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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 487-491
Copyright © 1998 by The Endocrine Society

Original Studies

Risk and Penetrance of Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A Families with Mutations at Codon 634 of the RET Proto-Oncogene1

Isabelle Schuffenecker2, Marie Virally-Monod, Richard Brohet, David Goldgar, Bernard Conte-Devolx, Laurence Leclerc, Olivier Chabre, Andree Boneu, Jean Caron, Chantal Houdent, Elisabeth Modigliani, Vincent Rohmer, Martin Schlumberger, Charis Eng3, Pierre Jean Guillausseau, Gilbert Marcel Lenoir and le groupe d’etude des tumeurs à calcitonine4

Laboratoire de Génétique, Hôpital Edouard Herriot, and CNRS UMR 5641, Université Claude Bernard (I.S., G.M.L.), Lyon, France; Service de Médecine Interne (M.V-M., P.J.G.), Hôpital Lariboisière, Paris, France; Unité d’Epidémiologie Génétique (R.B, D.G.), Centre International de Recherche sur le Cancer, Lyon, France; Service d’Endocrinologie (B.C.D), Centre Hospitalier Universitaire de Marseille, France; Service d’Endocrinologie (L.L.), Centre Hospitalier Universitaire de Lille, France; Service d’Endocrinologie (O.C.), Centre Hospitalier Universitaire de Grenoble, France; Service de Médecine Nucléaire (A.B.), Centre Claudius Régaud, Toulouse, France; Service de Médecine Interne (J.C.), Centre Hospitalier Universitaire de Reims, France; Service d’Endocrinologie (C.H.), Centre Hospitalier Universitaire de Rouen, France; Service d’Endocrinologie (E.M.), Hôpital Avicenne, Bobigny, France; Service de Médecine Interne (V.R.), Centre Hospitalier Universitaire d’Angers, France; Service de Médecine Nucléaire (M.S.), Institut Gustave Roussy, Paris, France; and Department of Adult Oncology (C.E.), Human Cancer Genetics Unit, Dana-Farber Institute, Harvard Medical School, Boston, Massachusetts; Service d’Endocrinologie, Centre Hospitalier Universitaire de Marseille, Marseille, France

Address all correspondence and requests for reprints to: Gilbert M. Lenoir, CNRS UMR 5641, Université Cloude Bernard, 8 avenue Rockefeller, 69373, Lyon cedex 08, France.

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.




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