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 bilateral ¹³
• cutaneous manifestations: fibrofolliculomas, trichodiscomas and acrochordons (skin tags) usually on the face, head & neck
• possible association with other tumours e.g. colon cancer

Epidemiology

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

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

• Skin papules in approximately 80%. Skin lesions develop in the third and fourth decades & progress over time
• Lung cysts develop in early or mid-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 growing ¹³

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 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
• predilection for subpleural lung including paramediastinal and parafissural 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

• early ipselateral VATS pleurodesis is recommended after a single pneumothorax
• contralateral pleurodesis is usually not required
• smoking avoidance 
• renal tumour surveillance by annual ultrasound (or MR if available)
• renal tumour prognosis depends on histology. Treatment options include partial nephrectomy or ablation
• genetic testing & counselling
• screening of family members 
• lung function does not deteriorate rapidly compared to other cystic lung disorders, although evidence is limited by the rarity of BHDS
• skin lesions tend to progress over time & may not be evident in younger individuals. A dermatologist can provide local treatments for these
• mTOR inhibition is not currently recommended: this is neither effective nor necessary on limited evidence

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 withabsence of sub-pleural cysts along fissures
  • underlying TSC orgene mutations occur in both TSC and sporadic LAM (cysts develop in women during their child-bearing years)
  • +/- renal angiomyolipomas & other features related to either TSC or sLAM. Adenoma sebaceum & other typical skin lesions in TSC.
• 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, especially men
• lymphocytic interstitial pneumonitis
  • lower zone predominant perivascular cysts which may contain internal structures
  • other features of the underlying disease e.g. nodules, ground-glass opacity, lymphoproliferative disease or amyloid in Sjögren’s syndrome; features of AIDS
• 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 & their distribution: they are more sensitive than MPRs.

Quantitative CT ‘emphysema’ software for total cyst volume measurement, distribution & monitoring

See also

• hereditary renal cancer syndromes

Acknowledgement

Thanks to Professor Deborah Yates for amendments & additions