Familial exudative vitreoretinopathy and related retinopathies

Abstract

Familial exudative vitreoretinopathy (FEVR) is a rare inherited disorder of retinal angiogenesis. Cases can be autosomal dominant, autosomal recessive, or X-linked. FEVR patients have an avascular peripheral retina which, depending on the degree of ischaemia, causes the secondary complications of the disease. Expressivity may be asymmetric and is highly variable. Five genes have been identified that when mutated, cause FEVR; NDP (X-linked), FZD4 (autosomal dominant and recessive), LRP5 (autosomal dominant and recessive), TSPAN12 (autosomal dominant and recessive), and ZNF408 (autosomal dominant). Four of these genes have been shown to have a central role in Norrin/Frizzled4 signalling, suggesting a critical role for this pathway in retinal angiogenesis. In addition to the ocular features, LRP5 mutations can cause osteopenia and osteoporosis. All FEVR patients in whom molecular testing is not easily accessible should have dual energy X-ray absorptiometry (DEXA) scans to assess bone mineral density, as treatment can be initiated to reduce the risk of bone fractures.

Figure 1

Vascular layers in the adult human retina with respect to (a) retinal depth and (b) retinal location. These figures were based on histopathology studies by Michealson and Campbell, Wise et al, and Bek and Jensen.^{, ,} IPL, inner plexiform layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PRL, photoreceptor layer; RPE, retinal pigment epithelium.

Figure 2

Absence of the deeper retinal plexuses in animal models of FEVR. Schematic representation of the retinal vascular phenotype seen in mouse models of FEVR.^{, , ,} IPL, inner plexiform layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PRL, photoreceptor layer; RPE, retinal pigment epithelium.

Figure 3

Retinal traction in FEVR. Fundus images of a 13-year-old female with mild FEVR and no family history. (a) The right eye has moderate dragging of the optic disc along with the macula and temporal vessels. Some retained hyaloid vascular remnants are present inferiorly. Snellen visual acuity is 6/12 in this eye. (b) The left eye has normal vision and has only mild straightening of the retinal vessels. A peripheral area of temporal retinal avascularity was seen in this eye (not imaged).

Figure 4

Radial retinal folds in FEVR. (a) Fundus image of the left eye of 1-year-old baby girl with FEVR showing a radial retinal fold towards an area of fibrosis and temporal avascularity. (b) Fundus image of the right eye of a neonate with recessive FEVR showing a severe retinal fold. This appearance is clinically identical to the ocular features seen in Norrie disease, and has previously been termed pseudoglioma.

Figure 5

Epiretinal membrane formation in FEVR. (a) Fundus image and (b) optical coherence tomography image of a patient with FEVR who had peripheral retinal exudation and avascularity resulting in secondary epiretinal membrane formation.