Birt-Hogg-Dube syndrome (BHD) was first described in 1977, characterized as dome-shaped small tumors primarily in the face, neck, and ear with hereditary features.1 As the knowledge of BHD deepens, BHD is now characterized as a constellation of clinical features including skin fibrofolliculomas associated with trichodiscomas and acrochordons, lung cysts, and spontaneous pneumothorax, and bilateral multifocal renal tumors.

BHD is an exceedingly rare condition, lacking precise epidemiological data. Research indicates a population prevalence of approximately 5.67 per 10 million in South Korea, with the median age at initial diagnosis being 51 years.2 Muller et al., through meta-analysis and Bayesian estimation, estimated the prevalence of BHD at approximately 1.86 per million.3 Although the prevalence of women with BHD is similar to or higher than that of men2, 3, 4, a study highlights a prolonged interval from the onset of symptoms to BHD diagnosis in women compared to men (p=0.009).5 Therefore, addressing the challenge of minimizing diagnostic delays, enhancing subsequent surveillance, and refining treatment strategies remains pivotal to improving prognosis.

Hu et al. conducted a comprehensive literature review spanning 2008 to 2020, revealing the prevalent clinical manifestations in Birt-Hogg-Dube syndrome (BHD) patients as lung cysts (92.4%), spontaneous pneumothorax (71%), skin lesions (18.1%), and renal tumors (3.6%).4 In a separate study focusing on 36 patients with FLCN variants in China, it was found that lung cysts were present in 100% (36/36) of cases, spontaneous pneumothorax in 58.3% (21/36), skin lesions in 47.2% (17/36), and renal masses in 30% (9/30).6 These findings underscore the prominence of lung cysts and spontaneous pneumothorax as primary manifestations in BHD patients. Updated penetrance data by Bruinsma et al. estimates that male carriers of FLCN variants exhibit a 19% risk of kidney tumors, 87% for lung involvement, and 87% for skin lesions by the age of 70, with analogous figures in female carriers.7 Discrepancies in skin lesion incidence between East Asian and Western populations, potentially stemming from differences in FLCN mutation loci, might contribute to this variation. There are discrepancies in skin lesion incidence between East Asian and Western populations2, which might stem from the differences in FLCN mutation loci.8

BHD is an autosomal dominant disorder with a variety of mutations occurring in FLCN including insertion, deletion, and whole exon deletion.8,9 Extensive research has highlighted a strong correlation between FLCN mutations and the clinical presentations observed in BHD patients.10, 11, 12, 13, 14 FLCN is located at chromosome 17 p11.2, whose expression product, folliculin, is a highly conserved protein containing 579 amino acids15. It can inhibit the translocation of TFE3 by regulating the amino acid-sensitive Rag GTPase, thereby regulating the transcriptional process.16 Degradation of FLCN protein by the proteasome via changing its structure may account for its loss of function.17 FLCN mutation plays an important role in tumorigenesis. Mutated FLCN loses the ability to inhibit the downstream TFEB, thereby perpetuating TFEB activation and inducing tumorigenesis through the mTORC1 pathway.18 Additionally, FLCN is implicated in the regulation of TGF-β and AMPK pathways, notably observed in BHD-related renal tumors where TGF-β expression is significantly reduced compared to normal renal tissues.15,19

The diagnosis of Birt-Hogg-Dube (BHD) syndrome relies on comprehensive assessment involving family history and distinctive clinical, histopathological, and genetic characteristics. CT imaging serves as a valuable tool for identifying BHD patients, particularly those presenting with spontaneous pneumothorax and lung cysts as the initial signs.20 Pathological examination provides essential clues for distinguishing BHD from other skin lesions and tumors. Individuals with BHD face an increased predisposition to renal neoplasms, where the long-term prognosis correlates closely with the specific tumor pathology. A multi-center retrospective study found that chromophobe renal cell carcinomas (ChRCC), hybrid oncocytic/chromophobe tumors (HOCT), and renal oncocytomas (RO) are the three predominant pathological types in BHD-related renal tumors while clear cell renal cell carcinoma (ccRCC) accounts for 9%, which deserves more alert due to its higher malignancy.21 Genetic analysis revealing FLCN mutations plays a foundational role in diagnosing BHD due to its hereditary nature.