Birt-Hogg-Dubé syndrome

Birt-Hogg-Dubé syndrome, BHDS or folliculin gene-associated syndrome is a multi-system disease characterised by:

• multiple lung cysts and spontaneous pneumothoraces
• renal tumours in up to 34%, most often chromophobe oncocytomas and chromophobe carcinomas which are typically slow-growing & may be multiple and bilateral¹³
• cutaneous manifestations: fibrofolliculomas and trichodiscomas

Epidemiology

Birt-Hogg-Dubé syndrome is rare but under-diagnosed

Diagnosis

One major criterion: 

• 5 adult-onset fibrofolliculomas
• pathogenic FLCN germline mutation

2 minor criteria: 

• typical lung cysts with no other explanation 
• multifocal/bilateral renal cancer before the age of 50
• renal cancer of mixed chromophobe and oncocytic histology
• first-degree relative with BHDS

Clinical presentation

• Lung cysts​ develop develop in early or mid adulthood-adulthood pre-dating renal cancer. Apart from a 50-fold increase in pneumothorax, they are usually asymptomatic.
• ​Pneumothorax can be recurrent, even bilateral. Risk increases with cyst volume and volume changes associated with flying and diving.​
• Renal cancer: 
  • 7-fold increased risk of malignancy. 
  • less usual histological forms should prompt a search for other features of BHD 
  • chromophobe oncocytomas (50%), chromophobe carcinomas (34%), clear cell carcinomas (9%), oncocytomas (5%), papillary renal cell cancers (2%)
  • frequently bilateral, multifocal, and slow growing¹³

Pathology 

Folliculin is thought to be an oncogene suppressor protein which may affect proteolytic metalloproteinase enzymes leading to lung matrix breakdown, tissue destruction, and cyst formation.The mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of BHDS ^13​

Genetics

Deletion mutation in the folliculin (FLCN) gene (17p11.2) with autosomal dominant inheritance. At least 142 unique DNA mutations of the FLCN gene have been implicated in the pathogenesis of BHDS, which would explain the variable features in different families ¹³

Radiographic features

CT

Lung cysts typically develop in early adulthood and are typically:

• multiple lower zone predominant and bilateral with a predilection for subpleural lung including paramediastinal and parafissural location
• adjacent to interlobular septa, arteries and veins
• thin-walled, variable in size, round or elongated, multilobulated or multiseptate¹³. Cysts adjoining the pleura may have a relatively narrow pleural base

Treatment and prognosis

Renal tumour prognosis depends on histology. Treatment options include partial nephrectomy or ablation. Annual surveillance of adults for renal cancer is ideal and MR is the optimal imaging modality in high risk individuals.

Pneumothoraces may be prevented by cyst resection and pleurodesis.

History and etymology

It is named after Canadian physicians Arthur R Birt (dermatologist), Georgina R Hogg (pathologist) and W James Dubé (internist) who published their findings in 1978 ⁷.

Differential diagnosis

Other causes of cystic lung disease or focal hyperlucencies:

• lymphangioleiomyomatosis, (LAM)
  • scattered distribution, ie no spared areas
  • associated with TSC or sporadic LAM (cysts develop in women during their child-bearing years)
  • +/- renal angiomyolipomas & other features related to either TSC or sLAM
• pulmonary Langerhans cell histiocytosis
  • upper zone predominant & bronchocentric cavitating nodules, branching or irregular cysts
  • spares costophrenic and costomediastinal angles
  • typically a disease of young adult smokers
• lymphocytic interstitial pneumonitis
  • lower zone predominant perivascular cysts which may contain internal structures
  • other features of the underlying disease such as nodules, ground-glass opacity, lymphoproliferative disease or amyloid in the case of Sjogren’s syndrome
• light-chain deposition disease
  • cysts, nodules & lymphadenopathy
  • older adult with multiple myeloma or macroglobulinaemia & renal failure
• Desquamative interstitial pneumonia, pneumatocoeles, cystic pulmonary metastases, alpha 1 antitrypsin deficiency, inherited connective tissue disease such as Marfan’s syndrome, and neurofibromatosis type 1 (thoracic manifestations) are less likely to be confused with BHDS

Practical points

Lung MinIPs help to identify lung cysts: they are more sensitive than MPRs

See also

• hereditary renal cancer syndromes