Segmental basal cell naevus syndrome caused by an activating mutation in smoothened

Summary Aberrant sonic hedgehog signalling, mostly due to PTCH 1 mutations, has been shown to play a central role in the pathogenesis of basal cell carcinoma ( BCC ), as well as in basal cell naevus syndrome ( BCNS ). Mutations in smoothened ( SMO ) encoding a receptor for sonic hedgehog have been reported in sporadic BCC s but not in BCNS . We report a case with multiple BCC s, pits and comedones in a segmental distribution over the upper part of the body, along with other findings compatible with BCNS . Histopathologically, there were different types of BCC . A heterozygous mutation (c.1234C>T, p.L412F) in SMO was detected in three BCC s but not in peripheral blood lymphocytes or the uninvolved skin. These were compatible with the type 1 mosaic form of BCNS . The p.L412F mutation was found experimentally to result in increased SMO transactivating activity, and the patient responded to vismodegib therapy. Activating mutations in SMO may cause BCNS . The identification of a gain‐of‐function mutation in SMO causing a type 1 mosaic form of BCNS further expands our understanding of the pathogenesis of BCC , with implications for the treatment of these tumours, whether sporadic or inherited.