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Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma
  1. Betty Gardie1,
  2. Audrey Remenieras2,
  3. Darouna Kattygnarath2,
  4. Johny Bombled2,
  5. Sandrine Lefèvre1,
  6. Victoria Perrier-Trudova1,
  7. Pierre Rustin3,
  8. Michel Barrois2,
  9. Abdelhamid Slama4,
  10. Marie-Françoise Avril5,6,
  11. Didier Bessis7,
  12. Olivier Caron8,
  13. Frédéric Caux9,
  14. Patrick Collignon10,
  15. Isabelle Coupier6,11,
  16. Carol Cremin12,
  17. Hélène Dollfus6,13,
  18. Catherine Dugast14,
  19. Bernard Escudier6,15,
  20. Laurence Faivre16,
  21. Michel Field17,
  22. Brigitte Gilbert-Dussardier6,18,
  23. Nicolas Janin19,
  24. Yves Leport20,
  25. Dominique Leroux21,
  26. Dan Lipsker22,
  27. Félicia Malthieu23,
  28. Barbara McGilliwray12,
  29. Christine Maugard24,
  30. Arnaud Méjean6,25,
  31. Isabelle Mortemousque26,
  32. Ghislaine Plessis27,
  33. Bruce Poppe28,
  34. Christelle Pruvost-Balland29,
  35. Serena Rooker30,
  36. Joelle Roume31,
  37. Nadem Soufir32,
  38. Michelle Steinraths33,
  39. Min-Han Tan34,
  40. Christine Théodore35,
  41. Luc Thomas36,
  42. Pierre Vabres37,
  43. Emmanuel Van Glabeke38,
  44. Jean-Baptiste Meric39,
  45. Virginie Verkarre6,40,
  46. Gilbert Lenoir2,
  47. Virginie Joulin41,
  48. Sophie Deveaux6,
  49. Veronica Cusin2,6,
  50. Jean Feunteun41,
  51. Bin Tean Teh42,
  52. Brigitte Bressac-de Paillerets2,
  53. Stéphane Richard1,6 on behalf of the French National Cancer Institute “Inherited predisposition to kidney cancer” network
  1. 1Génétique Oncologique EPHE, INSERM U753, Institut de cancérologie Gustave Roussy Villejuif; and Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
  2. 2Service de Génétique, Institut de cancérologie Gustave Roussy, Villejuif, France
  3. 3INSERM, U676, Paris, and Université Paris 7, Faculté de médecine Denis Diderot, IFR02, Paris, France
  4. 4Laboratoire de Biochimie, Hôpital de Bicêtre, AP-HP, Le Kremlin-Bicêtre, France
  5. 5Service de Dermatologie, Hôpital Cochin, AP-HP, Paris, France
  6. 6Centre Expert National Cancer Rares “PREDIR”, Institut National du Cancer (INCa), Service d'Urologie, Hôpital de Bicêtre, AP-HP, Le Kremlin- Bicêtre, France
  7. 7Service de Dermatologie, Hôpital Saint-Eloi, Montpellier, France
  8. 8Consultation d'Oncogénétique, Institut de cancérologie Gustave Roussy, Villejuif, France
  9. 9Service de Dermatologie, Hôpital Avicenne, AP-HP, Bobigny, France
  10. 10Service de Génétique Médicale, Centre Hospitalier Intercommunal, Toulon, France
  11. 11Service d'Oncogénétique et Génétique Médicale, Hôpital A. de Villeneuve, Montpellier, France
  12. 12BC Cancer Agency, Vancouver, Canada
  13. 13Service de Génétique Médicale, Hôpital Civil, Strasbourg, France
  14. 14Consultation d'Oncogénétique, CHU, Rennes, France
  15. 15Département d'Immunothérapie, Institut de cancérologie Gustave Roussy, Villejuif, France
  16. 16Centre de Génétique, CHU Hôpital d'Enfants, Dijon, France
  17. 17Genetic Services, Royal North Shore Hospital, St Leonards, Australia
  18. 18Service de Génétique, CHU, Poitiers, France
  19. 19Département de Génétique, CHU, Liège, Belgique
  20. 20Cabinet de Dermatologie, Vire, France
  21. 21Service de Génétique Médicale, CHU Michalon, Grenoble, France
  22. 22Service de Dermatologie, Hôpital Civil, Strasbourg, France
  23. 23Centre médico-chirurgical Atlantique, Puilboreau, France
  24. 24Laboratoire de diagnostic génétique, Hôpital Universitaire de Strasbourg, Strasbourg, France; and CR-CHUM, Université de Montréal, Montréal (QC), Canada
  25. 25Service d'Urologie, Hôpital Necker, AP-HP, Paris, France
  26. 26Service de Génétique Médicale, Hôpital Bretonneau, Tours, France
  27. 27Service de Génétique, CHU Clémenceau, Caen, France
  28. 28Center for Medical Genetics, Universiteit Gent, Gand, Belgique
  29. 29Service de Dermatologie, Hôpital Saint Louis, AP-HP, Paris, France
  30. 30Molecular Genetics Laboratory, Capital Coasts DHB, Wellington South, New Zealand
  31. 31Consultation de Génétique Médicale, Hôpital Ambroise Paré, AP-HP, Boulogne, France
  32. 32Consultation de Génétique, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
  33. 33Division of Medical Genetics, Victoria General Hospital, Victoria, BC, Canada
  34. 34Department of Medical Oncology, National Cancer Centre, Singapore
  35. 35Service d'Oncologie Médicale, Hôpital Foch, Suresnes, France
  36. 36Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon, France
  37. 37Service de Dermatologie, Hôpital du Bocage, CHU, Dijon, France
  38. 38Service d'Urologie, Hôpital André Grégoire, Montreuil, France
  39. 39Service d'Onco-Hématologie, Centre Médical de Bligny, Briis sous Forges, France
  40. 40Laboratoire d'Anatomie Pathologique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  41. 41Stabilité génétique et oncogénèse, CNRS UMR 8200, Institut de cancérologie Gustave Roussy, Villejuif, France
  42. 42Van Andel Research Institute, Grand Rapids, Michigan, USA
  1. Correspondence to Professor Stéphane Richard, Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, 63 avenue du Général Leclerc, 94276 Le Kremlin-Bicêtre, France; stephane.richard{at}


Background Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene.

Methods As part of the French National Cancer Institute (INCa) ‘Inherited predispositions to kidney cancer’ network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic).

Results The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations.

Conclusions This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

  • Leiomyomatosis
  • FH
  • papillary renal cell cancer type II
  • genetics
  • molecular genetics
  • cancer
  • urological

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  • Funding This work was supported by grants from the French National Cancer Institute (‘INCa’, PNES Rein; and Réseau National Prédispositions héréditaires au cancer du rein), the French Ligue Nationale contre le Cancer (Comités du Cher, de l'Indre et de l'Allier), and the Association de Recherches contre le Cancer (ARC).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the CCPPRB (Ethical Committee), Le Kremlin-Bicêtre, France.

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

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