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Chest. 2020 Jan 17. pii: S0012-3692(20)30031-3. doi: 10.1016/j.chest.2019.12.019. [Epub ahead of print]

Genetic Risk Factors for Spontaneous Pneumothorax in Birt-Hogg-Dubé Syndrome.

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Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany.
Medizinische Klinik und Poliklinik V, German Center for Lung Research, University Hospital, LMU Munich, Munich, Germany.
Institute for Medical Information Processing, Biometry, and Epidemiology, IBE, Medical Faculty, LMU Munich, Munich, Germany.
Institute of Human Genetics, University Hospital, LMU Munich, Munich, Germany. Electronic address:



Birt-Hogg-Dubé syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, spontaneous pneumothorax, fibrofolliculomas, and renal cell cancer. Because of its rarity and clinical heterogeneity, much is still unknown regarding the course of the disease and individual risk assessment. Therefore, we studied nonenvironmental risk factors for pneumothorax in a large sample of patients with BHDS.


Clinical data were available from 197 patients with BHDS (male patients, 103; female patients, 94) belonging to 63 unrelated families. The FLCN coding region including adjacent intronic sequences was analyzed by PCR and subsequent Sanger sequencing as well as by multiplex ligation-dependent probe amplification. Statistical analyses were performed, using adequate methods to account for familial clustering.


Patients who had only a single spontaneous pneumothorax were significantly older at the time of occurrence than those with multiple pneumothoraces (mean, 38.93 vs 29.74 years; P value, .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 with FLCN hotspot mutation c.1285dup (37% risk) (P value, .02).


We observed significant differences for the spontaneous pneumothorax risk regarding both age and sex in patients with BHDS. 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 patients with BHDS.


Birt-Hogg-Dubé syndrome; FLCN gene; genotype-phenotype correlation; pneumothorax

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