Clinical and genetic features of 334 Asian patients with Birt–Hogg–Dubé syndrome (BHDS) who presented with pulmonary cysts with or without a history of pneumothorax, with special reference to BHDS-associated pneumothorax

Abstract

BackgroundThe clinical pulmonary manifestations and genetic features of Birt–Hogg–Dubé syndrome (BHDS) in Asian patients remained unclear. We aimed to clarify the clinical features of BHDS-associated pneumothorax (PTX) and retrospectively investigate potential contributing factors in the largest Asian cohort to date.MethodsWe reviewed the clinical and genetic data collected in 2006–2017, from the BHDS patients who were Asian and presented with pulmonary cysts with or without a history of PTX.ResultsData from 334 (41.3% males; 58.7% females) patients from 297 unrelated families were reviewed. Among them, 314 (94.0%) patients developed PTX. The median age at the first occurrence of PTX was 32 years, which was significantly lower in males (P= 0.003) and patients without notable skin manifestations (P< 0.001). Seventy-six (24.2%) patients experienced their first PTX episode before the age of 25 years. PTX simultaneously occurred in the bilateral lungs of 37 (11.8%) patients. Among 149 patients who had their first PTX episode at least 10 years before BHDS diagnosis, PTX occurred more frequently in males (P= 0.030) and light smokers than in nonsmokers (P= 0.014). The occurrence of PTX peaked in the early 30s and gradually decreased with age but remained high in females (P= 0.001). We identified 70 uniqueFLCNgermline variants, including duplications (46.4%), substitutions (7.1%), insertions/deletions (30.0%), and variants affecting splicing (12.5%). Approximately 80% of Asian patients suspected of having BHDS could be genetically diagnosed by examiningFLCNexons 7, 9, 11, 12, and 13. No apparent genotype–phenotype correlation regarding pulmonary manifestations was identified.ConclusionsOur findings indicate that sex, smoking history, and skin manifestations at BHDS diagnosis significantly influence the clinical features of BHDS-associated PTX. These findings may contribute to the appropriate management and treatment of BHDS-associated PTX.