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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
MeSH Review

Multiple Endocrine Neoplasia Type 2a

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Disease relevance of Multiple Endocrine Neoplasia Type 2a


High impact information on Multiple Endocrine Neoplasia Type 2a

  • Our data show a strong correlation between disease phenotype and the nature and position of the RET mutation, suggesting that a simple, constitutive activation of the RET tyrosine kinase is unlikely to explain the events leading to MEN 2A and FMTC [5].
  • 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 [6].
  • The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only [7].
  • After identification of the mutation, premorbid genetic testing was performed in all MEN-II and VHL families, resulting in detection of asymptomatic carriers in the MEN-II families [8].
  • In four men (2%), increased iron stores was found with a distribution like that in the early stages of hemochromatosis [9].

Chemical compound and disease context of Multiple Endocrine Neoplasia Type 2a

  • To determine the validity of this presumption we have estimated--by applying modifications of the life-table method--the clinical and screening age-at-diagnosis distributions for MEN-2, using families from the Cancer Research Campaign Medullary Thyroid Cancer Register and one large American family [10].
  • In each of five families with HSCR with or without MEN 2A or FMTC, we have identified a nucleotide substitution in one of the five cysteine codons previously associated with MEN 2A or FMTC [11].
  • MEN 2A families with RET exon 10 Cys mutations had a substantially greater risk of developing HSCR1 than those with the more common RET exon 11 Cys634 or exon 14 c804 mutations (P = 0.0005) [12].
  • In addition to the MEN 2A mutations, we further introduced a mutation (lysine for asparaginic acid at codon 300 [D300K]) in a putative Ca(2+)-binding site of the cadherin-like domain [13].
  • MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine [14].

Biological context of Multiple Endocrine Neoplasia Type 2a


Anatomical context of Multiple Endocrine Neoplasia Type 2a


Gene context of Multiple Endocrine Neoplasia Type 2a


Analytical, diagnostic and therapeutic context of Multiple Endocrine Neoplasia Type 2a


  1. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. Eisenhofer, G., Lenders, J.W., Linehan, W.M., Walther, M.M., Goldstein, D.S., Keiser, H.R. N. Engl. J. Med. (1999) [Pubmed]
  2. RET oncogene. Mak, Y.F., Ponder, B.A. Curr. Opin. Genet. Dev. (1996) [Pubmed]
  3. Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. Melillo, R.M., Santoro, M., Ong, S.H., Billaud, M., Fusco, A., Hadari, Y.R., Schlessinger, J., Lax, I. Mol. Cell. Biol. (2001) [Pubmed]
  4. Somatic mutations of the RET proto-oncogene are not required for tumor development in multiple endocrine neoplasia type 2 (MEN 2) gene carriers. Landsvater, R.M., de Wit, M.J., Zewald, R.A., Hofstra, R.M., Buys, C.H., Ploos van Amstel, H.K., Höppener, J.W., Lips, C.J. Cancer Res. (1996) [Pubmed]
  5. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Mulligan, L.M., Eng, C., Healey, C.S., Clayton, D., Kwok, J.B., Gardner, E., Ponder, M.A., Frilling, A., Jackson, C.E., Lehnert, H. Nat. Genet. (1994) [Pubmed]
  6. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. Lips, C.J., Landsvater, R.M., Höppener, J.W., Geerdink, R.A., Blijham, G., van Veen, J.M., van Gils, A.P., de Wit, M.J., Zewald, R.A., Berends, M.J. N. Engl. J. Med. (1994) [Pubmed]
  7. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. Eng, C., Clayton, D., Schuffenecker, I., Lenoir, G., Cote, G., Gagel, R.F., van Amstel, H.K., Lips, C.J., Nishisho, I., Takai, S.I., Marsh, D.J., Robinson, B.G., Frank-Raue, K., Raue, F., Xue, F., Noll, W.W., Romei, C., Pacini, F., Fink, M., Niederle, B., Zedenius, J., Nordenskjöld, M., Komminoth, P., Hendy, G.N., Mulligan, L.M. JAMA (1996) [Pubmed]
  8. Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II. Neumann, H.P., Eng, C., Mulligan, L.M., Glavac, D., Zäuner, I., Ponder, B.A., Crossey, P.A., Maher, E.R., Brauch, H. JAMA (1995) [Pubmed]
  9. Preclinical hemochromatosis in a population on a high-iron-fortified diet. Olsson, K.S., Heedman, P.A., Staugárd, F. JAMA (1978) [Pubmed]
  10. The clinical and screening age-at-onset distribution for the MEN-2 syndrome. Easton, D.F., Ponder, M.A., Cummings, T., Gagel, R.F., Hansen, H.H., Reichlin, S., Tashjian, A.H., Telenius-Berg, M., Ponder, B.A. Am. J. Hum. Genet. (1989) [Pubmed]
  11. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Mulligan, L.M., Eng, C., Attié, T., Lyonnet, S., Marsh, D.J., Hyland, V.J., Robinson, B.G., Frilling, A., Verellen-Dumoulin, C., Safar, A. Hum. Mol. Genet. (1994) [Pubmed]
  12. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Decker, R.A., Peacock, M.L., Watson, P. Hum. Mol. Genet. (1998) [Pubmed]
  13. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Asai, N., Iwashita, T., Matsuyama, M., Takahashi, M. Mol. Cell. Biol. (1995) [Pubmed]
  14. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. Eisenhofer, G., Walther, M.M., Huynh, T.T., Li, S.T., Bornstein, S.R., Vortmeyer, A., Mannelli, M., Goldstein, D.S., Linehan, W.M., Lenders, J.W., Pacak, K. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  15. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Hofstra, R.M., Landsvater, R.M., Ceccherini, I., Stulp, R.P., Stelwagen, T., Luo, Y., Pasini, B., Höppener, J.W., van Amstel, H.K., Romeo, G. Nature (1994) [Pubmed]
  16. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Mulligan, L.M., Kwok, J.B., Healey, C.S., Elsdon, M.J., Eng, C., Gardner, E., Love, D.R., Mole, S.E., Moore, J.K., Papi, L. Nature (1993) [Pubmed]
  17. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Woodward, E.R., Eng, C., McMahon, R., Voutilainen, R., Affara, N.A., Ponder, B.A., Maher, E.R. Hum. Mol. Genet. (1997) [Pubmed]
  18. Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation. Ludwig, L., Kessler, H., Wagner, M., Hoang-Vu, C., Dralle, H., Adler, G., Böhm, B.O., Schmid, R.M. Cancer Res. (2001) [Pubmed]
  19. The gene causing multiple endocrine neoplasia type 2 (MEN 2). Ponder, B.A. Ann. Med. (1994) [Pubmed]
  20. Subtotal adrenalectomy by the posterior retroperitoneoscopic approach. Walz, M.K., Peitgen, K., Saller, B., Giebler, R.M., Lederbogen, S., Nimtz, K., Mann, K., Eigler, F.W. World journal of surgery. (1998) [Pubmed]
  21. Expression analysis of RET and the GDNF/GFRalpha-1 and NTN/GFRalpha-2 ligand complexes in pheochromocytomas and paragangliomas. Edström, E., Frisk, T., Farnebo, F., Höög, A., Bäckdahl, M., Larsson, C. Int. J. Mol. Med. (2000) [Pubmed]
  22. A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2. Vanhorne, J.B., Andrew, S.D., Harrison, K.J., Taylor, S.A., Thomas, B., McDonald, T.J., Ainsworth, P.J., Mulligan, L.M. Oncogene (2005) [Pubmed]
  23. Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. Marx, S.J., Agarwal, S.K., Kester, M.B., Heppner, C., Kim, Y.S., Skarulis, M.C., James, L.A., Goldsmith, P.K., Saggar, S.K., Park, S.Y., Spiegel, A.M., Burns, A.L., Debelenko, L.V., Zhuang, Z., Lubensky, I.A., Liotta, L.A., Emmert-Buck, M.R., Guru, S.C., Manickam, P., Crabtree, J., Erdos, M.R., Collins, F.S., Chandrasekharappa, S.C. Recent Prog. Horm. Res. (1999) [Pubmed]
  24. Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutation. Murakami, H., Iwashita, T., Asai, N., Shimono, Y., Iwata, Y., Kawai, K., Takahashi, M. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  25. New insights into the genetics of familial chromaffin cell tumors. Koch, C.A., Vortmeyer, A.O., Zhuang, Z., Brouwers, F.M., Pacak, K. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  26. Progress toward resolving the possible linkage of multiple endocrine neoplasia type 2A to haptoglobin and group-specific loci: use of restriction fragment length polymorphisms extends exclusion region. Kidd, K.K., Kidd, J.R., Castiglione, C.M., Pakstis, A.J., Sparkes, R.S. Genet. Epidemiol. (1986) [Pubmed]
  27. Direct, non-radioactive detection of mutations in multiple endocrine neoplasia type 2A families. McMahon, R., Mulligan, L.M., Healey, C.S., Payne, S.J., Ponder, M., Ferguson-Smith, M.A., Barton, D.E., Ponder, B.A. Hum. Mol. Genet. (1994) [Pubmed]
  28. Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. Xue, F., Yu, H., Maurer, L.H., Memoli, V.A., Nutile-McMenemy, N., Schuster, M.K., Bowden, D.W., Mao, J., Noll, W.W. Hum. Mol. Genet. (1994) [Pubmed]
  29. Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Kambouris, M., Jackson, C.E., Feldman, G.L. Hum. Mutat. (1996) [Pubmed]
  30. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Herfarth, K.K., Bartsch, D., Doherty, G.M., Wells, S.A., Lairmore, T.C. Surgery (1996) [Pubmed]
  31. A comparison of calcium pentagastrin and TRH tests in screening for medullary carcinoma of the thyroid in MEN IIA. O'Connell, J.E., Dominiczak, A.F., Isles, C.G., McLellan, A.R., Davidson, G., Gray, C.E., Connell, J.M. Clin. Endocrinol. (Oxf) (1990) [Pubmed]
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