Clinical and genetic spectrum of 59 Birt-Hogg-Dubé patients in a single-institution cohort.

Abstract

e22663 Background: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline pathogenic variants in the tumor suppressor gene FLCN , predisposing affected individuals to tumorigenesis. Clinically, it is characterized by fibrofolliculomas, pulmonary cysts with risk of spontaneous pneumothorax, and an increased risk of renal tumors. Early recognition and genetic confirmation are important to guide surveillance and family screening. Methods: We performed a retrospective review of 59 individuals with suspected or confirmed BHD disease evaluated and managed at Massachusetts General Hospital (Boston, MA) between 2008 and 2025. Demographic data, clinical manifestations, imaging findings, family history, and FLCN genetic testing results were extracted from medical records. Clinical BHD diagnoses were assigned based on the presence of at least two out of three characteristic clinical features when molecular confirmation was negative or unavailable. Results: The cohort included 59 individuals (44% male) with a median age of 55 years (IQR 44-68) at the time of data collection. FLCN genetic testing was performed in 55 of 59 individuals: 45 (82%) had a pathogenic/likely pathogenic FLCN variant, and 10 (18%) had no pathogenic variant identified. The remaining four individuals did not undergo genetic testing but were diagnosed clinically based on clinical manifestations and/or significant family history and were managed with BHD-directed surveillance. Overall, 42 of 59 individuals had clinical manifestations of the disease (71%), with a median age at first symptom or diagnosis of 38 years (IQR 25-50). Among those with clinical disease, 31 had a pathogenic/likely pathogenic FLCN variant (74%), and eight had no pathogenic variant identified (19%). Twenty-four had fibrofolliculomas/angiofibromas (57%), 20 had a history of pneumothorax (48%), and 18 developed renal tumors (43%). A positive family history of BHD or related manifestations was present in 47 of 59 individuals (80%), and 27 of 59 had genetically confirmed affected family members (46%). Consistent with this, the most common reason for referral was family history, followed by targeted or incidental germline detection and clinical suspicion of BHD. Conclusions: In this single-center cohort of individuals with suspected or confirmed BHD disease, renal tumors, pneumothoraces, and fibrofolliculomas were common among those with clinical disease. Most individuals with clinical disease carried a pathogenic/likely pathogenic FLCN variant. Family history was a major driver of diagnosis, emphasizing the value of genetic testing and longitudinal surveillance. Early recognition and coordinated management remain key to reducing BHD-related complications.