Pulmonary Manifestations of Birt-Hogg-Dubé Syndrome: A Single-Centre Retrospective Case Series of Seven Genetically Confirmed Patients.

Background/Objectives: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline pathogenic variants in the folliculin (FLCN) gene. Although it carries a substantial lifetime risk of renal cell carcinoma, its earliest manifestations are typically pulmonary cysts and spontaneous pneumothorax, which are frequently misclassified as primary spontaneous pneumothorax, resulting in diagnostic delay and inadequate oncological surveillance. We aimed to characterise the real-world phenotypic spectrum of BHD encountered in a respiratory referral setting. Methods: We retrospectively describe seven consecutive patients with genetically confirmed BHD syndrome diagnosed at our tertiary referral centre between 2022 and 2024. Demographic data, smoking history, FLCN variants, pneumothorax episodes, high-resolution computed tomography (HRCT) findings, pulmonary function tests and extrapulmonary neoplasms were collected. Reporting followed the PROCESS 2020 guideline. Results: Mean age at genetic diagnosis was 53.1 years (range 41-64). All seven patients had multiple thin-walled pulmonary cysts on HRCT, with the typical basal, subpleural and paramediastinal distribution; three had a pneumothorax history. Despite largely preserved spirometry-mean forced expiratory volume in 1 s (FEV1) of 82.4% predicted-the diffusing capacity of the lung for carbon monoxide (DLCO) was reduced in five patients (mean of 67.4% predicted) and was the most frequently affected functional parameter, although the overall functional picture was heterogeneous. Five patients had solid neoplasms (one renal, one colorectal, one thyroid/parathyroid, one ovarian, one lung adenocarcinoma). Conclusions: In this referral-based case series, pulmonary cysts were a constant finding and DLCO was the most frequently reduced functional parameter, although the functional picture varied across patients. These descriptive observations are hypothesis-generating and require prospective, controlled validation-including comparison with other diffuse cystic lung diseases-before any diagnostic algorithm can be proposed.