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

Abstract

Aberrant sonic hedgehog signalling, 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 naevus 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 three BCCs 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.

A Recurrent Mosaic Mutation in SMO , Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome

“…46 The mutation is likely to be associated with a spectrum of negative and positive selective consequences during organismal growth and homeostasis, depending on cell type, which most likely explains the apparent evolution of skin lesions and low mutation levels in blood (negative selection) and the predisposition to tumorigenesis (positive selection). The association between segmental BCNS and SMO p.Leu412Phe in a recent report 45 is compatible with a later occurrence of the somatic mutation during development than in subjects with the classical CJS phenotype.…”

“…For example, vismodegib is a clinically approved SMO inhibitor that contacts the extracellular domain and ligand-binding pocket. Interestingly, in a recent report of a subject with segmental BCNS associated with the identical SMO p.Leu412Phe substitution, 45 treatment with vismodegib for 4 months led to cessation of the appearance of new lesions and shrinkage of some existing BCCs. However, other reports have suggested that the p.Leu412Phe substitution confers resistance to vismodegib, supporting a role for Leu412 in autoinhibition and/or structural stability.…”

Clinical genetics of craniosynostosis

“…CJS has unusual abdominal symptomatology associated with smooth muscle hamartomas on the mesentery and surface of the bowel; motility disorders and upper gastrointestinal bleeding are frequent [34]. The identical SMO mutation has also been identified in several tumors, particularly involving the skin or brain; these are potentially treatable using hedgehog pathway inhibitors [35]. CDC45 encodes a key component of the machinery of DNA replication, present in all eukaryotes, so the identification of mutations in craniosynostosis may appear surprising.…”

Happle-Tinschert syndrome can be caused by a mosaicSMOmutation and is suggested to be a variant of Curry-Jones syndrome: reply from the authors

“…We believe that our case belongs to the spectrum of Gorlin syndrome (MIM #109400) because most of the biopsies in our patient demonstrated classical nodular, pigmented, adenoid and superficial basal cell carcinomas (BCCs) (Fig. 2a–c in our article) . This is not congruent with the findings typical of Happle–Tinschert syndrome (HTS), in which the skin lesions are basaloid follicular hamartomas (BFHs) by definition.…”