Birt-Hogg-Dubé syndrome: From molecular mechanisms to emerging systemic therapeutic strategies

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline mutations in the FLCN gene. It is characterized by pulmonary cysts with recurrent pneumothorax, renal tumors, and cutaneous lesions, with marked phenotypic variability. This review summarizes current evidence on the molecular basis and clinical manifestations of BHD, highlighting the role of folliculin in cellular metabolism through the AMPK-mTOR signaling pathway and related mechanisms involved in tumorigenesis. From a clinical perspective, diagnosis is often challenging and relies on combined genetic and phenotypic criteria. Management is currently based on surveillance strategies, particularly for early detection of renal cancer. Emerging therapeutic approaches targeting mTOR signaling, metabolic pathways, and transcriptional regulators show promising results in preclinical models, although their clinical impact remains to be established.