Genetic risk factors for spontaneous pneumothorax in Birt-Hogg-Dubé syndrome

Abstract Background Birt-Hogg-Dube syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, spontaneous pneumothorax, fibrofolliculoma and renal cell cancer. Due to its rarity and clinical heterogeneity, much is still unknown regarding the course of the disease and individual risk assessment. Therefore, we studied non-environmental risk factors for pneumothorax in a large sample of BHDS patients. Methods Clinical data were available from 197 BHDS patients (male 103, female 94) belonging to 63 unrelated families. The FLCN coding region including adjacent intronic sequences was analysed by PCR and subsequent Sanger sequencing as well as MLPA. Statistical analyses were performed using adequate methods to account for familial clustering. Results Patients who had only a single spontaneous pneumothorax were significantly older at the time of occurrence than those with multiple ones (mean 38.93 versus 29.74 years, p-value 0.010). The risk for three or more pneumothoraces drastically increased after the second event. Significantly increased pneumothorax risks were found for mutations c.1300G>C (59%) and c.250-2A>G (77%), compared to FLCN hotspot mutation c.1285dup (37% risk) (p-value 0.02). Conclusions We observed significant differences for the spontaneous pneumothorax risk regarding both age and gender in BHDS patients. Furthermore, two FLCN mutations were identified that are associated with significantly increased pneumothorax risk. Thus, formerly unknown individual predictors have been identified that provide improved risk stratification for BHDS patients.