Clinical characteristics.

VCAN-related vitreoretinopathy, which includes Wagner syndrome and erosive vitreoretinopathy (ERVR), is characterized by progressive degenerative changes of the vitreous (syneresis) and the vitreoretinal interface. 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. Although the first ocular signs usually become apparent during early adolescence, they can be evident as early as age two years. The vitreous degeneration, which is assumed to be the primary pathology, leads to secondary changes including presenile cataract, degeneration and atrophy of the retina and the underlying retinal pigment epithelium and choroid, and retinal detachment. Systemic abnormalities are not observed.

Diagnosis/testing.

The diagnosis of VCAN-related vitreoretinopathy is established in a proband with suggestive ocular findings and a heterozygous VCAN pathogenic (or likely pathogenic) variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Refractive error is corrected by spectacles or contact lenses. Visually disabling cataract is treated by cataract surgery, preferably by an experienced surgeon. Posterior capsule opacification is treated with YAG laser capsulotomy. Retinal breaks without retinal detachment are treated with laser retinopexy or cryocoagulation. 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.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to reduce morbidity by early diagnosis and treatment of ophthalmologic complications.

Genetic counseling.

VCAN-related vitreoretinopathy is inherited in an autosomal dominant manner. Most individuals diagnosed with VCAN-related vitreoretinopathy have an affected parent. Each child of an individual with VCAN-related vitreoretinopathy has a 50% chance of inheriting the pathogenic variant. Once the VCAN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for VCAN-related vitreoretinopathy are possible.

Suggestive Findings

VCAN-related vitreoretinopathy should be suspected in probands with the following clinical and imaging findings and family history.

Clinical findings

• "Optically empty vitreous" on slit lamp examination and avascular vitreous strands and veils
• Circumferential equatorial vitreous veil
• Mild or occasionally moderate-to-severe myopia
• Presenile cataract
• Night blindness of variable degree associated with progressive chorioretinal atrophy, the so-called aspect of erosive vitreoretinopathy (ERVR)
• Retinal traction and detachment at any stage of the disease
  Note: Presence of large retinal tears in young persons should raise the suspicion of a genetic disorder (see Differential Diagnosis).
• Reduced visual acuity resulting from the above manifestations
• Uveitis
• Absence of systemic abnormalities

Imaging findings

• Optical coherence tomography
  • Foveal hypoplasia
  • Atypical (double-layered) preretinal membrane
  • Equatorial retinal traction and schisis secondary to vitreous traction
• Autofluorescence. Diffuse hypofluorescence secondary to retinal pigment epithelial loss

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of VCAN-related vitreoretinopathy is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in VCAN identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous VCAN variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

VCAN-related vitreoretinopathy, which includes Wagner syndrome and erosive vitreoretinopathy (ERVR), is characterized by progressive degenerative changes of the vitreous (syneresis) and the vitreoretinal interface. 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. Although the first ocular signs usually become apparent during early adolescence, they can be evident as early as age two years [Miyamoto et al 2005].

The vitreous degeneration, which is assumed to be the primary pathology, leads to 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].

Ocular changes show considerable interfamilial and intrafamilial variability.

Commonly observed other ocular findings include the following.

• 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). Although axial myopia is common, the severity varies. In the family reported by Wagner [Graemiger et al 1995], most affected individuals 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 cataracts 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]. 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 RPE 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 nonsyndromic retinitis pigmentosa. Nyctalopia may or may not progress. In some individuals 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 (ffERG) 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 [Graemiger et al 1995], the Japanese family [Miyamoto et al 2005], and the British family [Meredith et al 2007].
• 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].
• Retinal detachment was initially found to be associated with increasing age; however, a later report indicated that retinal detachments occurred earlier (average age 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 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. Note: In a considerable number of young individuals, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration presents with only minor changes of the vitreous.
  • Exudative retinal detachment has been described, masquerading as familial exudative vitreoretinopathy (FEVR) [Brézin et al 2011].
  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. (Note: Follow-up publications of the original family published by Wagner reported an incidence of retinal detachment of greater than one in two.) Of the few retinal detachments described in the Swiss family reported originally by Wagner and in 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]. Affected individuals have been 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 reported rarely include the following. (Note: 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 pathologic vitreoretinal interface. In contrast to the usual age-related PVD, the PVD in VCAN-related vitreoretinopathy initially affects the peripheral vitreous 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]. Temporally dragged retinal vessels can mimic familial exudative vitreoretinopathy (FEVR).
• Phthisis bulbi (painful shrinking of the ocular globe due to 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 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 who had advanced chorioretinal atrophy, suggesting that optic atrophy is secondary to the massive loss in retinal ganglion cells [Graemiger et al 1995].
• Glaucoma may be an occasional feature of Wagner syndrome, or a sequela such as aphakia glaucoma or rubeotic glaucoma. In the original family, ten of 60 family members exhibited a dysgenetic chamber angle [Graemiger et al 1995]; one individual had congenital glaucoma. Three individuals with congenital glaucoma were reported by Jewsbury et al [2014].
• Exudative vitreoretinopathy with vascular abnormalities was reported in one French family [Brézin et al 2011]; in fact, familial exudative vitreoretinopathy (FEVR) was the initial diagnosis suspected in this family.
• Uveitis was reported in a French family [Brézin et al 2011] and a British family [Meredith et al 2007] as spontaneous anterior uveitis and otherwise unexplained severe and prolonged intraocular inflammation after uneventful cataract surgery, respectively [Rothschild et al 2011, Rothschild et al 2013b]. Given the role of versican core protein (encoded by VCAN) in inflammation and cancer that has been increasingly elucidated during recent decades, the occurrence of uveitis in individuals with VCAN-related vitreoretinopathy is likely related to the causative genetic defect [Du et al 2013, Wight et al 2014].

No systemic abnormalities associated with VCAN-related vitreoretinopathy have been reported to date; consequently, it is considered an isolated vitreoretinal degeneration.

Genotype-Phenotype Correlations

Because of the highly variable frequency of findings and the low number of VCAN pathogenic variants identified to date, no clinically relevant genotype-phenotype correlations have been established.

Penetrance

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

Nomenclature

Stickler syndrome associated with pathogenic variants in exon 2 of COL2A1 has been referred to as Wagner syndrome type II [Gupta et al 2002].

The VCAN-related phenotype has been referred to as vitreoretinochoroidopathy (VRCP) Wagner syndrome type I [Gupta et al 2002] or hyaloideoretinal degeneration of Wagner.

Prevalence

VCAN-related vitreoretinopathy is a very rare disorder. After the first Swiss pedigree reported by Wagner [1938], several additional families (some of them very large) have been reported. Fewer than 50 families or simplex cases of VCAN-related vitreoretinopathy have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VCAN-related vitreoretinopathy, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Care to improve quality of life, maximize function, and reduce complications is recommended (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, an annual ophthalmologic examination by a vitreoretinal specialist is indicated.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual to reduce morbidity by early diagnosis and 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 in the US and EU Clinical Trials Register in Europe 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.

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 the disorder as the result of a pathogenic variant inherited from an affected parent. Note: A parent with somatic mosaicism for a VCAN pathogenic variant may be mildly affected [Burin-des-Roziers et al 2017].
• Some individuals diagnosed with VCAN-related vitreoretinopathy have the disorder as the result of a de novo pathogenic variant [Rothschild et al 2013a]. The proportion of probands who have a de novo pathogenic variant is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case), ophthalmologic evaluation and/or molecular genetic testing is recommended for the parents of the proband to evaluate their status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in mildly/minimally affected family members. Therefore, de novo occurrence of a VCAN pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the VCAN pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a VCAN pathogenic variant may be mildly/minimally affected [Burin-des-Roziers et al 2017].

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the VCAN pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the VCAN pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the VCAN pathogenic variant but are clinically unaffected on ophthalmologic evaluation, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for VCAN-related vitreoretinopathy because of the possibility of parental gonadal mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the VCAN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for VCAN-related vitreoretinopathy are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Versican core protein, encoded by VCAN, is an essential molecule of the extracellular matrix that is also involved in several molecular pathways. Some clinical features are congenital, like the optically empty vitreous, the ectopic fovea, and dragged retinal vessels, whereas others are acquired and progressive, like the pigment clumping and the chorioretinal atrophy as well as cataracts, glaucoma, or uveitis.

Mechanism of disease causation. Haploinsufficiency or imbalanced quantitative ratios of specific VCAN isoforms

VCAN-specific laboratory technical considerations

• VCAN splice site variants. To date, most pathogenic variants reported in individuals with VCAN-related vitreoretinopathy involve splice acceptor or donor sites of exons 7 and 8. Reported variants include both single-nucleotide variants (SNVs) and copy number variants (CNVs) that may include large deletions ranging in size from 3 to 12 kb. Therefore, molecular methods optimized for the detection of these variants are recommended. While many of these variants can be detected using standard methods such as Sanger sequencing or exome sequencing, some pathogenic variants (including large deletions) may require other methods such as quantitative real-time PCR, long-range PCR, and/or long-read sequencing [Burin-des-Roziers et al 2017].
• Targeted testing for mosaicism. A postzygotic or mosaic deletion involving VCAN has been reported in a parent with a mild phenotype. Therefore, testing methods optimized for the detection of mosaicism should be considered, such as deep coverage next-generation sequencing methods, especially in individuals who test negative using standard methods [Burin-des-Roziers et al 2017].

Author History

Christoph Amstutz, MD, PhD; Luzerner Kantonsspital (2009-2026)
Barbara Kloeckener-Gruissem, PhD; University of Zurich (2009-2026)
Pierre-Raphael Rothschild, MD, PhD (2026-present)

Revision History

• 19 May 2026 (bp) Comprehensive update posted live
• 7 January 2016 (me) Comprehensive update posted live
• 16 August 2012 (me) Comprehensive update posted live
• 3 February 2009 (me) Review posted live
• 18 April 2008 (bkg) Original submission

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