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  • Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer

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Original article
Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer
  1. M-H Wei1,
  2. O Toure1,
  3. G M Glenn1,
  4. M Pithukpakorn1,
  5. L Neckers2,
  6. C Stolle3,
  7. P Choyke4,
  8. R Grubb2,
  9. L Middelton2,
  10. M L Turner5,
  11. M M Walther2,
  12. M J Merino6,
  13. B Zbar7,
  14. W M Linehan2,
  15. J R Toro1
  1. 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA
  2. 2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894, USA
  3. 3Molecular Genetics Laboratory, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
  4. 4NCI Molecular Imaging Program, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA
  5. 5Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
  6. 6Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894, USA
  7. 7Laboratory of Immunobiology, National Cancer Institute Frederick, Frederick, MD 21702, USA
  1. Correspondence to:
 Dr Jorge 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; toroj{at}mail.nih.gov

Abstract

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839) is the predisposition to develop smooth muscle tumours of the skin and uterus and/or renal cancer and is associated with mutations in the fumarate hydratase gene (FH). Here we characterise the clinical and genetic features of 21 new families and present the first report of two African-American families with HLRCC.

Methods: Using direct sequencing analysis we identified FH germline mutations in 100% (21/21) of new families with HLRCC.

Results: We identified 14 germline FH mutations (10 missense, one insertion, two nonsense, and one splice site) located along the entire length of the coding region. Nine of these were novel, with six missense (L89S, R117G, R190C, A342D, S376P, Q396P), one nonsense (S102X), one insertion (111insA), and one splice site (138+1G>C) mutation. Four unrelated families had the R58X mutation and five unrelated families the R190H mutation. Of families with HLRCC, 62% (13/21) had renal cancer and 76% (16/21) cutaneous leiomyomas. Of women FH mutation carriers from 16 families, 100% (22/22) had uterine fibroids. Our study shows that expression of cutaneous manifestations in HLRCC ranges from absent to mild to severe cutaneous leiomyomas. FH mutations were associated with a spectrum of renal tumours. No genotype-phenotype correlations were identified.

Conclusions: In combination with our previous report, we identify 31 different germline FH mutations in 56 families with HLRCC (20 missense, eight frameshifts, two nonsense, and one splice site). Our FH mutation detection rate is 93% (52/56) in families suspected of HLRCC.

  • CDC, collecting duct carcinoma
  • FHD, fumarate hydratase deficiency
  • HIF, hypoxia inducible factor
  • HLRCC, hereditary leiomyomatosis and renal cell cancer
  • NCI, National Cancer Institute
  • SDH, succinate dehydrogenase
  • VEGF, vascular endothelial growth factor
  • VHL, von Hippel-Lindau
  • WT, wildtype
  • fumarate hydratase
  • germline mutations
  • HLRCC
  • leiomyomas
  • renal cancer

https://doi.org/10.1136/jmg.2005.033506

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    Footnotes

    • Published Online First 10 June 2005

    • This publication has been funded in whole or in part with federal funds from the National Cancer Institute

    • Competing interests: none declared

    • 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 U.S. Government

      Family members who participated in this study gave written informed consent