Vcan-Related Vitreoretinopathy

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Retrieved

2021-01-18

Source

Gene_reviews

Trials

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Genes

VCAN, COL2A1, PAX6, WT1, VCAN-AS1, COL11A1, HAPLN1

Drugs

Methotrexate ( LEDERTREXATE, NORDIMET, METHOTREXATE WYETH LEDERLE )

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Summary

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.

Diagnosis

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 variant in VCAN by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

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.

Table 1.

Molecular Genetic Testing Used in VCAN-Related Vitreoretinopathy

Gene ¹	Method	Proportion of Probands with a Pathogenic Variant ² Detectable by Method
VCAN	Sequence analysis ³	18/20 families with VCAN-related vitreoretinopathy ⁴
VCAN	Gene-targeted deletion/duplication analysis ⁵	Unknown ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: In 18 of 20 families with VCAN-related vitreoretinopathy, sequence analysis of the entire VCAN coding region and flanking introns identified pathogenic variants; in two families no pathogenic variant was found (see references in Table 2).
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

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 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 individuals 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].

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 detachments can occur 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 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, in a considerable number of young individuals rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration 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 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]. 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 pathologic 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 be an occasional feature of Wagner syndrome, or a sequela of the disease such as aphakia glaucoma or rubeotic glaucoma. In the original pedigree, ten individuals out of the sixty 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 has been reported in one French family [Brézin et al 2011]; in fact, familial exudative vitreoretinopathy (FEVR) was the initial diagnosis suspected in this family.

Uveitis is a rare clinical feature of VCAN-related vitreoretinopathy that has come to attention only recently. Uveitis was reported in a French [Brézin et al 2011] and a British [Meredith et al 2007] family 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 versican's role in inflammation and cancer that was increasingly elucidated during the last decade, 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].

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

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.

Differential Diagnosis

Syndromes with overlapping features. A review by Edwards [2008] summarizes the clinical features of inherited vitreoretinopathies and points out the importance of consulting an expert ophthalmologist in diagnostic assessment of the disease.

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 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].

Management

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.