Differential Diagnosis and a Novel Mutation in Birt-Hogg-Dubé Syndrome: Insights from 2 Cases.

BACKGROUND Birt-Hogg-Dube (BHD, OMIM# 135150) syndrome is an inherited autosomal dominant disorder predominantly caused by mutation of FLCN gene, which encodes for folliculin. Although FLCN has been suggested to be involved in the mechanistic target of the rapamycin (mTOR) signaling pathway, the functional role of folliculin is poorly understood. BHD is characterized by skin abnormalities, pulmonary cysts, spontaneous pneumothorax, and kidney neoplasms. BHD can be asymptomatic or occur with symptoms such as cough or shortness of breath, or in extremis after an episode of spontaneous pneumothorax. The purpose of this report is to describe 2 Chinese cases of BHD syndrome, with a literature review of this rare disease. CASE REPORT The patients were 2 Chinese women diagnosed as BHD syndrome, aged 57 and 58 years old. Both patients had a history of pneumothorax, and physical examination revealed skin abnormalities. High-resolution computed tomography (HRCT) demonstrated sparsely-distributed, thin-walled lung cysts. Whole-exome sequencing (WES) analysis identified a mutation in the FLCN gene, confirming the diagnosis of BHD. In addition, a novel pathogenic variant of FLCN mutation in exon 12 (NM_144997.5: c.1341delC, p.Thr448Profs*20) was identified, and this is the first report of an unprecedented FLCN mutation in exon 12. CONCLUSIONS As an autosomal dominant hereditary disease, BHD should be distinguished from emphysema, TSC, LAM, and other diffuse cystic lung diseases for differential diagnosis. When BHD is suspected, identification of pathogenic FLCN germline mutations is essential for a definitive diagnosis.