The Birt-Hogg-Dubé Syndrome

ABSTRACT

• The phenotypic features of the Birt-Hogg-Dubé syndrome (BHD) (OMIM#135150) are benign tumors of the hair follicle (fibrofolliculomas), spontaneous pneumothorax, and an increased risk for developing renal tumors. The BHD syndrome is inherited in an autosomal dominant pattern. Fibrofolliculomas are pilar hamartomas characterized by proliferation of both epithelial and fibrous tissue.

• BHD patients are predisposed to develop renal carcinomas. Renal tumors may be solitary or multiple and bilateral. All histologic types of renal carcinoma occur in BHD patients. The most common type found in association with the BHD syndrome is a hybrid oncocytic tumor with features of both renal oncocytoma and chromophobe renal carcinoma.

• BHD is caused by germline mutations in the FLCN gene, located at chromosome 17p11.2. FLCN encodes a novel protein, folliculin, that has no characteristic domains to suggest function but is conserved across species. FLCN is widely expressed in multiple tissues, and alternative transcripts have been reported.

• The majority of germline mutations in the FLCN gene are frameshift, nonsense or splice site mutations that are predicted to truncate the protein. The most frequent mutation is a cytosine insertion or deletion in a hypermutable C₈ tract within exon 11 of the FLCN gene.

• Loss or mutational inactivation of the wild type copy of FLCN in BHD-associated renal tumors, and loss of tumorigenic properties of a FLCN-null renal tumor cell line upon FLCN re-expression support a tumor suppressor role for FLCN.

• Although the mechanism by which FLCN inactivation leads to BHD syndrome remains unclear, research findings with FLCN-deficient in vitro and in vivo models suggest that FLCN may be involved in modulating mTOR signaling and potentially in other pathways as well.

• Genetic testing for FLCN should include DNA sequencing, and in those patients for whom DNA sequencing is mutation-negative, the multiple ligation-dependent probe amplification assay (MLPA) or real-time quantitative PCR (RQ-PCR) methods to detect large intragenic deletions or duplications. Annual or biannual surveillance by abdominal MRI or CT screening is recommended for at-risk BHD family members for early detection and management of kidney tumors.

INTRODUCTION

The Birt-Hogg-Dubé(BHD) syndrome (OMIM#135150) is named for three Canadian physicians, Arthur Birt, Georgina Hogg, and James Dubé, who in 1977 described a large Canadian family with this disorder (Birt et al,⁷). The major hallmarks of BHD are benign tumors of the hair follicle (fibrofolliculomas), spontaneous pneumothorax, and a unique histologic type of renal cancer.

Germline mutations in a novel gene, FLCN, located at chromosome 17p11.2 have been identified in affected individuals from families with BHD. The role of FLCN in developmental pathways of skin, lung, and kidney remains unclear, and functional analyses are underway to determine how mutations in FLCN lead to dysregulated cell growth, cutaneous hamartomas and kidney tumors.

CLINICAL MANIFESTATIONS OF BIRT-HOGG-DUBÉ SYNDROME

Fibrofolliculomas, Trichodiscomas, and Acrochordons: Cutaneous Manifestations of the Birt-Hogg-Dubé Syndrome

Fibrofolliculomas ...