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  • Review Article
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Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

Nature Reviews Urology volume 12, pages 558–569 (2015)Cite this article

Subjects

Key Points

  • Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant inherited renal cancer disorder that predisposes at-risk individuals to benign, cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothoraces and increased risk of renal neoplasia

  • Renal tumours that develop in the setting of BHD syndrome are most often bilateral, multifocal hybrid oncocytic tumours and chromophobe renal cell carcinomas, but patients can present with other histologies

  • Germline mutations in FLCN, predicted to prematurely truncate the protein, predispose to BHD syndrome; renal tumours show somatic inactivation or loss of the remaining FLCN allele, confirming a tumour suppressor function

  • FLCN interacts with the novel proteins FNIP1 and FNIP2, as well as AMPK, a negative regulator of mTOR, and acts to modulate the AKT–TOR pathway

  • Other pathways in which FLCN might have a role include regulation of TFE3 and TFEB transcriptional activity, amino-acid-dependent mTOR activation through Rag GTPases, TGFβ signalling, PGC1α-driven mitochondrial biogenesis, and autophagy

  • Surgery is currently the only available therapy for BHD-associated renal tumours, but elucidation of FLCN-interacting pathways, deregulated in FLCN-deficient renal cancer, will hopefully enable the development of effective targeted therapies

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.

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Figure 1: Cutaneous and pulmonary manifestations of Birt–Hogg–Dubé (BHD) syndrome.
Figure 2: Renal manifestations of Birt–Hogg–Dubé (BHD) syndrome.
Figure 3: Birt–Hogg–Dubé (BHD) renal tumour histology.
Figure 4: Phenotypic heterogeneity in a family affected with Birt–Hogg–Dubé (BHD) syndrome.
Figure 5: Germline FLCN mutations responsible for Birt–Hogg–Dubé (BHD) syndrome.
Figure 6: Somatic second hit FLCN mutations in multiple renal tumours from a Birt–Hogg–Dubé (BHD)-affected patient with a germline FLCN mutation.
Figure 7: FLCN-interacting proteins and associated pathways that might contribute to renal tumorigenesis under FLCN deficiency.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Centre 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 (L.S.S.). 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. L.S.S. is an employee of Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.

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  1. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, CRC Room 15940, Bethesda, 20892-1107, MD, USA

    Laura S. Schmidt & W. Marston Linehan

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  1. Laura S. Schmidt
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  2. W. Marston Linehan
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Both authors contributed to researching data for article and made substantial contributions to discussion of content, as well as writing and review/editing of the manuscript before submission.

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Correspondence to Laura S. Schmidt.

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Schmidt, L., Linehan, W. Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome. Nat Rev Urol 12, 558–569 (2015). https://doi.org/10.1038/nrurol.2015.206

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