Birt-Hogg-Dubé syndrome, prevalence of identified cases according to clinical indication in a cohort of 1,084 patients with genetic analysis.

Abstract

Purpose: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by pathogenic variants (PVs) in the FLCN gene. This study aimed to characterize the clinical presentation of patients carrying a FLCN pathogenic variation and to identify the most indicative clinical features of the syndrome.

Methods: We analysed clinical and molecular data from 1,084 consecutive probands with a clinical suspicion of BHD. The frequency of FLCN PVs was assessed, based on clinical presentation and family history.

Results: Among the 1,084 probands analysed, 29% carried a PV in FLCN. Isolated fibrofolliculomas showed the highest diagnostic yield (55.8%, 95% CI: 44.7-66.5%), whereas isolated pulmonary cysts and renal cancer were less frequently associated with FLCN PVs (4.8%, 95% CI: 2.9-7.5% and 0.6%, 95% CI: 0.0-3.2%, respectively). Multivariable analysis identified fibrofolliculomas (OR=12.9) and pneumothorax (OR=5.8) as the strongest predictors. A family history of BHD-related symptoms increased the likelihood of detecting a FLCN PV. 244 relatives who carry the familial pathogenic variation were assessed: in the age 50-60 years group, only 60% had developed BHD-related symptoms. Finally, two patients with a mosaic FLCN PV were discovered.

Conclusion: Fibrofolliculomas represent the strongest predictor of FLCN pathogenic variants. The combination of clinical features significantly improves diagnostic yield, supporting a targeted genetic screening approach.