Birt-Hogg-Dubé syndrome

BHDS is a multisystem disorder with cutaneous, pulmonary, and renal manifestations. Affected individuals typically present with multiple skin-coloured, opaque, whitish or yellowish dome-shaped papules known as fibrofolliculomas, which start to appear between the second and fourth decades of life. Cutaneous manifestations are observed in 87-97% of affected individuals, pulmonary cysts in 70-85%, spontaneous recurrent pneumothorax in 24-48%, and renal cell carcinoma in 15-30%. Spontaneous pneumothorax is often the first manifestation, with an average age of onset of 30.2 years in females and 38.4 years in males (range 13-69 years). Renal tumours occur in 19-35 % of individuals with a germline FLCN pathogenic variant, with a median age of diagnosis of 54.5 years in females and 57.0 years in males, well below the median for sporadic renal cell carcinoma. Intra- and interfamilial variation in disease severity can be significant. Women tend to have smaller and fewer cutaneous lesions than men.

The estimated prevalence of BHD in the general population is approximately 1:200,000.

BHDS is caused by germline pathogenic variants in FLCN (17p11.2), which account for approximately 96% of affected individuals. FLCN is a tumour suppressor gene encoding folliculin, a cytoplasmic protein that acts as a guanine exchange factor and regulates signalling pathways central to tumorigenesis and cellular metabolism, including mTOR, AMPK, EGFR and HIF1α. The folliculin-FNIP complex controls amino-acid-dependent activation of mTOR at the lysosome. Disease causation is through loss of function, consistent with a tumour suppressor mechanism.

BHDS is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the familial pathogenic variant. The vast majority of affected individuals have an affected parent; de novo occurrence appears to be uncommon. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical diagnosis of Birt-Hogg- Dubé syndrome can be established based on published consensus criteria, with one major or two minor criteria being sufficient. Histological confirmation of fibrofolliculomas is required to fulfil the cutaneous major criterion. However, molecular genetic testing for pathogenic variants in the FLCN gene is recommended to confirm the diagnosis. High-resolution chest CT is used to detect multiple, bilateral, basally predominant pulmonary cysts. Abdominal imaging, preferably by MRI, is performed to assess for renal tumours and for ongoing surveillance.

Main differential diagnoses include:

• : bilateral and multifocal clear cell renal cell carcinoma with increased risk for phaeochromocytoma, CNS haemangioblastoma, retinal angioma and endolymphatic sac tumours, contrasting with the oncocytic/chromophobe-predominant histology of BHDS-related renal tumours; VHL
• : lung cysts and skin papules (facial angiofibromas) accompanied by additional skin lesions (hypomelanotic macules, shagreen patches, ungual fibromas) and pulmonary lymphangioleiomyomatosis, features not typical of BHDS; TSC1, TSC2
• : cutaneous and uterine leiomyomas with usually solitary renal tumours that are less likely to be oncocytoma or chromophobe type, in contrast with the often bilateral oncocytic/chromophobe hybrid tumours of BHDS; FH

• Establishing the molecular diagnosis confirms the clinical suspicion and enables precise classification of the underlying condition.
• Identification of the causative variant enables specific and individualised surveillance, including regular renal imaging and pulmonary assessment, and is a prerequisite for targeted medical care planned by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive testing of at-risk relatives can clarify their genetic status and inform lifelong clinical surveillance for variant carriers.

• Sattler EC, Steinlein OK. Birt-Hogg-Dubé Syndrome. GeneReviews. 2006 Feb 27 [Updated 2024 Dec 5]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301695. Available from:
• Ntinidi C, Tomos I, Matthaiou AM, Bizymi N, Liapikou A. Birt-Hogg-Dubé Syndrome: A Mini Review of the Clinical Manifestations, Investigation, and Management. Journal of Personalized Medicine. 2025;15(12). doi: 10.3390/jpm15120583. PMID: . PMCID: PMC12734140.