BACKGROUND Birt-Hogg-Dubé syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, spontaneous pneumothorax, fibrofolliculoma and renal cell cancer. Due to its rarity and clinical heterogeneity, much is still unknown regarding the course of the disease and individual risk assessment. Therefore, we studied non-environmental risk factors for pneumothorax in a large sample of BHDS patients. METHODS Clinical data were available from 197 BHDS patients (male 103, female 94) belonging to 63 unrelated families. The FLCN coding region including adjacent intronic sequences was analysed by PCR and subsequent Sanger sequencing as well as MLPA. 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 ones (mean 38.93 versus 29.74 years, p-value 0.010). 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 to FLCN hotspot mutation c.1285dup (37% risk) (p-value 0.02). CONCLUSIONS We observed significant differences for the spontaneous pneumothorax risk regarding both age and gender in BHDS patients. 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 BHDS patients.

中文翻译：

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Birt-Hogg-Dubé 综合征自发性气胸的遗传危险因素

背景 Birt-Hogg-Dubé 综合征 (BHDS) 是一种遗传性肿瘤综合征，其特征是肺囊肿、自发性气胸、纤维滤泡瘤和肾细胞癌。由于其罕见性和临床异质性，关于疾病的进程和个体风险评估仍有很多未知。因此，我们在大量 BHDS 患者样本中研究了气胸的非环境危险因素。方法 从属于 63 个无关家庭的 197 名 BHDS 患者（男性 103 名，女性 94 名）获得临床数据。通过PCR和随后的Sanger测序以及MLPA分析包括相邻内含子序列的FLCN编码区。使用适当的方法进行统计分析以解释家族聚类。结果 仅发生一次自发性气胸的患者在发生时显着高于发生多次自发性气胸的患者（平均 38.93 岁 vs 29.74 岁，p 值 0.010）。在第二次事件后，发生三个或更多气胸的风险急剧增加。与 FLCN 热点突变 c.1285dup（37% 风险）相比，c.1300G>C（59%）和 c.250-2A>G（77%）突变的气胸风险显着增加（p 值 0.02）。结论 我们观察到 BHDS 患者的自发性气胸风险在年龄和性别方面存在显着差异。此外，还确定了两个与气胸风险显着增加相关的 FLCN 突变。因此，已经确定了以前未知的个体预测因子，可以为 BHDS 患者提供改进的风险分层。