{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:34:36Z","timestamp":1791858876224,"version":"4.3.4"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>The clinical pulmonary manifestations and genetic features of Birt\u2013Hogg\u2013Dub\u00e9 syndrome (BHDS) in Asian patients remained unclear. We aimed to clarify the clinical features of BHDS-associated pneumothorax (PTX) and retrospectively investigate potential contributing factors in the largest Asian cohort to date.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>We reviewed the clinical and genetic data collected in 2006\u20132017, from the BHDS patients who were Asian and presented with pulmonary cysts with or without a history of PTX.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>Data from 334 (41.3% males; 58.7% females) patients from 297 unrelated families were reviewed. Among them, 314 (94.0%) patients developed PTX. The median age at the first occurrence of PTX was 32 years, which was significantly lower in males (<jats:italic>P<\/jats:italic>= 0.003) and patients without notable skin manifestations (<jats:italic>P<\/jats:italic>&lt; 0.001). Seventy-six (24.2%) patients experienced their first PTX episode before the age of 25 years. PTX simultaneously occurred in the bilateral lungs of 37 (11.8%) patients. Among 149 patients who had their first PTX episode at least 10 years before BHDS diagnosis, PTX occurred more frequently in males (<jats:italic>P<\/jats:italic>= 0.030) and light smokers than in nonsmokers (<jats:italic>P<\/jats:italic>= 0.014). The occurrence of PTX peaked in the early 30s and gradually decreased with age but remained high in females (<jats:italic>P<\/jats:italic>= 0.001). We identified 70 unique<jats:italic>FLCN<\/jats:italic>germline variants, including duplications (46.4%), substitutions (7.1%), insertions\/deletions (30.0%), and variants affecting splicing (12.5%). Approximately 80% of Asian patients suspected of having BHDS could be genetically diagnosed by examining<jats:italic>FLCN<\/jats:italic>exons 7, 9, 11, 12, and 13. No apparent genotype\u2013phenotype correlation regarding pulmonary manifestations was identified.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusions<\/jats:title><jats:p>Our findings indicate that sex, smoking history, and skin manifestations at BHDS diagnosis significantly influence the clinical features of BHDS-associated PTX. These findings may contribute to the appropriate management and treatment of BHDS-associated PTX.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0289175","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T17:31:53Z","timestamp":1690306313000},"page":"e0289175","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Clinical and genetic features of 334 Asian patients with Birt\u2013Hogg\u2013Dub\u00e9 syndrome (BHDS) who presented with pulmonary cysts with or without a history of pneumothorax, with special reference to BHDS-associated pneumothorax"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1155-3204","authenticated-orcid":true,"given":"Yukiko","family":"Namba","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6835-1681","authenticated-orcid":true,"given":"Hiroki","family":"Ebana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8721-0382","authenticated-orcid":true,"given":"Shouichi","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsuko","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Kurihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9546-3056","authenticated-orcid":true,"given":"Yasuhito","family":"Sekimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Tsuboshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko Kunogi","family":"Okura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichiro","family":"Mitsuishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1374-2500","authenticated-orcid":true,"given":"Kuniaki","family":"Seyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"pone.0289175.ref001","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1111\/jdv.16190","article-title":"Hornstein-Knickenberg syndrome vs. Birt-Hogg-Dub\u00e9 syndrome: a critical review of an unjustified designation","volume":"34","author":"R. 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