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Previous Volume 331:828-835 September 29, 1994 Number 13 Next

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ABSTRACT

Background Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene.

Methods Starting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene.

Results Of 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia.

Conclusions Unlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers.

Source Information

From the Departments of Internal Medicine (C.J.M.L., R.M.L., J.W.M.H., R.A.G., G.B., J.M.J.-S.V., M.J.W., R.A.Z.), Radiology (A.P.G.G.), Surgery (T.J.M.V.V.), and Pathology (R.M.L., J.W.M.H., M.J.W., R.A.Z., T.M.V.), University Hospital Utrecht, Utrecht; the Department of Pathology, Westeinde Hospital, The Hague (M.J.H.B.); and the Clinical Genetics Center, Utrecht (F.A.B., J.B.-S., R.P.M.J., H.K.P.A.) -- all in the Netherlands.

Address reprint requests to Dr. Lips at the Department of Internal Medicine, University Hospital Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.

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• Ahmed, S. A., Snow-Bailey, K., Highsmith, W. E., Sun, W., Fenwick, R. G., Mao, R. (2005). Nine Novel Germline Gene Variants in the RET Proto-Oncogene Identified in Twelve Unrelated Cases. J. Mol. Diagn. 7: 283-288 [Abstract] [Full Text]  
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• Smith, V V, Eng, C, Milla, P J (1999). Intestinal ganglioneuromatosis and multiple endocrine neoplasia type 2B: implications for treatment. Gut 45: 143-146 [Abstract] [Full Text]  
• Eng, C. (1999). RET Proto-Oncogene in the Development of Human Cancer. JCO 17: 380-380 [Abstract] [Full Text]  
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• Eng, C. (1996). The RET Proto-Oncogene in Multiple Endocrine Neoplasia Type 2 and Hirschsprung's Disease. NEJM 335: 943-951 [Full Text]  
• Neumann, H. P. H., Eng, C., Mulligan, L. M., Glavac, D., Zauner, I., Ponder, B. A. J., Crossey, P. A., Maher, E. R., Brauch, H. (1995). Consequences of Direct Genetic Testing for Germline Mutations in the Clinical Management of Families With Multiple Endocrine Neoplasia, Type II. JAMA 274: 1149-1151 [Abstract]  
• Utiger, R. D. (1994). Medullary Thyroid Carcinoma, Genes, and the Prevention of Cancer. NEJM 331: 870-871 [Full Text]