Birt-Hogg-Dubé syndrome is an autosomal dominant genetic disorder due to FLCN gene mutation, typically affecting adults in their mid-40s, characterised by skin fibrofolliculomas, lung cysts, and an increased risk for renal tumours.
Description
Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genetic disorder characterised by the development of cutaneous follicular tumours, pulmonary cysts, spontaneous pneumothorax, and an increased risk of renal tumours.
Pathogenesis
BHDS is caused by mutations in the FLCN gene, located on chromosome 17, which encodes the protein folliculin. While the precise function of folliculin is not fully understood, it’s believed to play a role in cellular energy sensing and signalling, potentially acting as a tumour suppressor.
Epidemiology, Risk Factors & Associations
BHDS is a rare disorder, with its exact prevalence unknown. It affects both males and females of all ethnic groups. It usually presents in adulthood, with skin manifestations often appearing first, usually in the third or fourth decade of life. The syndrome is associated with an increased risk of renal cell carcinoma, particularly chromophobe renal cell carcinoma and renal oncocytomas.
Clinical Features
- Cutaneous lesions, including fibrofolliculomas, trichodiscomas, and acrochordons (skin tags), typically located on the face, neck, and upper body.
- Pulmonary cysts leading to spontaneous pneumothorax.
- Increased risk of renal cell carcinoma, with a wide range of histological subtypes reported.
- Less commonly, patients may experience colonic polyps and lipomas.
Pathological Features
- Cutaneous lesions in BHDS are typically benign, composed of overgrowths of hair follicle cells (fibrofolliculomas and trichodiscomas).
- Renal tumours that can develop are typically hybrid oncocytic tumours, but can also include other types such as chromophobe renal cell carcinoma, oncocytomas, clear cell renal cell carcinoma, and papillary renal cell carcinoma.
- Chromophobe renal cell carcinoma and oncocytomas are the most commonly observed tumours in individuals with BHDS. These tumours tend to be less aggressive compared to clear cell and papillary renal cell carcinomas.
- Pulmonary cysts are air-filled spaces in the lung that lack an epithelial lining.
Radiological Features
CT
- Lungs: Numerous thin-walled, pulmonary cysts of varying sizes are seen, predominantly in the lower lobes and peripheral lungs. Cysts may be multilobulated or multiseptated. Cyst rupture may present with pneumothorax, pneumomediastinum or pneumopericardium.
- Abdomen: Renal tumours may be identified, usually presenting as solid renal masses.
MRI
- Abdomen: Renal tumours typically appear as hypointense on T1-weighted images and hyperintense on T2-weighted images, with variable enhancement patterns following contrast administration.
Differential Diagnosis
Differential diagnosis includes other genetic syndromes with overlapping features, such as:
- Tuberous sclerosis: Also leads to cutaneous lesions and renal tumours (angiomyolipoma), but additionally causes neurological symptoms and cardiac rhabdomyomas.
- Von Hippel-Lindau disease: Also causes renal cell carcinoma (predominantly clear cell) and multiple cysts in various organs.
Management
Management of BHDS involves regular surveillance to monitor for complications:
- Skin examinations to monitor cutaneous lesions. Surgical removal (dermabrasion, laser therapy or excision) for cosmesis.
- Chest CT to assess for pulmonary cysts and risk of pneumothorax.
- Renal imaging (MRI or CT) to monitor for the development of renal tumours.
- Genetic counselling for family members.
- Surgical intervention for renal tumours may be required, with an emphasis on nephron-sparing surgery to preserve renal function.
- For pneumothorax, management can range from observation for small, asymptomatic pneumothoraces to tube thoracostomy for larger or symptomatic pneumothoraces. In cases of recurrent pneumothorax, pleurodesis or surgical intervention may be considered.