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J Med Genet 45:321-331 doi:10.1136/jmg.2007.054304
  • Original article

BHD mutations, clinical and molecular genetic investigations of Birt–Hogg–Dubé syndrome: a new series of 50 families and a review of published reports

Open Access
  1. J R Toro1,
  2. M-H Wei1,2,
  3. G M Glenn1,
  4. M Weinreich1,
  5. O Toure1,
  6. C Vocke3,
  7. M Turner4,
  8. P Choyke5,
  9. M J Merino6,
  10. P A Pinto3,
  11. S M Steinberg7,
  12. L S Schmidt2,3,
  13. W M Linehan3
  1. 1
    Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
  2. 2
    Basic Research Program, SAIC–Frederick Inc, Frederick, Maryland, USA
  3. 3
    Urologic Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
  4. 4
    Dermatology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
  5. 5
    Molecular Imaging Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
  6. 6
    Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
  7. 7
    Biostatistics and Data Management Section, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
  1. Dr J R Toro, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Room 7012, Rockville, MD 20892-7231, USA; torojo{at}mail.nih.gov
  • Received 6 September 2007
  • Revised 20 December 2007
  • Accepted 21 December 2007
  • Published Online First 30 January 2008

Abstract

Background: Birt–Hogg–Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations.

Objective: To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS.

Methods: Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences.

Results: The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with BHD germline mutation is discussed.

Conclusion: BHDS is characterised by a spectrum of mutations, and clinical heterogeneity both among and within families.

Footnotes

  • Competing interests: None declared.

  • Funding: This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the Division of Cancer Epidemiology and Genetics. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400. 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 organisations imply endorsement by the US government.

  • Patient consent: Informed consent was obtained from the patients and family members for publication of this report.