Phenotypic Spectrum of FZD4 Mutations

Johane M. Robitaille MD, Binyou Zheng MD, Karen Wallace, Mark Samuels PhD, Jill Beis, Duane Guernsey PhD; Dalhousie University, Halifax, Nova Scotia, Canada Introduction: The Wnt pathway was recently implicated in cases of familial exudative vitreoretinopathy (FEVR). In 2002, we identified the first mutated gene in this pathway, FZD4, causing a human disease in a large family with the autosomal-dominant form of FEVR. Since this discovery, we have been interested in describing the full range of the phenotype caused by FZD4 mutations, including testing for genotype–phenotype associations. Methods: Patients with clinical features within the phenotypic spectrum of FEVR were invited to participate. DNA was used for direct sequencing of the coding regions of the two FZD4 exons. Phenotypic information was acquired from eye examination or chart review. Results: Two separate pedigrees were identified with distinct causal mutations: one with a M493_W494del, and the other with a I114T missense mutation. The proband in each pedigree had severe bilateral fundus anomalies consisting of an optic nerve fibrovascular stalk with attachments to the inferotemporal lens and retinal dysplasia. Other family members carrying the same mutation within each of these pedigrees were asymptomatic with minimal fundus anomalies. Discussion: FZD4 mutations can be associated with retinal dysplasia and features that overlap with posterior persistent hyperplastic primary vitreous (PHPV). This severe phenotype is not mutation specific, as other family members with the same mutation can manifest the mildest form of FEVR. Conclusions: Bilateral posterior PHPVlike features are part of the FEVR spectrum and, in the absence of a family history, this phenotype should prompt screening of the parents and siblings for clinical and molecular identifiers of FEVR.