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

Abstract

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.

Birt-Hogg-Dube syndrome presenting as multiple oncocytic parotid tumors

“…In 2008, Toro et al, reported on 51 families (50 were new) with 89 gene mutation carriers and in this series two individuals has parotid gland oncocytomas,at ages 20 and 39 (it is not clear if this overlapped the Schmidt study or if the same ages were coincidental) [7]. Finally, Maffé et al, reported two parotid tumors among 19 patients with suspected Birt–Hogg–Dubé syndrome: a Warthin parotid tumor occurred in a 59 year old male in whom no FLNC mutation was found; and of most relavance to the current report, bilateral parotid tumors not otherwise specified, occurred at ages 32 and 43 years old in one man with a documented FLNC mutation [8]. …”

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

“…A number of other clinical features have been reported in BHD patients including lipomas 12,13,16,19 , parathyroid adenomas 12,19 , thyroid nodules 19 and cancer 17,22 , and parotid oncocytomas 16,17 ,36,37,38 , but whether these are incidental findings or true phenotypic features of BHD syndrome is unclear.…”

BIRT-HOGG-DUBÉ SYNDROME: Metalloproteinase ACTIVITY AND RESPONSE TO DOXYCYCLINE

“…Patients with BHDS have an increased risk of renal cell carcinoma, colorectal neoplasia (3,21) and parotid oncocytomas (22). Abnormal pleuropulmonary findings include lung cysts, pleural blebs and spontaneous pneumothorax (4).…”