Familial exudative vitreoretinopathy (FEVR) can be defined as a group of disorders characterized by failure of peripheral retinal vascularization, which leads to further retinal vascular complications. Expressivity within the same family may be highly variable. The disorder can rarely be asymmetric or even unilateral. Most patients are affected bilaterally and symmetrically. Individuals may be entirely asymptomatic or present with severe visual loss usually due to retinal detachment. The incidence of FEVR is unknown as so many individuals are asymptomatic. Retinal findings may be subtle and only detectable by intravenous fluorescein angiography showing peripheral nonperfusion. More obvious signs include peripheral nonperfusion with or without a demarcation zone characterized by exudate, hemorrhage or neovascularization, peripheral fibrovascular mass, traction with possible macular drag, vessel straightening, retinal detachment, posterior retinal exudates, and falciform folds (▶ Fig. 13.1).
Fig. 13.1 Familial exudative vitreoretinopathy. (a) Peripheral avascular retina with abnormal vessels and neovascularization. (b) Falciform retinal fold extending temporally through the macula.
Laser photocoagulation of the ischemic areas is useful to prevent and induce regression of new vessel formation and prevent retinal detachment. In case of significant retinal traction, vitreoretinal surgery may be needed. The role of intravitreal antivascular endothelial growth factor (anti-VEGF) drugs is not fully known for this condition.
13.2 Molecular Genetics
Mutations in one of five genes are known to be associated with this phenotype: FZD4 (11q14.2; encodes protein frizzled-4), LRP5 (11q13.2; encodes low-density lipoprotein receptor-related protein 5), TSPAN12 (7q31.31; encodes tetraspanin-12), NDP (Xp11.3; encodes norrin), and ZNF408 (11p11.2; encodes zinc finger protein 408). These genes are all involved in the Wnt pathway, which determines retinal vascular development. Mutations of these genes are responsible for FEVR in approximately 70% of cases. Reported mutations include missense, nonsense, small deletions, and small insertions. The mutation prevalence is 20 to 40% for FZD4, 10 to 25% for LRP5, and 3 to 10% for TSPAN12. FZD4 and TSPAN12 are associated with autosomal dominant (AD) FEVR. Mutations of LRP5 are usually associated with autosomal recessive (AR) FEVR but can also be seen with AD inheritance. The gene also has phenotypic heterogeneity as do NDP mutations which can cause osteoporosis-pseudoglioma syndrome (OPPG; OMIM 259770) and Norrie disease (OMIM 310600), respectively. Recently, KIF11 mutations have been identified as a common cause of AD FEVR (up to 8% in one cohort). Individuals with KIF11 mutations presented typical but variable signs of FEVR, with or without systemic findings, such as microcephaly, lymphedema, and mental retardation.
13.3 Differential Diagnosis
13.3.1 Retinopathy of Prematurity
Retinopathy of prematurity (ROP) is considered a sporadic condition, although there is some evidence that genetic changes in the Wnt receptor signaling pathway may be associated with the development of advanced ROP stages. ROP is also characterized by failure of development of the peripheral retinal vasculature. Two of the most important risk factors are premature birth and low weight at birth.
13.3.2 Coats’ Disease
Coats’ disease usually presents with severe retinal telangiectasia, typically in the periphery and often unilaterally in only one quadrant of retina. It may represent a sporadic intraretinal mutation of a Wnt pathway gene. It is usually sporadic with variable age of onset. These abnormal vessels can produce massive exudates that lead to retinal detachment. Male-to-female ratio is 10:1. Age of onset ranges from birth to milder presentations in adulthood.
13.3.3 Persistent Fetal Vasculature
Persistent fetal vasculature (formerly persistent hyperplastic primary vitreous) is associated with failure of regression of the hyaloid vasculature. It is usually (90%) unilateral and sporadic. Eyes are often microphthalmic with cataract. Persistent hyaloid artery has been described in AR FEVR. Although peripheral retinal vascular abnormalities may occur, nonperfusion is unusual.
13.3.4 Peripheral Granulomatous Toxocariasis
Peripheral granulomatous toxocariasis may resemble FEVR because of retinal traction and retinal folds. Nevertheless, uveitis associated with toxocariasis is not seen in FEVR. Toxocara is not present in infancy and is almost always unilateral.
13.3.5 Incontinentia Pigmenti
Incontinentia pigmenti is a rare X-linked dominant disease that affects multiple organs, including skin, hair, teeth, nails, and eyes. The eye findings resemble FEVR and are present in 30% of patients.
13.3.6 Morning Glory Disc
Morning glory disc is a rare congenital disc anomaly. The optic nerve is large with a posterior conical excavation. There is glial tissue over the disc and the vessels are splayed outward to the edges of the disc. These eyes may have peripheral nonperfusion of the retina.
13.3.7 Wyburn–Mason Syndrome
Wyburn–Mason syndrome is a rare disorder that presents with arteriovenous malformations of the midbrain and retina. Retinal peripheral nonperfusion has been reported.
13.3.8 Adams–Oliver Syndrome (OMIM 100300)
Adams–Oliver syndrome (OMIM 100300) is a rare condition defined by the combination of aplasia cutis congenita usually of the scalp vertex and terminal transverse limb defects. Patients may have vascular anomalies including pulmonary hypertension, portal hypertension, and retinal hypervascularization with peripheral nonperfusion.
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