These conditions are characterized by several clinical findings, the hallmark being “optically empty vitreous” on slit-lamp examination with avascular vitreous strands and veils at the equatorial vitreoretinal interface. VCAN-related vitreoretinopathies include Wagner syndrome (WS) and erosive vitreoretinopathy (ERVR). They are autosomal dominant (AD) with full penetrance but variable expression. Myopia is a typical finding, ranging from mild to severe. Early cataract can also be found, with no particular type described. Approximately 50% of patients have cataract surgery before the fourth decade. Microphthalmia, ectopia lentis, and persistent fetal vasculature have rarely been associated with WS. One significant feature is the absence of systemic abnormalities. ERVR is characterized by pronounced vitreous abnormalities, complicated retinal detachments, and a progressive pigmentary retinopathy, in particular with thinning and progressive “erosion” in the equatorial periphery. The most distinctive feature is the progressive change in retinal pigment epithelium (RPE) associated with visual field constriction and rod and cone dysfunction.

In WS, progressive chorioretinal atrophy associated with night blindness and retinal detachment can occur. Night blindness and visual field constriction are not as severe as those seen in patients with retinitis pigmentosa. Retinal detachment can be caused by shrinkage of the preretinal membranes, vitreous strands, and veils, and therefore is either tractional or rhegmatogenous. Reported incidence varies from 15 to 50% of affected patients, especially in ERVR. It has been associated with increasing age, although it can occur at young ages. Other findings include outer retinal layer and choroidal thinning and abnormal dark adaptation.

15.2 Molecular Genetics

The VCAN gene (5q14.3; previously known as CSPG2) encodes a large proteoglycan called versican. Versican is found in the extracellular matrix, facilitating the assembly of the extracellular matrix and ensuring its stability. Within the eye, versican plays a role in maintaining the vitreous structure. Other additional functions include cell growth regulation and division, cell adhesion, and migration. Angiogenesis, scarring, and inflammation regulation have also been described. The VCAN gene produces four different isoforms of the versican protein: V0, V1, V2, and V3. VCAN is the only known gene in which mutations cause WS or ERVR. WS and ERVR are allelic disorders, which mean they are both caused by different mutations in the same gene.

15.3 Differential Diagnosis

15.3.1 Stickler Syndrome (OMIM 108300)

Stickler syndrome (OMIM 108300) is a systemic disorder associated with a skeletal dysplasia and craniofacial abnormalities, particularly cleft palate. Retinal detachment and myopia are frequent (up to 50%), but unlike VCAN-related vitreoretinopathies, abnormal dark adaptation has not been described in Stickler syndrome. For certain pathogenic variations in COL2A1, an ophthalmic nonsyndromic phenotype can be present. Some authors have described this form as WS type II.

15.3.2 Snowflake Vitreoretinal Degeneration (OMIM 193230)

Snowflake vitreoretinal degeneration (OMIM 193230) shows vitreous abnormalities, but avascular strands and veils are not observed. Retinal abnormalities affect the superficial retinal layers, whereas in VCAN-related vitreoretinopathy the outer retinal layers and choroid are more affected. Mutations in KCNJ13 are associated.

15.3.3 Autosomal Dominant Vitreoretinochoroidopathy (OMIM 193229)

AD vitreoretinochoroidopathy (OMIM 193229) is a rare disease due to VMD2 splicing defects, characterized by fibrillar condensation of the vitreous, but not optically empty vitreous. Patients have a characteristic well-demarcated peripheral band of chorioretinal hyperpigmentation and variable electroretinographic (ERG) findings.

15.3.4 Goldmann–Favre Syndrome

Goldmann–Favre syndrome is due to mutations in NR2E3. Patients experience night blindness and visual field constriction. Progressive vitreous changes and chorioretinal atrophy with pigmentary retinal degeneration occur in association with retinoschisis in the periphery and macula, which are not typically seen in VCAN vitreoretinopathies.

15.3.5 Knobloch Syndrome (OMIM 267750)

Knobloch syndrome (OMIM 267750) is characterized by high myopia, a typical fundus appearance with geographic macular atrophy occipital scalp/skull defects even ranging to encephalocele. Mutations in COL18A1 are causative.

15.3.6 Marshall Syndrome (OMIM 154780)

Marshall syndrome (OMIM 154780) overlaps with Stickler syndrome, but is distinguished by flat midface, thick calvaria, abnormal frontal sinuses, shallow orbits, and intracranial calcifications. It is also associated with hearing loss and joint alterations. It is caused by COL11A1 mutations.

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