Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome

Abstract

Birt-Hogg-Dubé (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk of developing benign cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumours. Bilateral multifocal renal tumours that develop in BHD syndrome are most frequently hybrid oncocytic tumours and chromophobe renal carcinoma, but can present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome--BHD-associated renal tumours display inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumour suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3 and/or TFEB transcriptional activity, amino-acid-dependent mTOR activation through Rag GTPases, TGFβ signalling, PGC1α-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumours, but improved understanding of the FLCN pathway will hopefully lead to the development of effective forms of targeted systemic therapy for this disease.

Figure 1. Cutaneous and pulmonary manifestations of Birt-Hogg-Dubé syndrome

(A) Multiple fibrofolliculomas on the face of a BHD patient (arrow). (B) H&E staining of a fibrofolliculoma showing strands of epithelial cells surrounded by fibrous stroma (arrow) with adjacent hair follicle (left). (4X). (C, D) Chest CT scans of BHD patients showing bilateral multiple pulmonary cysts of various sizes. (Panel A and B images are provided courtesy of Dr. Mary Eid and Dr. Edward Cowen, Dermatology Branch, National Cancer Institute, NIH).

Figure 2. Renal manifestations of Birt-Hogg-Dubé syndrome

Abdominal coronal CT scans of BHD renal tumors (A,D) demonstrating bilateral multifocal tumors in BHD patients. Axial CT scans demonstrating multifocal bilateral tumor presentation (B,C).

Figure 3. BHD renal tumor histology

A) Hybrid oncocytic tumor (150x). (B) Chromophobe renal tumor with characteristic perinuclear halos (150X). (C) Clear cell renal tumor. (D) Renal oncocytoma in a BHD patient (150x). (E) Renal oncocytosis in normal kidney parenchyma of a BHD patient (100X). (Images are provided courtesy of Dr. Maria J. Merino, Laboratory of Pathology, National Cancer Institute, NIH).

Figure 4. Phenotypic heterogeneity in a family affected with BHD syndrome

A BHD kindred in which affected family members who inherit the same germline mutation present with different phenotypes. Blue= fibrofolliculoma; red=renal tumor; yellow=pulmonary cysts/pneumothorax. Square, male; circle, female; arrow, proband; mutation carrier, +; N.D., not determined.

Figure 5. Germline FLCN mutations responsible for BHD syndrome

FLCN exon structure showing spectrum of mutation types and their location in all coding exons. FS, frameshift; MS, missense; NS, nonsense; AAΔ, amino acid deletion inframe; pMet1?, proposed deletion of initiator codon; SS, splice site. Blue bar, intragenic deletion; red bar, intragenic duplication. ATG, initiator codon. CpG, putative promoter region. References: sequence variant information from LOVD Gene Homepage for FLCN; ex 5-14 del and ex12-14 del, Houweling et al; ex 1 del, ex 2-5 del, ex 7-14 del and ex 10-11 dup, Benhammou et al.; ex 9-14 del and ex 14, Kunogi et al.; ex 14 del, Sempau et al.

Figure 6. Somatic second hit FLCN mutations in multiple renal tumors from a BHD patient with a germline FLCN mutation

Somatic inactivation of the remaining wild-type FLCN allele by mutation or chromosomal loss drives renal tumorigenesis in BHD syndrome. Multiple tumors in a BHD patient's kidneys have different FLCN second hit mutations. Used with permission from Vocke et al.

Figure 7. FLCN-associated pathways that may contribute to renal tumorigenesis under FLCN deficiency

Arrows indicate activation, T indicates inhibition; where both are indicated the data are conflicting or unclear.