Clinical features, genetics and potential therapeutic approaches for Birt–Hogg–Dubé syndrome

Abstract

Introduction: Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant disorder that predisposes to fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal neoplasia. BHD is characterized by germline mutations in the tumor suppressor gene folliculin (FLCN) gene. Inactivation of the remaining FLCN allele in kidney cells drives tumorigenesis. Novel FLCN-interacting proteins, FNIP1 and FNIP2, were identified. Studies with FLCN-deficient in vitro and in vivo models support a role for FLCN in modulating AKT-mechanistic target of rapamycin (mTOR) signaling. Emerging evidence suggests that FLCN may interact in a number of pathways/processes. Identification of FLCN’s major functional roles will provide the basis for developing targeted therapies for BHD patients.

Areas covered: This review covers BHD diagnostic criteria, clinical manifestations and genetics, as well as molecular consequences of FLCN inactivation. Recommended surveillance practices, patient management and potential therapeutic options are discussed.

Expert opinion: In the decade since FLCN was identified as causative for BHD, we have gained a greater understanding of the clinical spectrum and genetics of this cancer syndrome. Recent studies have identified interactions between FLCN and a variety of signaling pathways and cellular processes, notably AKT-mTOR. Currently, surgical intervention is the only available therapy for BHD-associated renal tumors. Effective therapies will need to target primary pathways/processes deregulated in FLCN-deficient renal tumors and fibrofolliculomas.

Keywords:

• BHD
• chromophobe renal cancer
• fibrofolliculoma
• FLCN
• inherited renal cancer syndrome
• mTOR
• rapamycin
• tumor suppressor

Declaration of interest

The authors declare no conflict of interest. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under Contract HHSN261200800001E (LSS). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsements by the US government.

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