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

• cutaneous manifestations, typically fibrofolliculomas

• multiple lung cysts and spontaneous pneumothoraces

• increased risk of renal tumours in some families, typically chromophobe oncocytomas and chromophobe carcinomas

Epidemiology

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

Diagnosis

The diagnosis of BHDS is established on identifying one major or two minor criteria ¹⁶.

Major criterion:

• five adult-onset fibrofolliculomas

• pathogenic FLCN germline mutation

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

Clinical presentation

• 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

  • unusual 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

    • chromophobe oncocytomas (50%), chromophobe carcinomas (34%), clear cell carcinomas (9%), oncocytomas (5%), papillary renal cell cancers (2%)

  • tumours 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​

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. However, the exact function of folliculin is unknown 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 Birt-Hogg-Dubé syndrome, which would explain the variable features in different families ¹³.

Radiographic features

CT

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 

Treatment and prognosis

General recommendations include:

• genetic testing and counselling

• screening of family members 

• smoking avoidance

Regarding renal cancer:

• renal cancer surveillance, initially by MRI, followed by MRI or CT ¹⁷ every 1-3 years.

• 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

History and etymology

It is named after Canadian physicians Arthur R Birt (dermatologist), Georgina R Hogg (pathologist) and William 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, i.e. no spared areas

  • absence of sub-pleural cysts along fissures

  • underlying TSC gene mutations occur in both tuberous sclerosis and sporadic LAM (cysts develop in women during their child-bearing years)

  • renal angiomyolipomas or other LAM-associated features

• pulmonary Langerhans cell histiocytosis

  • upper zone predominant and bronchocentric cavitating nodules, branching or irregular cysts

  • spares costophrenic and costomediastinal angles

  • typically a disease of young adult smokers, especially men

• Sjögren syndrome ¹⁵:

  • perivascular cysts containing soft-tissue strands or vessels

  • ground glass opacity

  • consolidation

  • tree in bud opacities

  • lymphoma

• light chain deposition disease

  • perivascular cysts identical to Sjogren syndrome

  • nodules and lymphadenopathy

  • older adult with a plasma cell dyscrasia (e.g. multiple myeloma) and renal failure

• desquamative interstitial pneumonia, pneumatocoeles, cystic pulmonary metastases, alpha 1 antitrypsin deficiency, inherited connective tissue disease such as Marfan syndrome, and neurofibromatosis type 1 are less likely to be confused with Birt-Hogg-Dubé syndrome

Practical points

• lung MinIPs help to identify lung cysts and their distribution: they are more sensitive than MPRs and are especially useful when screening young adults in whom small cysts can be hard to detect

• quantitative CT ‘emphysema’ software for total cyst volume measurement, distribution and monitoring

See also

• hereditary renal cancer syndromes