FLCN (Birt-Hogg-Dube) - risk management

Birt-Hogg-Dubé Syndrome (BHDS) is an autosomal dominant condition with a predisposition to benign skin lesions, renal tumours and lung cysts leading to pneumothoraces, caused by a mutation in the folliculin (FLCN) gene.

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up. 

• Individuals with a pathogenic germline mutation in the FLCN gene.
• Individuals with clinical diagnosis of BHDS.^r
• Individuals at 50% risk of BHDS.

* BHDS-associated renal cancers are usually, but not exclusively, bilateral and multifocal. Chromophobe or mixed oncocytic-chromophobe histology is characteristic, but clear cell and papillary cancers also occur.^rr

**the impact of lifestyle on cancer risk should be discussed e.g. recommend regular exercise, maintain healthy weight, have a healthy diet, limit alcohol intake, do not smoke.

Pulmonary manifestations

Pulmonary cysts

There is evidence that pulmonary cysts occur with nearly complete penetrance in BHDS.^r Approximately 80-90% of patients with BHDS have lung cysts.^rr BHDS-associated lung cysts likely develop in early-mid adulthood.^r  In sporadic primary pneumothorax, pulmonary cysts are typically found in the apical zones, while in BHDS, the lung cysts are most often located in the basal regions.   

Consequences of BHDS-associated cystic lung disease appear worse in smokers.^r

Facilitate patient education about the risk of future pneumothoraces. Refer to a respiratory physician prior to any high-risk activity e.g. scuba diving or high altitude mountain climbing.

Avoid smoking.^r 

Pneumothoraces

The lifetime risk for incident pneumothorax to age 70 years is 29% (95% CI, 9-49%).^r Risk factors for pneumothorax in this population include family history of pneumothorax,^r past history of pneumothorax,^r presence of lung cysts, cyst size and volume;^r whereas age and smoking status have not been consistently found to be associated with pneumothorax.

Strongly recommend: medical alert bracelet, action plan for pneumothorax.

The reported recurrence rate of pneumothorax in patients with BHDS varies from 30%^r-70%.^r The management of BHDS-associated pneumothorax is similar to that for the general population.

Skin manifestations

Fibrofolliculomas, which are benign, are the most common skin manifestation occurring on the central face, neck and upper aspect of the trunk. They are present in the majority of BHDS patients, and typically appear after age 20 years. If no lesions are present at age 40, they are unlikely to develop. Multiple biopsies and careful sectioning are often required for correct diagnosis. Other skin lesions associated with BHDS include angiofibromas, trichodiscomas, perifollicular fibromas.^r  Patients with BHDS may also develop multiple epidermoid cysts.

Oral lesions have been reported, described as small, discrete mucosa-coloured or white papules on the lips, gingiva, tongue or buccal mucosa.^r

Currently available treatments only remove cutaneous lesions temporarily; at the present time there does not appear to be a treatment that works permanently.

Kidney

Surgical

Management depends on the lesion size, location, growth rate, number of tumours, and the patient’s comorbidities. In general, surgical resection with renal sparing surgery whenever possible is recommended once a solid lesion exceeds the 3 cm threshold.^r

Surveillance

There is only expert opinion to support the use of renal imaging, as the effectiveness of screening in BHDS has not been evaluated to date. To reduce the cumulative radiation exposure, MRI (gold standard) and high-resolution renal ultrasound are preferred over CT with contrast. There is concern that renal ultrasound is inadequate in identifying small renal tumours,^rr and may miss some forms of BHDS-associated renal cancers.^r The youngest age of onset of renal cancer in patients with BHD has been reported to be 20 years.^rr A recent paper reported 115 mutation carriers ascertained from genetics units, of whom 14 developed renal cancers, with age at diagnosis ranging from 34 to 74;^r therefore surveillance commencing at age 30 years was thought to be appropriate. The risk of renal cancer in patients with BHDS does not decrease with age, hence lifelong screening approach is recommended.^r

First degree relatives (parents/brothers/sisters/children) are at 50% risk of having the condition. First degree relatives should be referred to their local family cancer clinic.

Link to information sheet on Informing family members about hereditary cancer.

Centre for Genetics Education NSW Health
Genetic Alliance Australia 
GeneReview
Birt-Hogg-Dubé Foundation

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