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Guiding the future of clinical care and clinical research in Birt-Hogg-Dubé

European Journal of Human Genetics volume 32, pages 1522–1523 (2024)Cite this article

The Original Article was published on 31 July 2024

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in the Folliculin gene (FLCN). The Folliculin (FLCN) protein forms a complex with the folliculin interacting proteins 1 and 2 (FNIP1, FNIP2) and functions in multiple signaling and metabolic pathways such as AMPK-mediated energy sensing and mTORC1-dependent cell proliferation. BHD is associated with benign skin tumors (~90% penetrance by age 70 years), renal cell carcinoma (RCC, penetrance of 15–30%), and cystic lung disease (24–48% penetrance). The lung cysts can rupture spontaneously, leading to pneumothorax (median age at first pneumothorax is 34 years with a range from 7 to 78 yrs) [1]. It is estimated that 10% of individuals with pneumothorax have an underlying genetic syndrome with BHD having the highest prevalence. The RCC in BHD can have distinctive features, including chromophobe-oncocytic morphology [2].

Geilswijk et al. [3] have developed an international consensus clinical practice guidelines for the diagnosis, surveillance, and management of individuals with BHD. These guidelines are much-needed, especially since recent data from a population-based health care setting indicates an incidence of loss-of-function FLCN mutation, about 60-fold higher than prior estimates. Accurate diagnosis is often challenging: the skin manifestations can be subtle and difficult to diagnose, and age-dependent penetrance might not be evident until later adulthood, after a pneumothorax or renal tumor has developed.

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References

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Authors and Affiliations

  1. Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Michel Alchoueiry & Elizabeth P. Henske

  2. Departments of Dermatology and Pathology, Immunology, and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ, USA

    W. Clark Lambert

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  1. Michel Alchoueiry
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  2. W. Clark Lambert
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  3. Elizabeth P. Henske
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MA, WCL, and EPH wrote the manuscript.

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Correspondence to Elizabeth P. Henske.

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The authors declare no competing interests.

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Alchoueiry, M., Lambert, W.C. & Henske, E.P. Guiding the future of clinical care and clinical research in Birt-Hogg-Dubé. Eur J Hum Genet 32, 1522–1523 (2024). https://doi.org/10.1038/s41431-024-01696-7

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