Segmental Basal cell nevus syndrome caused by an activating mutation in Smoothened

Abstract

Aberrant sonic hedgehog signaling, mostly due to PTCH1 mutations, has been shown to play a central role in the pathogenesis of basal cell carcinoma (BCC), as well as in Basal Cell Nevus Syndrome (BCNS). Mutations in Smoothened (SMO) encoding a receptor for sonic hedgehog, have been reported in sporadic BCCs but not in BCNS.

We report a case with multiple BCCs, 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 3 BCCs but not in peripheral blood lymphocytes or the uninvolved skin. These were compatible with type 1 mosaic form of BCNS. The p.L412F mutation was found experimentally to result in an increased SMO transactivating activity, and the patient responded to vismodegib therapy.

Activating mutations in SMO may also 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 tumors, whether sporadic or inherited.

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