Birt-Hogg-Dubé syndrome: clinical and genetic studies of 20 families

Birt-Hogg-Dubé syndrome (BHD) is an autosomal-dominant genodermatosis characterized by skin fibrofolliculomas and an increased risk of spontaneous pneumothorax, renal and possibly other tumors. A causative gene (FLCN) on chromosome 17p has recently been identified. We here report clinical and genetic studies of 20 BHD families ascertained by the presence of multiple fibrofolliculomas or trichodiscomas in the proband. Pathogenic FLCN germline mutations were found in 11 (69%) of 16 probands tested and in 14 family members. Six different FLCN germline mutations were detected, four of which have not been reported previously. The clinical features were variable. None and less than 10 skin lesions were observed in two mutation carriers at the age of 67 and 29 years, respectively. Spontaneous pneumothorax was reported in four and renal carcinoma of mixed histological types in two of 36 BHD-affected individuals and/or FLCN mutation carriers. Both the prevalence of spontaneous pneumothorax and renal tumors appeared to be relatively low compared with previously reported data. Various other extracutaneous tumors were observed in 11 of 36 BHD-affected individuals and/or FLCN mutation carriers. This study of the second largest cohort to date contributes to the expanding data on the variable phenotype and underlying gene defects in BHD