (see Figure 1). A central domain of the protein, encoded by both exons 7 and 8, carries glycosaminoglycan (GAG) residue modifications, which may be involved in preventing collagen fibrils from sticking together and thus ensuring gel-like properties of the vitreous content.FigureFigure 1. Vitreoretinopathy-associated mutations in VCAN and their effects on naturally occurring splice variants and protein isoforms. Under normal conditions, differential splicing leads to four transcript variants and protein isoforms V0, V1, V2, or (more...)Abnormal gene product. Mutations in splice recognition sequences result in skipping of exon 8 and in the production of aberrant splice products [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Mukhopadhyay et al 2006]. One consequence is increased accumulation of isoforms V2 (no exon 8) and V3 (no exon 7 and 8) [Mukhopadhyay et al 2006] and most likely also of the protein isoforms. This may result in severe reduction of GAG modification, which will render the physical properties of the vitreous, leading to a process of premature liquefaction.