title: 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.
authors.affiliation: Department of Dermatology, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion, POX 9602, Haifa, 31096, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Khamaysi
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Bochner
authors.affiliation: Department of Dermatology, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion, POX 9602, Haifa, 31096, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Indelman
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Magal
authors.affiliation: Department of Dermatology, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion, POX 9602, Haifa, 31096, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Avitan-Hersh
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Sarig
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Sprecher
authors.affiliation: Department of Dermatology, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion, POX 9602, Haifa, 31096, Israel.|Department of Pathology, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion, POX 9602, Haifa, 31096, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Bergman
mesh_terms: D001478:Basal Cell Nevus Syndrome / Q000235:genetics*; D001483:Base Sequence / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics*; D000072086:Smoothened Receptor / Q000235:genetics*
chemical_list: C491023:SMO protein, human; D000072086:Smoothened Receptor