1. Introduction

Birt–Hogg–Dubé (BHD) syndrome (OMIM 135150) is an autosomal, dominantly inherited, monogenic condition, characterised by the development of fibrofolliculomas (benign skin tumours) on the face, head and upper torso, pulmonary cysts and pneumothorax (collapsed lung), and predisposition to kidney cancers with clear cell, chromophobe, papillary or oncocytic features. The clinical manifestations of BHD syndrome are discussed in Section 2.

BHD syndrome was described in 1977 by three Canadian doctors – Birt, Hogg and Dubé. Hornstein and Knickenberg had also identified the syndrome in 1975, and it has been suggested that the syndrome be renamed Hornstein-Birt-Hogg-Dubé. In 2001, a BHD-associated gene locus was localised to chromosome 17p11.2 and a novel gene, Folliculin (FLCN), was subsequently identified as being inactivated in individuals with BHD syndrome. The FLCN gene codes for a protein called Folliculin (FLCN), which has a putative tumour suppressor function. To date, approximately 512 families have been diagnosed with BHD (See Section 1.1). As of July 2015, 150 different FLCN mutations have been identified, 112 of which are likely to be pathogenic. The Folliculin gene and its mutations are described in Section 3.

BHD syndrome shares many clinical features with hamartoma syndromes. Hamartoma syndromes are dominantly inherited, predispose to cancer that affects multiple organs, and result in the development of benign tumours. Such syndromes include Cowden syndrome, Peutz-Jeghers syndrome, and Tuberous sclerosis complex (TSC), caused by inactivation of the tumour suppressor genes PTEN, LKB1 and TSC1 or TSC2 respectively. The hereditary nature of renal cell carcinoma in BHD is also seen in association with mutations in other genes: VHL in VHL syndrome; MET in hereditary papillary renal carcinoma (HPRC); FH in hereditary leiomyomatosis and renal cell cancer (HLRCC); BAP1 and CDKN2B. The histological features of renal tumours alongside other phenotypes can help differentiate between the forms of hereditary RCC.

Folliculin and its known interacting proteins – FNIP1, FNIP2, PKP4, RPT4 and RagA/B – are discussed in Section 4. The structure of the C-terminal domain of FLCN suggests that the protein functions as a Rab guanine nucleotide exchange factor (GEF). FLCN is subject to a number of post-transcriptional modifications, including phosphorylation and ubiquitinylation. FNIP1, FNIP2 and 5’-AMP-activated protein kinase (AMPK), are able to phosphorylate FLCN, and all three proteins have also been found to be subject to post-translational modification themselves.

FLCN has been implicated in numerous signalling pathways and cellular processes:  mTOR signalling; AMPK signalling; HIF signalling and mitochondrial biogenesis; stress resistance and autophagy; Ras-Raf-MEK-Erk signalling and rRNA synthesis; JAK-STAT and TGF-β signalling; RhoA signalling; Wnt and cadherin signalling; cell cycle; apoptosis; membrane trafficking; stem cell maintenance and pluripotency; ciliogenesis; and matrix metalloproteinase function.

The function of FLCN and its role in these pathways is discussed in detail in Section 5, whilst cell lines and animal models of BHD are described in Section 6. Future avenues of research are considered in Section 7.

Recent BHD reviews include those from Hasumi et al., 2015 which focuses on clinical features, management and molecular aspects, and Schmidt & Lineham 2015 which covers the clinical features, genetics and potential therapies for BHD.