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 and otherwise unexplained 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 pre-dating renal cancer, and are usually asymptomatic apart. Apart from a 50-fold risk ofincrease in pneumothorax:
  they are usually asymptomatic.
• ​can​Pneumothorax can be recurrent, even bilateral
• risk factors are. Risk increases with cyst volume &and volume changes associated with flying

^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 Cysts adjoining the pleura may have a narrowerrelatively narrow pleural base

Treatment and prognosis

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 (CLD) 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 specificrelated 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, lymphoproliferative disease, or amyloid,
  • predisposing cause such as in the case of Sjogren’s syndrome or AIDS
• light-chain deposition disease
  • cystcysts, nodules & lymphadenopathy
  • older adult with multiple myeloma or macroglobulinaemia & renal failure
• other cystic lung diseasesDesquamative interstitial pneumonia, pneumatocoeles, cystic pulmonary metastases or emphysema (, alpha 1 antitrypsin deficiency, inherited collagen disordersconnective tissue disease such as Marfan’s syndrome, etc and neurofibromatosis type 1 (thoracic manifestations) are less likely to be confused with BHD BHDS

Practical points

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

See also

• hereditary renal cancer syndromes