Birt-Hogg-Dubé Syndrome Genetic Mutation
Birt-Hogg-Dubé (BHD) syndrome is caused by autosomal dominant germline mutations in the FLCN gene, which encodes the protein folliculin. 1
Genetic Basis
- The FLCN gene mutation is the definitive genetic cause of BHD syndrome, inherited in an autosomal dominant pattern 1
- The protein product, folliculin, functions as a tumor suppressor 2, 3
- Mutations typically result in loss of functional folliculin protein through various mechanisms 2
Types of FLCN Mutations Reported
The mutation spectrum in FLCN is heterogeneous and includes:
- Frameshift mutations (most common), such as the hotspot mutation c.1285dupC (p.H429fs) 2
- Nonsense mutations, including c.1429C>T (p.Arg477Ter) 4
- In-frame deletions, such as p.F143del (c.427_429delTTC) 5
- Splice site mutations 6
- Insertion mutations 6
- Missense mutations (rare), including c.1978A>G (K508R) occurring in highly conserved amino acids 6
The mutation detection rate reaches 88% when comprehensive genetic testing is performed 6.
Clinical Significance of FLCN Mutations
The FLCN mutation leads to a classic triad of manifestations:
- Skin lesions: Fibrofolliculomas, perifollicular fibromas, trichodiscomas, or angiofibromas 1
- Pulmonary manifestations: Multiple bilateral lung cysts (present in >80% of patients) and recurrent spontaneous pneumothorax (affects >50% of patients) 3
- Renal tumors: Affect approximately 30% of patients, typically showing eosinophilic/oncocytic differentiation including chromophobe RCC, renal oncocytoma, hybrid oncocytoma-chromophobe tumors, and less commonly clear cell carcinoma 1, 3, 4
Molecular Pathogenesis
FLCN inactivation results in deregulation of critical cellular pathways:
- Loss of folliculin leads to dysregulation of the mTOR signaling pathway 2
- FLCN deficiency causes nuclear localization of oncogenic transcription factors TFEB and TFE3 2
- The mutations demonstrate a tumor suppressor mechanism with germline mutation plus somatic "second hit" 2
Important Clinical Considerations
Family history is a critical diagnostic clue - patients with BHD germline mutations and positive family history of kidney cancer have significantly increased probability of developing renal tumors (p=0.0032), and those with family history of pneumothorax have significantly increased risk of spontaneous pneumothorax (p=0.011) 6.
Renal tumors in BHD show distinctive features:
- Multiple bilateral tumors with slightly different histologies 1
- Frequent microscopic foci of oncocytic cell clusters ("oncocytosis") in non-neoplastic kidney tissue 1
- Broad uniparental disomy (copy-neutral loss of heterozygosity) on molecular analysis 1
Unlike other cystic lung diseases, BHD does not lead to progressive loss of lung function or chronic respiratory insufficiency 3, which is an important prognostic distinction.