Division of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.
PLoS One. 2023 Jul 25;18(7):e0289175. doi: 10.1371/journal.pone.0289175. eCollection 2023.
The clinical pulmonary manifestations and genetic features of Birt-Hogg-Dubé 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.
We reviewed the clinical and genetic data collected in 2006-2017, from the BHDS patients who were Asian and presented with pulmonary cysts with or without a history of PTX.
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 (P = 0.003) and patients without notable skin manifestations (P < 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 (P = 0.030) and light smokers than in nonsmokers (P = 0.014). The occurrence of PTX peaked in the early 30s and gradually decreased with age but remained high in females (P = 0.001). We identified 70 unique FLCN 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 FLCN exons 7, 9, 11, 12, and 13. No apparent genotype-phenotype correlation regarding pulmonary manifestations was identified.
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.
亚洲患者的 Birt-Hogg-Dubé 综合征（BHDS）的临床肺部表现和遗传特征尚不清楚。我们旨在阐明迄今为止最大的亚洲队列中 BHDS 相关气胸（PTX）的临床特征，并回顾性调查潜在的致病因素。
我们回顾了 2006 年至 2017 年期间收集的来自亚洲且具有肺囊肿病史（无论是否有 PTX 病史）的 BHDS 患者的临床和遗传数据。
共分析了来自 297 个无关家庭的 334 名（41.3%为男性；58.7%为女性）患者的数据。其中，314 名（94.0%）患者发生了 PTX。首次发生 PTX 的中位年龄为 32 岁，男性明显较低（P = 0.003），无明显皮肤表现的患者也较低（P < 0.001）。76 名（24.2%）患者在 25 岁之前首次发生 PTX。37 名（11.8%）患者双侧肺部同时发生 PTX。在 149 名至少在 BHDS 诊断前 10 年首次发生 PTX 的患者中，PTX 在男性（P = 0.030）和轻度吸烟者中比不吸烟者（P = 0.014）更常见。PTX 的发生高峰在 30 岁出头，随着年龄的增长逐渐减少，但女性仍较高（P = 0.001）。我们鉴定了 70 个独特的 FLCN 种系变异，包括重复（46.4%）、取代（7.1%）、插入/缺失（30.0%）和影响剪接的变异（12.5%）。约 80%疑似 BHDS 的亚洲患者可通过检查 FLCN 外显子 7、9、11、12 和 13 进行基因诊断。未发现肺表现的明显基因型-表型相关性。
我们的研究结果表明，BHDS 诊断时的性别、吸烟史和皮肤表现显著影响 BHDS 相关 PTX 的临床特征。这些发现可能有助于 BHDS 相关 PTX 的适当管理和治疗。
