Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations

• Published in: Clinical genetics 2011-04, Vol.79 (4), p.345-354
• Main Authors: Maffé, A, Toschi, B, Circo, G, Giachino, D, Giglio, S, Rizzo, A, Carloni, A, Poletti, V, Tomassetti, S, Ginardi, C, Ungari, S, Genuardi, M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Base Sequence; Biological and medical sciences; Birt-Hogg-Dube Syndrome - genetics; Birt-Hogg-Dube Syndrome - pathology; Cysts; Dermatology; DNA; DNA Mutational Analysis; Family Health; Female; fibrofolliculoma; Follicles; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic disorders; Genetic screening; Genetics of eukaryotes. Biological and molecular evolution; Hair; Humans; Kidney; Kidney - pathology; Lung; Lung - pathology; Male; Medical diagnosis; Medical genetics; Medical sciences; Middle Aged; Molecular and cellular biology; Mutation; Neoplasia; Pedigree; Pneumothorax; Proto-Oncogene Proteins - genetics; renal carcinoma; renal chromophobe carcinoma; renal oncocytoma; Skin; Skin - pathology; trichodiscoma; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2010.01480.x

Maffé A, Toschi B, Circo G, Giachino D, Giglio S, Rizzo A, Carloni A, Poletti V, Tomassetti S, Ginardi C, Ungari S, Genuardi M. Constitutional FLCN mutations in patients with suspected Birt–Hogg–Dubé syndrome ascertained for non‐cutaneous manifestations. Birt–Hogg–Dubé syndrome (BHDS) is characterized by a clinical triad including cutaneous hamartomas originating from hair follicles, lung cysts/pneumothorax, and kidney tumors. Inactivating mutations of the tumor suppressor gene FLCN are identified in most families with BHDS. Usually, patients are referred for genetic examination by dermatologists because of the presence of typical multiple skin tumors with or without additional symptoms. However, because of phenotypic variability and incomplete penetrance, the clinical presentation of BHDS is not yet fully defined. Criteria for genetic testing and diagnosis that take into account variable manifestations have recently been proposed by the European BHD Consortium. We sequenced the FLCN gene coding region in a series of 19 patients selected for kidney and/or lung manifestations. Overall, FLCN mutations were found in 9 of 19 (47%) families and were detected only in probands who had either >2 components of the clinical triad or a single component (renal or pulmonary) along with a family history of another main BHDS manifestation. Typical cutaneous lesions were present only in 8 of 21 FLCN mutation carriers aged >20 years identified in the mutation‐positive families. In addition, we provide clinical and molecular evidence that parotid oncocytoma, so far reported in six BHDS cases, is associated with this condition, based on the observation of a patient with bilateral parotid involvement and marked reduction of the wild‐type FLCN allele signal in tumor DNA. Overall, the results obtained in this study contribute to the definition of the phenotypic characteristics that should be considered for BHDS diagnosis and FLCN mutation testing.