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.
Psoriasis, a chronic inflammatory skin disease affecting 2%-3% of the general population, is thought to result from complex interactions between still poorly defined environmental factors and a genetically determined predisposition, resulting in immunological and epidermal defects. 1,2 Psoriasis is characterized by inflammation and epidermal hyperproliferation, a typical histopathological feature reflecting excessive proliferation and resistance to apoptosis of epidermal keratinocytes (KCs). [3][4][5][6][7] Therapeutic options for psoriasis include topical (eg corticosteroids, vitamin D analogues) and oral (eg systemic retinoids, methotrexate and cyclosporine) treatments, 8-11 phototherapy, 12 as well as biologic therapies. [13][14][15][16][17] Most of these modalities target
A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy. Clin Endocrinol (Oxf) 69:61-8 Bonne G, Di Barletta MR, Varnous S et al. (1999) Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 21:285-8 De Sandre-Giovannoli A, Bernard R, Cau P et al. (2003) Lamin a truncation in Hutchinson-Gilford progeria. Science 300:2055 Doubaj Y, De Sandre-Giovannoli A, Vera EV et al. (2012) An inherited LMNA gene mutation in atypical progeria syndrome. Am J Med Genet A 158A:2881s-7s Eriksson M, Brown WT, Gordon LB et al. (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.
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