Chest
Diffuse Lung Disease: Original ResearchGenetic Risk Factors for Spontaneous Pneumothorax in Birt-Hogg-Dubé Syndrome
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
References (30)
- et al.
Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome
Cancer Cell
(2002) - et al.
European BHD Consortium. Birt-Hogg-Dubé syndrome: diagnosis and management
Lancet Oncol
(2009) - et al.
GEE for longitudinal ordinal data: comparing R-geepack, R-multgee, R-repolr, SAS-GENMOD, SPSS-GENLIN
Comput Stat Data Anal
(2014) - et al.
Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues
Mod Pathol
(2004) - et al.
Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients
J Invest Dermatol
(2007) - et al.
Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome
Am J Hum Genet
(2005) - et al.
Perifollicular fibromatosis cutis with polyps of the colon: a cutaneo-intestinal syndrome sui generis
Arch Derm Res
(1975) - et al.
Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons
Arch Derm
(1977) - et al.
Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dubé syndrome
PLoS One
(2018) - et al.
Childhood pneumothorax in Birt-Hogg-Dubé syndrome: a cohort study and review of the literature
Mol Genet Genomic Med
(2018)
Novel clinical scoring system to identify patients with pneumothorax with suspicion for Birt-Hogg-Dubé syndrome
Respirology
A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt-Hogg-Dubé syndrome
Br J Dermatol
The ABCs of BHD: an in-depth review of Birt-Hogg-Dubé syndrome
AJR Am J Roentgenol
Lymphangioleiomyomatosis (LAM) presenting as recurrent pneumothorax in an infant with tuberous sclerosis: treated successfully with sirolimus
BMJ Case Rep
Cystic lung disease in genetic syndromes with deficient tumor suppressor gene function
Respiration
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Birt-Hogg-Dubé syndrome in an overall view: Focus on the clinicopathological prospects in renal tumors
2024, Seminars in Diagnostic PathologyDelayed diagnosis of Birt-Hogg-Dubé syndrome might be aggravated by gender bias
2022, eClinicalMedicineCitation Excerpt :Birt-Hogg-Dubé syndrome (BHDS, MIM: 135150) is an inherited tumor syndrome with major symptoms that affect lung, skin and kidney.1 Nearly all patients develop lung bullae, resulting in an average risk for spontaneous pneumothorax of about 44%.2 There are gender differences regarding pneumothorax risk; female patients tend to be affected more often before age 20 years but rarely after age 50 years.
Frequency of truncating FLCN variants and Birt-Hogg-Dubé–associated phenotypes in a health care system population
2022, Genetics in MedicineCitation Excerpt :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 CancerCitation Excerpt :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].
FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.