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© 2012 The Authors. doi: 10.2340/00015555-1236 Journal Compilation © 2012 Acta Dermato-Venereologica. ISSN 0001-5555 Birt-Hogg-Dubé syndrome (BHD) (1) is currently defined as an autosomal dominant disorder predisposing for fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cancer, but clinical expression is highly variable. Further associations with other malignancies have been described, but it remains uncertain whether they are part of the syndrome or merely coincidental (2). BHD is caused by germline mutations in a novel gene, the FLCN gene, encoding for the protein folliculin (3), whose functions remain unclear. The mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of BHD, just as in several other hereditary hamartoma syndromes (4, 5). Yet, opposite and conflicting evidence of the role of FLCN in mTOR signalling/ phosphorylated ribosomal protein S6 (p-S6) activation has been reported (6, 7). FLCN has been shown to act as a general tumour suppressor in the kidney in a mouse model (7). One mechanism might be that, in the absence of FLCN, an increased hypoxia-inducible factor (HIF) transcriptional activity occurs (8). As HIF influences angiogenesis and cellular metabolism as well as cellular proliferation, it seems to play a central role in tumour growth in inherited diseases that give rise to renal cell carcinoma (8). The FLCN gene is composed of 14 exons. Germline insertion or deletion of a cytosine in the polycytosine (C8) tract in exon 11 of the BHD gene has been detected in 53% of BHD families and is considered as a mutation “hot spot” (9). More than 40 unique mutations in BHD have been reported, all affecting exons 4 to 14 and flanking intronic borders (10). The FLCN germline mutation c.779G>A that leads to a premature stop codon (p.W260X) had been found previously in a Swiss family reportedly presenting with lung cysts only (11). In all three members of the Swiss family carrying the p.W260X mutation, no skin changes or kidney manifestations were described. Isolated familial spontaneous pneumothorax has also been found in association with two other mutations of the FLCN gene, one nonsense mutation and one 4-bp deletion (12, 13). We describe here a patient and his family in which FLCN mutation p.W260X is associated with a wider range of BHD manifestations in different organs.

Late Onset of Skin Manifestations in Birt-Hogg-Dubé Syndrome with FLCN Mutation p.W260X