Birt-Hogg-Dubé Syndrome

Birt-Hogg-Dube syndrome is an autosomal dominant disorder caused by pathogenic variants in FLCN (folliculin), with skin fibrofolliculomas, multiple lung cysts with spontaneous pneumothorax, and an increased risk of renal tumours. Penetrance is high but expression varies in the family.

Lung cysts are present in over 80% of adults, and about a quarter to a third have at least one pneumothorax, a 50-fold increased risk. Renal cancer arises in about a third, often multifocal and of chromophobe or hybrid oncocytic type. It is under recognised, and is often diagnosed after a pneumothorax.

Pathophysiology. Loss of folliculin (a tumour suppressor) causes dysregulation of the mTOR, AMPK and TFEB signalling, with altered cell adhesion and mechanical stress on alveolar walls. Lower lobe cysts form near the pleura, and rupture leads to pneumothorax.

Skin: small, firm, skin coloured papules (fibrofolliculomas, trichodiscomas) on the face, neck and upper trunk, appearing after age 20. Lung: often no symptoms, or sudden chest pain and dyspnoea from pneumothorax, usually between 30 and 40 years. Kidney: haematuria, flank pain or incidental mass.

Sudden chest pain with breathlessness needs urgent chest radiography. Haematuria or a flank mass needs prompt imaging.

• Clinical diagnosis from the major features: at least 5 fibrofolliculomas (one histologically confirmed), or an FLCN pathogenic variant, supported by multiple lung cysts (with no other cause), early renal cancer, or a family history.
• High resolution CT: multiple thin walled cysts of varied size, basal and subpleural, often along the vessels and near the mediastinum, with normal intervening lung.
• Genetic testing of FLCN, and cascade testing of relatives.
• Skin biopsy for fibrofolliculoma.
• Renal imaging: MRI (or ultrasound) of the abdomen, repeated at intervals.

Differential diagnosis.

• Lymphangioleiomyomatosis (tuberous sclerosis, women, with chylous effusion)
• Lymphoid interstitial pneumonia and Sjogren syndrome
• Pulmonary Langerhans cell histiocytosis (smokers, nodules and cysts)
• Emphysema and bullous disease
• Light chain deposition disease and amyloid cysts
• Other causes of recurrent pneumothorax

• Pneumothorax: manage in the usual way, with drainage for large or symptomatic episodes. Because recurrence rates are high (up to 75%), early definitive pleurodesis by video assisted surgery with pleurectomy or abrasion is considered after the first or second episode. Chemical pleurodesis with talc (4 to 5 g) is an option for those unfit for surgery.
• Advice on risk: avoid smoking. Air travel after a pneumothorax is deferred until resolution is confirmed, and scuba diving is generally avoided.
• Renal surveillance: MRI of the abdomen every 12 to 24 months from age 20 (or 18), with annual imaging when tumours are known. Tumours of 3 cm or larger are treated by nephron sparing surgery or ablation, with total nephrectomy avoided where possible because of the risk of metachronous tumours.
• Skin: laser ablation, electrodessication or surgical removal of lesions for cosmetic reasons, with recurrence.
• No treatment for the cysts themselves.
• Genetic counselling, with offering of cascade testing for first degree relatives, and screening before age 20 for those with the variant.
• Pregnancy: counselling about the risk of pneumothorax, which can recur.

Complications and prognosis. Recurrent pneumothorax and renal malignancy are the main problems. Life expectancy is near normal with early renal detection, and lung function is usually preserved.

Monitoring. Renal imaging every 1 to 2 years, a baseline CT chest with lung function, and a review of symptoms yearly. Early imaging for chest pain or breathlessness.

Referral and escalation. Refer to genetics, urology or nephrology for renal tumours, and a thoracic surgeon for recurrent pneumothorax.