Birt-Hogg-Dubé syndrome

Abstract

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant tumour predisposition disorder caused by pathogenic variants in the folliculin (FLCN) gene. It is characterised by benign skin tumours, renal neoplasia and cystic lung disease with a risk of spontaneous pneumothorax. Although historically considered rare, population genomic data indicate that FLCN pathogenic variants are substantially more common than expected from clinically ascertained cases, suggesting that many variant carriers are not currently recognised in clinical practice. Advances in the molecular biology of BHD have established that FLCN loss-of-function is associated with dysregulation of the mTORC1/TFEB lysosomal signalling pathway, which has been implicated in mouse models of BHD-associated renal and lung pathology. Clinically, diagnosis relies on recognising characteristic patterns across dermatological, renal and pulmonary presentations, with genetic confirmation enabling cascade testing and targeted surveillance. Management is centred on lifelong renal imaging, early intervention for tumours and prevention and treatment of pneumothorax, delivered through multidisciplinary care. Despite generally indolent renal tumour behaviour, malignant progression can occur. Ongoing research aims to improve early diagnosis through population genomics and to develop targeted therapies. These advances are likely to transform the identification and management of BHD and provide broader insights into tumour suppressor biology.