Chest
Volume 157, Issue 5, May 2020, Pages 1199-1206
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Diffuse Lung Disease: Original Research
Genetic Risk Factors for Spontaneous Pneumothorax in Birt-Hogg-Dubé Syndrome

https://doi.org/10.1016/j.chest.2019.12.019Get rights and content

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Section snippets

Patients

Clinical data were available from 197 patients with BHDS (male patients, 103; female patients, 94) belonging to 63 unrelated families. From these 197 patients with BHDS a subset of 102 patients was treated/genotyped in our interdisciplinary BHDS outpatient clinic, and DNA was available for germline FLCN testing. The remaining 95 patients were family members who either were obligate carriers of the familial FLCN mutation or were affected by at least two typical symptoms. Informed consent was

Probability of Spontaneous Pneumothorax

The clinical details are given in e-Table 1. The sample consisted of 197 patients. The age distribution within the sample ranged from 12 to 90 years for female patients (mean, 53.82 years; median, 53.00 years; SD, ± 16.39) and from 21 to 90 years for male patients (mean, 57.65 years; median, 58.00 years; SD, ± 17.01). The age of 13 patients (three women, 10 men) was not recorded. Regarding the complete sample of patients with BHDS there were no significant differences in age between male and

Discussion

This study, through representing a large cohort of BHDS families collected over a period of 10 years in a national BHDS center, has limitations that need to be addressed in future research. We were not able to correct for risk factors such as smoking history or size and number of lung cysts, which are potential sources for confounding. In addition, familial clustering—unavoidable in family studies—reduced statistical power. Such limitations are common in studies involving rare genetic

Conclusion

In conclusion, we have found significant associations between pneumothorax risk and age/sex in patients with BHDS. Furthermore, we have identified two FLCN mutations that are associated with significantly increased pneumothorax risks. Thus, valuable risk predictors have been identified that will help to provide patients and medical personnel with a framework regarding the course of lung affection in BHDS. Future studies will show if the associations with age and sex, as well as the

Acknowledgments

Author contributions: O. K. S. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. O. K. S. assumes full responsibility for the integrity of the submission as a whole, from inception to published article. O. K. S., E. C. S., and Z. S. obtained, analyzed, and interpreted the data. O. K. S. performed the statistical analyses and the genetic testing, and was a major contributor in writing the manuscript. All

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      Identifying patients at risk for BHD-phenotypes could inform appropriate management. For example, in patients with BHD, a first pneumothorax might be treated more aggressively with pleurectomy/pleurodesis given the risk for recurrent pneumothoraces36,37 and identification of individuals with FLCN variants could enable earlier screening for kidney cancer, potentially allowing detection of cancers at earlier stages.38 This study has several limitations.

    • Colorectal cancer risk in families with Birt-Hogg-Dubé syndrome increased

      2021, European Journal of Cancer
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      This family is now believed to have had the same condition that was first described in 1925 in a single patient and later by Birt, Hogg and Dubè in a family with fibrofolliculoma but without reported intestinal neoplasm [2,3]. Named Birt-Hogg-Dubé syndrome (BHDS), the disorder now is known to be caused by mutations in the FLCN gene and characterised by three major symptoms: multiple lung cysts with spontaneous pneumothorax, numerous fibrofolliculoma mainly on the head and neck, and various histological types of benign and malignant renal tumours [4,5]. Associations of BHDS with different additional types of malignancies have been described, but only a few were repeatedly reported, including thyroid cancer, parotid oncocytoma and colorectal cancer (CRC) [6–12].

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    FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

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