title: Clinical Features, Genetics and Potential Therapeutic Approaches for Birt-Hogg-Dubé Syndrome.
abstract: BACKGROUND
  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 tumor suppressorFLCN. Inactivation of the remainingFLCNallele in kidney cells drives tumorigenesis. Novel FLCN-interacting proteins, FNIP1 and FNIP2, were identified. Studies withFLCN-deficientin vitroandin vivomodels support a role for FLCN in modulating AKT-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.
  
  
  METHODS
  This review covers BHD diagnostic criteria, clinical manifestations and genetics, as well as molecular consequences ofFLCNinactivation. Recommended surveillance practices, patient management, and potential therapeutic options are discussed.
  
  
  CONCLUSIONS
  In the decade sinceFLCNwas 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 inFLCN-deficient renal tumors and fibrofolliculomas.
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702 ; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
keywords: BHD; Birt-Hogg-Dubé syndrome; FLCN; chromophobe renal cancer; fibrofolliculoma; folliculin; inherited renal cancer syndrome; mTOR; rapamycin; tumor suppressor