A collaborative study to disseminate the clinical practice of diagnosing and managing Birt-Hogg-Dubé syndrome in Japan.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.