Birt-Hogg-Dubé syndrome

Last revised by Yaïr Glick on 30 Apr 2022

Birt-Hogg-Dubé syndrome (BHDS), also known as folliculin gene-associated syndrome, is a multi-system disease characterized by:

  • cutaneous manifestations, typically fibrofolliculomas
  • multiple lung cysts and spontaneous pneumothoraces
  • increased risk of renal tumors, typically chromophobe oncocytomas and/or chromophobe carcinomas

Birt-Hogg-Dubé syndrome is rare but likely under-diagnosed. It may be diagnosed incidentally after a CT scan, dermatological review or a spontaneous pneumothorax. Men and women are equally affected as this an autosomal dominant disorder. There is often a family history of pneumothorax.

One major criterion:

  • five adult-onset fibrofolliculomas
  • pathogenic FLCN germline mutation

Two minor criteria:

  • typical lung cysts with no other explanation 
  • multifocal/bilateral renal cancer before the age of 50 years
  • renal cancer of mixed chromophobe and oncocytic histology
  • first-degree relative with Birt-Hogg-Dubé syndrome
  • skin lesions
    • develop in approximately 80% and manifest in the third and fourth decades and progress over time
    • fibrofolliculomas are the characteristic lesion, typically seen in the midface 
    • other skin lesions include trichodiscomas and acrochordons (skin tags)
  • renal cancer
    • seven-fold increased risk of malignancy
    • less usual histological forms of renal cancer should prompt a search for other features of Birt-Hogg-Dubé syndrome, most often chromophobe oncocytomas and/or chromophobe carcinomas
    • tumors are frequently bilateral, multifocal, and slow-growing 13
  • lung cysts
    • develop in early or mid-adulthood, predating renal cancer
    • aside from a 50-fold increase in pneumothorax, they are usually asymptomatic
    • ​when manifesting, pneumothorax can be recurrent and even bilateral, risk increases with cyst volume and volume changes associated with activities such as flying and diving​

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;​ however, the exact function of folliculin is unknown 13.

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 Birt-Hogg-Dubé syndrome, which would explain the variable features in different families 13.

Lung cysts typically develop in early adulthood and have the following characteristics:

  • multiple lower zone predominant and bilateral
  • predilection for subpleural lung including paramediastinal and perifissural location
  • adjacent to interlobular septa, arteries and veins
  • thin-walled, variable in size, round or elongated, sometimes multilobulated or multiseptate 13
  • ​cysts adjoining the pleura may have a relatively narrow pleural base
  • cyst rupture may cause pneumothorax, pneumomediastinum or pneumopericardium 

General recommendations include:

  • genetic testing and counseling
  • screening of family members 
  • smoking avoidance

Regarding renal cancer:

  • renal cancer surveillance by annual ultrasound (or MR if available)
  • renal cancer prognosis depends on histology

Regarding pneumothoraces and lung disease:

  • early ipsilateral VATS pleurodesis is recommended after a single pneumothorax
  • contralateral pleurodesis is usually not required

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.

Other causes of cystic lung disease or focal hyperlucencies:

  • lung MinIPs help to identify lung cysts and their distribution: they are more sensitive than MPRs
  • quantitative CT ‘emphysema’ software for total cyst volume measurement, distribution and monitoring

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