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Systematic review
Update of penetrance estimates in Birt-Hogg-Dubé syndrome
  1. Fiona Jane Bruinsma1,2,
  2. James G Dowty3,
  3. Aung Ko Win2,
  4. Laura C Goddard1,
  5. Prachi Agrawal4,
  6. Domenico Attina'5,
  7. Nabil Bissada6,
  8. Monica De Luise7,
  9. Daniel B Eisen8,
  10. Mitsuko Furuya9,10,
  11. Giuseppe Gasparre7,
  12. Maurizio Genuardi11,12,
  13. Anne-Marie Gerdes13,
  14. Thomas Van Overeem Hansen13,14,
  15. Arjan C Houweling15,
  16. Paul Christiaan Johannesma16,
  17. André Lencastre17,
  18. Derek Lim18,
  19. Noralane M Lindor19,
  20. Valentina Luzzi20,
  21. Maeve Lynch21,
  22. Antonella Maffé22,
  23. Fred H Menko23,
  24. Guido Michels24,
  25. Jose S Pulido25,26,
  26. Jay H Ryu25,
  27. Elke C Sattler27,
  28. Ortrud K Steinlein28,
  29. Sara Tomassetti29,
  30. Kathy Tucker30,31,
  31. Daniela Turchetti7,
  32. Irma van de Beek32,
  33. Lore van Riel32,
  34. Maurice van Steensel33,
  35. Thierry Zenone34,
  36. Maurizo Zompatori35,
  37. Jennifer Walsh36,
  38. Davide Bondavalli1,
  39. Eamonn R Maher37,38,
  40. Ingrid M Winship39,
  41. Genetic Susceptibility Working Group I-CONFIRM40
  1. 1 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  2. 2 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, Victoria, Australia
  3. 3 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Victoria, Australia
  4. 4 Department of Radiology, University of Michigan Michigan Medicine, Ann Arbor, Michigan, USA
  5. 5 Department of Radiology, Azienda Ospedaliero-Universitaria di Bologna IRCCS, Bologna, Italy
  6. 6 Department of Urology, Baylor College of Medicine, Houston, Texas, USA
  7. 7 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
  8. 8 Department of Dermatology, University of California Davis, Davis, California, USA
  9. 9 Pathology Centre, Genetic Lab Co., Ltd, Sapporo, Japan
  10. 10 BHD-Net Japan, Hokkaido, Japan
  11. 11 Department of Life Sciences and Public Health, Universita' Cattolica di Sacro Cuore, Roma, Italy
  12. 12 Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
  13. 13 Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  14. 14 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Kobenhavn, Denmark
  15. 15 Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
  16. 16 Department of Pulmonary Disease, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
  17. 17 Servico de Dermatologia, Hospital de Santo Antonio dos Capuchos, Lisboa, Portugal
  18. 18 Clinical Genetic Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
  19. 19 Mayo Clinic, Phoenix, Arizona, USA
  20. 20 Department of Experimental and Clinical Medicine, Interventional Pulmonology Unit, Careggi University Hospital, Florence, Italy
  21. 21 St Vincent's University Hospital, Dublin, Ireland
  22. 22 SS Genetica e Biologia Molecolare ASO.S, Cuneo, Italy
  23. 23 Family Cancer Clinic, Antoni van Leeuwenhoek Hospital, the Netherlands Cancer Institute, Amsterdam, Netherlands
  24. 24 Department of Acute and Emergency Care, St Antonius Hospital Eschweiler, Eschweiler, Germany
  25. 25 Mayo Clinic, Rochester, Minnesota, USA
  26. 26 Department of Translational Ophthalmology, Wills Eye Hospital, Philadelphia, Pennsylvania, USA
  27. 27 Department of Dermatology and Alleregy, LMU Munich, Munich, Germany
  28. 28 Department of Genetics, University Hospital, LMU Munich, Munich, Germany
  29. 29 Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy
  30. 30 Hereditary Cancer Centre, Prince of Wales Hospital, Sydney, New South Wales, Australia
  31. 31 Division of Medicine, University of New South Wales, Sydney, New South Wales, Australia
  32. 32 Department of Human Genetics, Amsterdam UCM, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
  33. 33 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
  34. 34 Department of Internal Medicine, Centre Hospitalier de Valence, Valence, France
  35. 35 IRCCS Multimedica Group, San Giuseppe Hospital, Milan, Italy
  36. 36 Centre of Research Excellence in Pulmonary Fibrosis, The University of Sydney, Sydney, New South Wales, Australia
  37. 37 Birmingham Women's and Children's NHS Foundation Trust, Clinical Genetics Unit, West Midlands Regional Genetics Services, Birmingham, UK
  38. 38 Department of Medical Genetics, University of Cambridge, Cambridge, UK
  39. 39 Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
  40. 40 Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA
  1. Correspondence to Dr Fiona Jane Bruinsma, Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; fiona.bruinsma{at}cancervic.org.au

Abstract

Background Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series.

Methods A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN. Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants.

Results Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers.

Conclusions These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

  • Gene Expression
  • Genetic Predisposition to Disease
  • Genetic Research
  • Human Genetics

Data availability statement

Data are available upon reasonable request. Data are available upon reasonable request and with permission from the relevant authors.

https://doi.org/10.1136/jmg-2022-109104

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    Data availability statement

    Data are available upon reasonable request. Data are available upon reasonable request and with permission from the relevant authors.

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    Footnotes

    • Correction notice The article has been corrected since it was published online first (author's name).

    • Collaborators Gianluca Severi, Ingrid Winship, Fiona Bruinsma, Eamonn Maher, Tracy Dudding, Kathy Tucker, Todd Edwards, Min-Han Tan, Stephen Chanock, Marsten Linehan, Mark Jenkins, Maurice van Steensel and Ian Tomlinson.

    • Contributors FJB is the guarantor for the study, accepting full responsibility for the conduct of the study, had access to the data and controlled the decision to publish. FJB and IMW were responsible for the design and conduct of the study. The I-CONFIRM genetic susceptibility working group and KT provided advice on the design of the study and clinical context. DB, JW and LCG undertook data extraction, assisted in the analysis and in the writing of the manuscript. JGD and AKW undertook the analysis and assisted with the writing of the manuscript. ERM provided the data, advised on the design and clinical aspects of the study and in writing the manuscript. PA, DA, NB, MDL, DBE, MF, GG, MG, A-MG, TVOH, ACH, PCJ, AL, DL, NML, VL, ML, AM, FHM, GM, JSP, RHJ, ECS, OKS, ST, DT, IvdB, LvR, MvS, TZ and MZ provided data and assisted with the interpretation of the findings and writing of the manuscript.

    • Funding This work was supported by Cancer Council Victoria via salary support for FJB. ERM acknowledges support from the National Institute for Health Research (NIHR) (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre, BRC-1215–20014). The University of Cambridge received salary support in respect of ERM from the NHS in the East of England through the Clinical Academic Reserve.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.