Namba Yukiko, Yamashita Atsushi, Kobayashi Etsuko, Hayashi Takuo, Iwabuchi Chikako, Ishiko Akira, Kishikawa Satsuki, Tsuboshima Kenji, Kurihara Masatoshi, Takahashi Kazuhisa, Seyama Kuniaki
Department of Respiratory Medicine, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu City, 279-0021, Chiba, Japan.
Department of Human Pathology, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, 113-8431, Tokyo, Japan.
Respir Investig. 2025 Jul 10;63(5):877-884. doi: 10.1016/j.resinv.2025.06.021.
Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant disorder caused by germline pathogenic variants in the folliculin (FLCN) gene and characterized by multiple pulmonary cysts, pneumothorax, fibrofolliculoma and/or trichodiscoma, and renal tumors. However, frontline physicians who manage lung manifestations have limited clinical experience with BHDS because of its rarity. Therefore, we initiated a collaborative study to assist physicians with limited BHDS diagnostic and management experience.
We conducted this study to support a series of diagnostic procedures for BHDS by frequently communicating with referral doctors. We expect that the successful clinical experience gained through this collaborative study will confer positive confidence on doctors to manage BHDS.
Thirty-three hospitals and 155 patients were included in this study. Of the 155 patients, 138 were diagnosed with BHDS using two diagnostic criteria: the results of the skin biopsy and FLCN genetic test. FLCN genetic test revealed 41 unique variants, including 38 pathogenic, two likely pathogenic variants, and one variant of uncertain significance. We performed skin biopsy on 66 patients with BHDS; in 16 patients (22.9 %), both central and participant diagnoses were concordant as FF/TD, whereas 13 patients (18.6 %) had false positives (FF/TD by participant and not by central diagnosis), and 1 patient (1.4 %) had a false negative (FF/TD by central and not by participant diagnosis). A questionnaire survey revealed increased confidence in majority of participants who would see suspected patients with BHDS. However, there were some uncertainties regarding the characteristics of skin papules and genetic issues related to FLCN genetic test.
Our study contributes to the successful clinical expertise in the diagnosis and management of BHDS, indicating that hands-on support from experienced institutions can serve as a management model for other rare diseases.
Birt-Hogg-Dubé综合征（BHDS）是一种罕见的常染色体显性疾病，由卵泡抑素（FLCN）基因的种系致病性变异引起，其特征为多发性肺囊肿、气胸、纤维毛囊瘤和/或毛发上皮瘤，以及肾肿瘤。然而，由于BHDS罕见，处理肺部表现的一线医生对其临床经验有限。因此，我们发起了一项合作研究，以协助BHDS诊断和管理经验有限的医生。
我们开展这项研究，通过与转诊医生频繁沟通来支持一系列BHDS诊断程序。我们期望通过这项合作研究获得的成功临床经验能让医生在管理BHDS时充满信心。
本研究纳入了33家医院的155例患者。在这155例患者中，138例根据两项诊断标准被诊断为BHDS：皮肤活检结果和FLCN基因检测。FLCN基因检测发现了41种独特变异，包括38种致病性变异、2种可能致病性变异和1种意义未明的变异。我们对66例BHDS患者进行了皮肤活检；16例患者（22.9%）的中心诊断和参与诊断均为一致的纤维毛囊瘤/毛发上皮瘤（FF/TD），而13例患者（18.6%）出现假阳性（参与诊断为FF/TD而中心诊断不是），1例患者（1.4%）出现假阴性（中心诊断为FF/TD而参与诊断不是）。一项问卷调查显示，大多数将会诊治BHDS疑似患者的参与者信心增强。然而，关于皮肤丘疹的特征以及与FLCN基因检测相关的遗传问题仍存在一些不确定性。
我们的研究有助于成功积累BHDS诊断和管理方面的临床专业知识，表明来自经验丰富机构的实际支持可作为其他罕见病的管理模式。
