Clinical characteristics.

VCAN-related vitreoretinopathy, which includes Wagner syndrome and erosive vitreoretinopathy (ERVR), 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 traction and retinal detachment in the advanced stages of disease, and reduced visual acuity. Optic nerve inversion as well as uveitis has also been described. Systemic abnormalities are not observed. The first signs usually become apparent during early adolescence, but onset can be as early as age two years.

Diagnosis/testing.

The diagnosis of VCAN-related vitreoretinopathy is established in a proband with characteristic ocular findings and a family history consistent with autosomal dominant inheritance. Identification of a heterozygous VCAN pathogenic variant establishes the diagnosis if clinical features are inconclusive.

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: For the purpose of early diagnosis and treatment of ophthalmologic complications in at-risk relatives: molecular genetic testing if the pathogenic variant has been identified in the family; otherwise, ophthalmologic evaluation.

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 affected individual has a 50% chance of inheriting the pathogenic variant. Prenatal testing is possible for families in which the pathogenic variant is known.

Suggestive Findings

VCAN-related vitreoretinopathy should be suspected in individuals with the following characteristic features:

• "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 traction and detachment at advanced stages of the disease
• Reduced visual acuity resulting from the above manifestations
• Uveitis
• Absence of systemic abnormalities

Establishing the Diagnosis

The diagnosis of VCAN-related vitreoretinopathy is established in a proband with the above 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. Establishing the diagnosis may be more difficult in a simplex case (i.e., a single occurrence in a family). Identification of a heterozygous pathogenic (or likely pathogenic) variant in VCAN by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

Note: (1) Per ACMG/AMP 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 testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. All VCAN pathogenic variants associated with Wagner syndrome and erosive vitreoretinopathy found to date have been in the splice acceptor or splice donor site of introns 7 and 8; sequence analysis of this DNA region is recommended as a first step. If targeted testing is not available, sequence analysis of VCAN should be done.
• A multigene panel that includes VCAN and other genes of interest (see Differential Diagnosis) may also be considered. Note (1): The genes included and sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) The presence of characteristic connective tissue abnormalities in the proband or relatives could prompt genetic testing for Stickler syndrome rather than or in addition to sequence analysis of VCAN.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

VCAN-related vitreoretinopathy comprises the phenotypic continuum of Wagner vitreoretinal degeneration (Wagner syndrome) and erosive vitreoretinopathy (ERVR).

Vitreoretinal degeneration. 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 sex-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].

Genotype-Phenotype Correlations

Because of the highly variable frequency of findings and the low number of pathogenic variants identified to date, no definite 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

Some authors have referred to Stickler syndrome associated with pathogenic variants in exon 2 of COL2A1 as Wagner syndrome type II. 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

Wagner syndrome 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. 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 northern European, Japanese, and Chinese.

Autosomal Dominant Vitreoretinopathies

Snowflake vitreoretinal degeneration (SVD) (OMIM 193230). SVD is caused by pathogenic variants in KCNJ13.

• 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.
• Stickler syndrome, or hereditary arthroophthalmopathy, is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Pierre Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity. Stickler syndrome caused by mutation of COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner.
• Retinal detachment is much more common in Stickler syndrome (50%) than in VCAN-related vitreoretinopathy (15%).
• Abnormal dark adaptation associated with alterations in the electroretinogram (ERG) that is common in VCAN-related vitreoretinopathy has not been described in Stickler syndrome.
• Type 1 Stickler syndrome (in which individuals have the membranous type of vitreous abnormality) is caused by pathogenic variants in COL2A1 encoding collagen alpha-1(II) chain. Certain pathogenic variants in COL2A1 cause a predominantly ocular or nonsyndromic phenotype which can be readily distinguished from Wagner syndrome by 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). Pathogenic variants in BEST1, the gene encoding bestrophin-1, are causative. Only a few families with vitreoretinochoroidopathy (VRCP) have been described. High myopia and retinal detachment do not appear to be part of VRCP [Oh & Vallar 2006]. 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 atrophy
• Breakdown of the blood retinal barrier (observed in one family)
• Normal full-field (Ganzfeld) ERG but altered multifocal ERG pattern
• Cataract

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) (OMIM 193235). Pathogenic variants in CAPN5 are causative [Mahajan et al 2012]. 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.

Autosomal Recessive Vitreoretinopathies

Goldmann-Favre syndrome (included in enhanced S-cone syndrome) (OMIM 268100). Pathogenic variants in NR2E3 (photoreceptor-specific nuclear receptor) have been identified in Goldmann-Favre syndrome, enhanced S-cone syndrome (ESCS), and clumped pigmentary retinal degeneration [Haider et al 2000]. 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 retinoschisis 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. Pathogenic variants in COL18A1 (encoding collagen, type XVIII, alpha 1) are causative [Menzel et al 2004, Keren et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
• Visual field examination
• Photographic fundus documentation
• Optical coherence tomography (OCT), if available. While not mandatory, OCT scan is useful to assess the vitreoretinal interface, quantify atrophic changes of the central retina, and evaluate for cystoid macular edema.
• Electroretinogram
• Orthoptic assessment
• Consultation with a clinical geneticist and/or genetic counselor

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 individuals 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 Risk

It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to reduce morbidity by early diagnosis and treatment of ophthalmologic complications. Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known.
• Ophthalmologic exam if the pathogenic variant in the family is not known

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 an affected parent.
• A proband with VCAN-related vitreoretinopathy may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is not known.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include ophthalmologic evaluation and/or molecular genetic testing of both parents.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (although no instances of germline mosaicism have been reported, it remains a possibility).
• The family history of some individuals diagnosed with VCAN-related vitreoretinopathy 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., ophthalmologic exam and/or molecular genetic testing) have been performed on the parents of the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant 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%.
• If the VCAN pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline 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 of a proband. 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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Since VCAN is expressed in many human tissues, pathogenic variants 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 pathogenic variants in nonocular tissues is that splicing of the VCAN transcripts may be tissue specific.

Gene structure. The genomic region (109,399 nucleotides) of VCAN includes 15 exons (NM_004385.4, splice variant V0). 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; see Figure 1) that exhibit a tissue-specific expression pattern. The respective exon-intron boundaries show the consensus sequences for splice acceptor and splice donor sites. For a detailed summary of gene, splice variants, and protein information, see Table A, Gene.

Figure 1.

Vitreoretinopathy-associated pathogenic variants 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...)

Pathogenic variants. Eleven different single nucleotide variants, all located in conserved splice consensus sites of introns 7 and 8, were identified in 17 families with vitreoretinopathy. In some cases, identical pathogenic variants have been found in different, unrelated families (Table 2). In several individuals, it was shown that the pathogenic variants can lead to aberrant splice products and/or to quantitative changes of the naturally occurring splice variants lacking exon 8. No pathogenic exon variants have been found.

Normal gene product. The extracellular matrix proteoglycan (chondroitin sulfate proteoglycan type 2), also named versican core protein, is found in many different tissues in the human body, including the eye [White & Bruzzone 2000]. Four naturally occurring protein isoforms 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 adhering, thus ensuring the gel-like properties of the vitreous content. Versican appears to have a central role in the outflow resistance through the trabecular meshwork, and splicing variant patterns in the trabecular meshwork extracellular matrix are altered in glaucoma [Keller et al 2007, Keller et al 2011].

Abnormal gene product. Pathogenic variants in splice consensus sites 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 splice variant V2 (no exon 8; NP_001157570.1) and V3 (no exon 7 and 8; NP_001119808.1) [Mukhopadhyay et al 2006] and most likely their respective 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.

Acknowledgments

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

Revision History

• 16 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
• 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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