Mosaicism for ATP2A2 mutations causes segmental Darier's disease

Epidermal naevi are localized malformations of the epidermis consisting of verrucoid scaly papules and plaques following Blaschko's Lines. Genetic mos aicism has been proposed to underlie the development of linear epidermal na evi, Rarely, epidermal naevi show acantholytic histology similar to Darier' s disease, a dominantly inherited skin condition characterized by widesprea d warty papules. As patients with acantholytic dyskeratotic naevi often giv e a history of worsening after sun exposure and the lesions are typical of Darier's disease, numerous authors have proposed that these patients have s egmental Darier's disease. The postulated relationship has not been proven, however. Recently, we identified ATP2A2, which encodes the sarco/endoplasm ic reticulum Ca2+ ATPase isoform 2 as the defective gene in Darier's diseas e. In this report, we investigated the involvement of ATP2A2 in acantholyti c dyskeratotic naevi following Blaschko's lines in two patients. We identif ied a nonsense mutation (Y894X) in the first patient and a nonconservative glycine to arginine mutation at codon 769 (G769R) in the other patient. The se mutations were present in affected skin, and were not detected in unaffe cted skin or in leukocytes. We conclude that acantholytic dyskeratotic naev i can arise from a somatic mutation in ATP2A2. These individuals are mosaic s for the mutation, but the risk of transmission of generalized Darier's di sease will depend on whether the germline is affected. Our findings provide further evidence that Blaschko's lines do reflect genetic mosaicism and th at the term acantholytic dyskeratotic naevus might be replaced in the futur e by segmental Darier's disease induced by postzygotic mosaicism.