Exudative Vitreoretinopathy 2, X-Linked

A number sign (#) is used with this entry because of evidence that exudative vitreoretinopathy-2 (EVR2) is caused by mutation in the NDP gene (300658), which is also mutant in Norrie disease (310600), on Xp11.

Description

Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by the incomplete development of the retinal vasculature. Its clinical appearance varies considerably, even within families, with severely affected patients often registered as blind during infancy, whereas mildly affected patients with few or no visual problems may have such a small area of avascularity in their peripheral retina that it is visible only by fluorescein angiography. It is believed that this peripheral avascularity is the primary anomaly in FEVR and results from defective retinal angiogenesis. The sight-threatening features of the FEVR phenotype are considered secondary to retinal avascularity and develop because of the resulting retinal ischemia; they include the development of hyperpermeable blood vessels, neovascularization, vitreoretinal traction, retinal folds, and retinal detachments (summary by Poulter et al., 2010).

For a discussion of genetic heterogeneity of FEVR, see EVR1 (133780).

Clinical Features

Familial exudative vitreoretinopathy is an inherited disorder characterized by retinal traction, peripheral vitreous opacities, and subretinal and intraretinal exudates (Plager et al., 1992).

Plager et al. (1992) observed a family in which 4 boys, the children of 3 sisters, had FEVR. They pointed to the family reported by Dudgeon (1979) in which 2 brothers and 2 of their male second cousins related through female relatives had this disorder. The 2 brothers, aged 18 and 14 years, had the features of FEVR, whereas the 2 cousins, aged 9 and 7.5 years, showed congenital retinal folds. A link between the 2 conditions has been postulated in the case of the autosomal dominant form as well. Plager et al. (1992) also commented on the fact that sporadic cases seemed most often to be male.

Fullwood et al. (1993) restudied the kindred originally reported by Dudgeon (1979) in which 7 affected males in 4 sibships were connected through carrier females. They commented that the findings at birth were those of a retinopathy superficially resembling retinopathy of prematurity (ROP), retinal folds, or, in advanced cases, enophthalmos or even phthisis.

Fulton et al. (2001) studied the electroretinographic (ERG) responses in 25 children characterized by maximum, acute phase ROP (none, mild, moderate, severe, and very severe). In the none to severe categories, the ERG responses varied significantly with the severity of acute phase ROP. In the very severe category, the ERG responses were too attenuated to calculate the responses. The authors concluded that rod photoreceptors must be involved in ROP. They found that the more severe the acute phase ROP, the more severe the compromise of the processes involved in the activation of phototransduction in the rods.

Inheritance

FEVR is usually inherited as an autosomal dominant (see 133780), but there is also an X-linked form (Plager et al., 1992; Chen et al., 1993).

Mapping

Fullwood et al. (1991) reported the findings of a linkage analysis which gave a peak lod score of 2.10 at zero recombination with DXYS1 (Xq21.31). Multipoint analysis with the loci DXS255, DXS1, and DXYS1 supported this localization. Fullwood et al. (1993) reviewed the suggestion of linkage to DXYS1 (Fullwood et al., 1991) and stated further that DXS228 gave a maximum lod score of 1.81 at zero recombination. Since the latter marker is located at Xp11, the finding raised the possibility that Norrie disease and X-linked exudative vitreoretinopathy are allelic since Norrie disease is located in the Xp11 region. They pointed out that one of the pedigrees reported by Criswick and Schepens (1969) was compatible with X linkage.

Molecular Genetics

That the phenotypes of both X-linked exudative vitreoretinopathy and Norrie disease can result from different mutations in the same gene was supported strongly by the demonstration by Chen et al. (1993) of a leu124-to-phe mutation in the NDP gene in the same family as that reported by Dudgeon (1979) and Fullwood et al. (1993); see 300658.0006.

Kondo et al. (2007) screened 62 FEVR and 3 ND Japanese probands and family members for mutations in the NDP gene and identified 5 different mutations (1 splicing and 4 missense) in 4 FEVR patients and 2 ND patients. One proband with a missense mutation in the signal sequence of NDP had significant phenotypic heterogeneity between the affected eyes, indicating a diagnosis of FEVR or ND. The proband with a splicing mutation had typical features of ND, whereas a maternal nephew had a diagnosis of FEVR. X-inactivation profiles indicated that skewing was not significantly different between FEVR affected and unaffected women.

In studies of 2 previously unreported X-linked families in which FEVR segregated as an X-linked recessive trait, Shastry et al. (1997) could find no mutation in the NDP gene.