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Clinical and genetic studies of Birt-Hogg-Dubé syndrome
  1. S K Khoo1,
  2. S Giraud2,3,
  3. K Kahnoski1,
  4. J Chen1,
  5. O Motorna1,
  6. R Nickolov4,
  7. O Binet5,
  8. D Lambert6,
  9. J Friedel7,
  10. R Lévy8,
  11. S Ferlicot9,
  12. P Wolkenstein10,
  13. P Hammel11,
  14. U Bergerheim12,
  15. M-A Hedblad13,
  16. M Bradley13,14,
  17. B T Teh1,
  18. M Nordenskjöld15,
  19. S Richard2,16
  1. 1Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA
  2. 2Génétique Oncologique EPHE, UPRESS 1602, and Service d’Urologie, CHU Bicêtre, 94276 Le Kremlin Bicêtre, France
  3. 3Laboratoire de Génétique, Hôpital E Herriot, 69437 Lyon Cedex, France
  4. 4Department of Mathematical Sciences, Michigan Technological University, Houghton, MI 49931, USA
  5. 5Service de Dermatologie, Fondation Rothschild, 75018 Paris, France
  6. 6Service de Dermatologie, CHU, 21000 Dijon, France
  7. 7Service de Dermatologie, Centre Hospitalier, 71100 Chalons sur Saône, France
  8. 8Service d’Oncologie, Clinique de l’Orangerie, 94170 Le Perreux sur Marne, France
  9. 9Laboratoire d’Anatomie Pathologique, CHU Bicêtre, 94276 Le Kremlin Bicêtre, France
  10. 10Service de Dermatologie, CHU Henri Mondor, 94000 Créteil, France
  11. 11Service de Gastroentérologie, Hôpital Beaujon, 92000 Clichy, France
  12. 12Department of Urology, Danderyds Hospital, Danderyd, Sweden
  13. 13Department of Dermatology and Venereology, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden
  14. 14Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
  15. 15Departments of Molecular Medicine and Clinical Genetics, Karolinska Hospital, Karolinska Institutet, Stockholm,
  16. 16Service de Néphrologie, Hôpital Necker, Paris, France
  1. Correspondence to:
 Professor S Richard, Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, 94276 Le Kremlin Bicêtre, France;


Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, expressing a novel protein called folliculin. We report the clinical and genetic studies of four sporadic BHD cases and four families with a total of 23 affected subjects. Haplotype analysis of these families using BHD linked markers showed they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified two germline mutations on exon 11 (c.1733insC and c.1733delC) in three of four families as well as two of four sporadic cases. A novel somatic mutation, c.1732delTCinsAC, was detected in a BHD related chromophobe renal carcinoma. Our results confirmed the (C)8 tract in exon 11 as a mutational hot spot in BHD and should always be considered for future genetic testing. Our observation also indicated that the second hit (of Knudson’s two hit theory) in some BHD related tumours is in the form of somatic mutation rather than LOH. In a large French family in which eight affected subjects carry the c.1733delC mutation, a phenocopy who has multiple episodes of spontaneous pneumothorax was identified. A total of five mutation carriers (aged between 37 to 66) did not have any evidence of BHD features, suggesting either reduced penetrance or late age of onset of the disease. In addition, six out of eight affected subjects who have positive germline mutation have confirmed neoplastic colonic polyps, indicating that colorectal neoplasia is an associated feature of BHD in some families. Our studies have observed several interesting genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset of disease; (4) association with colorectal neoplasia in some families; and (5) somatic mutation instead of LOH as the second hit in BHD tumours.

  • skin tumours
  • colorectal neoplasia
  • BHD hot spot mutation
  • Birt-Hogg-Dubé syndrome

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