Clinical Diagnosis

VCAN-related vitreoretinopathy is characterized by:

• “Optically empty vitreous” on slit-lamp examination and avascular vitreous strands and veils

• Mild or occasionally moderate to severe myopia

• Presenile cataract

• Night blindness of variable degree associated with progressive chorioretinal atrophy

• Retinal detachment at advanced stages of the disease

• Reduced visual acuity resulting from the above manifestations

• Absence 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. 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 Testing

Gene. VCAN (previously CSPG2), encoding the large extracellular matrix proteoglycan versican, is the only gene currently known to be associated with Wagner syndrome and erosive vitreoretinopathy (ERVR) [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Meredith et al 2006, Mukhopadhyay et al 2006].

Clinical testing

• Sequence analysis. Sequence analysis of the entire VCAN coding region and flanking introns performed in ten families with either Wagner syndrome or ERVR identified mutations in eight; in the two remaining families no presumably disease-related mutations were found [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Meredith et al 2006, Mukhopadhyay et al 2006].

Table1 summarizes molecular genetic testing for this disorder.

Table 1. Summary of Molecular Genetic Testing Used in VCAN-Related Vitreoretinopathy

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
VCAN	Sequence analysis	Sequence variants	8/10 families with VCAN-related vitreoretinopathy 1	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. In eight of ten 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, Meredith et al 2006, Mukhopadhyay et al 2006].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing the diagnosis in a proband

• 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.

• 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) Disorders

No phenotypes other than VCAN-related vitreoretinopathy have been reported to be associated with mutations in VCAN.

Natural History

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].

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, Meredith et al 2006, Mukhopadhyay et al 2006].

Common ocular features (occurring in ≤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 2006].

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.

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 2006]. 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 2006].

Retinal detachment is a finding that increases with age. 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]. In contrast, 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 2006].

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 2006].

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).

Systemic findings

To 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.

Genotype-Phenotype Correlations

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.

Penetrance

Penetrance appears to be complete. Within families reported to date, no unaffected individuals had a VCAN mutation.

Anticipation

Anticipation is not observed.

Nomenclature

Once the molecular basis of Wagner syndrome, originally described by Wagner in 1938, and ERVR, originally described by Brown and colleagues in 1994, was identified, the high similarity of the clinical phenotypes and the fact that both were caused by mutations in the same gene led to the conclusion that both were descriptions of the same disorder, which has been called VCAN-related vitreoretinopathy in this GeneReview [Brown et al 1994, Brown et al 1995, Mukhopadhyay et al 2006].

The predominantly ocular, or nonsyndromic, phenotype of Stickler syndrome, associated with specific mutations in exon 2 of COL2A1, encoding the alpha 1 chain of collagen type II [Richards et al 2000], can readily be distinguished from Wagner syndrome because of its distinctive vitreous phenotype [Snead & Yates 1999]. However, some authors have referred to this form of Stickler syndrome as Wagner syndrome type II and have designated the VCAN-related phenotype as vitreoretinochoroidopathy (VRCP) Wagner syndrome type I [Gupta et al 2002].

Syndrome alias: hyaloideoretinal degeneration of Wagner

Prevalence

Wagner syndrome is a very rare disorder. After the first Swiss pedigree reported by Wagner in 1938, several additional families, some of them very large, have been reported. Including families with ERVR, not more than 50 families or simplex cases of VCAN-related vitreoretinopathy have been reported.

Wagner syndrome has been reported in families of various ethnic backgrounds including Caucasian, Japanese, and Chinese.

Evaluations Following Initial Diagnosis

To 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 segment

• Family history

• Visual field examination

• Photographic fundus documentation

• Optical 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 assessment

Treatment of Manifestations

Refractive 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.

Testing of Relatives at Risk

Family 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 Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

VCAN-related vitreoretinopathy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with VCAN-related vitreoretinopathy have an affected parent.

• A proband with VCAN-related vitreoretinopathy may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is not known.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include ophthalmologic evaluation of both parents. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with VCAN-related vitreoretinopathy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband has VCAN-related vitreoretinopathy, the risk to the sibs is 50%.

• When the parents are clinically unaffected and/or the disease-causing mutation found in the proband has not been found in the parents, the risk to the sibs of a proband appears to be low.

• If the disease-causing mutation cannot be found in the proband’s parents, the occurrence of a de novo mutation in the proband is presumed. Germline mosaicism has not been described but remains a possibility.

Offspring of a proband. Each child of an individual with VCAN-related vitreoretinopathy has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is found to be affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the mutation found in the proband cannot be found in the DNA of one of the parents, it is likely that the proband has a de novo mutation.

Family planning

• The optimal time for determination of genetic risk is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories listed in the GeneTests Laboratory Directory offer molecular genetic testing for prenatal diagnosis of VCAN-related vitreoretinopathy. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Requests for prenatal testing for conditions such as VCAN-related vitreoretinopathy are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Since 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 nt) of VCAN includes 15 exons (NCBI Genbank accession number NM_004385.3). The two largest exons, 7 (2961 nt) and 8 (5262 nt), 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, Meredith et al 2006, Mukhopadhyay et al 2006]. 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.

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.

Figure

Figure 1. Vitreoretinopathy-associated mutations in VCAN and their effects on splice variants and protein isoforms. Under normal conditions, differential splicing leads to four transcript variants and protein isoforms V0, V1, V2, or V3, depending on the (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.

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Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Acknowledgments

The authors would like to thank Drs. Wolfgang Berger and John Neidhardt for critical reading of the manuscript.

Revision History

• 3 February 2009 (me) Review posted live

• 18 April 2008 (bkg) Original submission