A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation.

PURPOSE To describe the clinical and genetic characteristics of a new ophthalmic syndrome, which consists of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen, that segregates as an autosomal recessive trait in a family with four affected siblings. The membrane-type frizzled-related protein (MFRP) and CEH10 homeodomain-containing homolog (CHX10) genes, previously implicated in autosomal recessive forms of nanophthalmos/microphthalmos, were analyzed as candidate genes for this novel disease. METHODS Complete ophthalmologic examinations were performed in four affected siblings and their parents. Ophthalmologic manifestations, fundus photographs, ultrasonographic (US) assessment, electroretinography (ERG), fluorescein retinal angiography (FA), Goldmann kinetic perimetry (GKP), and optical coherence tomography (OCT), as well as mutational status of MFRP and CHX10 genes in genomic DNA. RESULTS In all affected siblings, ophthalmologic examination demonstrated normal horizontal corneal diameters and high hyperopia; funduscopy, ERG, and FA evidenced a progressive retinal dystrophy compatible with retinitis pigmentosa; A- and B-mode ultrasonography revealed decreased axial eye length and optic disc drusen; OCT showed localized macular retinoschisis. MFRP molecular analysis disclosed a one base pair insertion in exon 5 (c.498_499insC) in all affected individuals, a mutation that predicts a truncated protein (P165fsX198). Both parents were heterozygous for this mutation. CONCLUSIONS A distinct autosomal recessive ophthalmic syndrome characterized by microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is described. We demonstrated that this clinical association is caused by a mutation in MFRP, a gene previously implicated in isolated nanophthalmos. Our data indicate that defects in MFRP could be responsible for syndromic forms of microphthalmos/retinal degeneration and that this gene is necessary for photoreceptor maintenance.