Darier disease, multiple bone cysts, and aniridia due to double de novo heterozygous mutations in ATP2A2 and PAX6

Abstract

Darier disease (DD) is an autosomal dominant genodermatosis caused by mutations in ATP2A2 and characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Rare patients are described with variable bone involvement, but this association has never been sufficiently emphasized. Aniridia is a developmental disorder of the eye due to heterozygous mutations in PAX6. DD and aniridia are Mendelian traits mapping on independent loci and have never been reported in association. Here, we describe a 14-year-old girl showing the unique combination of DD, multiple bone cysts, and bilateral aniridia. Molecular investigations demonstrated that such a complex phenotype is due to double de novo heterozygous mutations in ATP2A2 and PAX6. Review of the literature indicates that, in DD, bone cysts are true developmental abnormalities of the skeleton. This finding suggests a role for ATP2A2 in bone biology. More systematic studies are expected in order to estimate the true prevalence of bone cysts in DD and the relationship between skeletal changes and ATP2A2 perturbation.