Phenotypic overlap of familial exudative vitreoretinopathy (FEVR) with persistent fetal vasculature (PFV) caused by FZD4 mutations in two distinct pedigrees

Purpose: To describe a severe familial exudative vitreoretinopathy (FEVR) phenotype seen in infancy that resembles persistent fetal vasculature (PFV) caused by mutations in the FZD4 gene in two pedigrees with high intrafamilial variability. Methods: Three infants presented with features compatible with bilateral PFV. Eye examinations from the affected children and their relatives were reviewed retrospectively (follow-up:18 months-9 years). Mutation screening was performed using direct sequencing of the FZD4, LRP5 and NDP genes. Results: Bilateral retinal folds extending from the optic nerve to the inferotemporal aspect of the lens mimicing PFV were observed in two of the three affected children before the age of two months. The third child was examined at birth, and the avascular peripheral retina treated with diode laser within one week of age, with subsequent arrest of the disease process. A FZD4 mutation, M493-W494del, was identified in one affected child in pedigree 1, and a novel missense mutation, I114T, was detected in 2 affected children in pedigree 2; while no mutations were found in NDP or LRP5 genes in the 3 affected children. In both pedigrees, at least one affected relative was asymptomatic and failed to show the characteristic avascular changes of FEVR. Conclusions: The clinical features in the three children and their relatives with a documented FZD4 mutation support the previous reports of a high degree of intrafamilial and interfamilial variability in FEVR. In extreme cases with very early onset, the development of a retinal fold can mimic PFV, a non-hereditary condition with rare exception.