Abstract
BACKGROUND AND OBJECTIVE: Multiple Endocrine Neoplasia type 2 (MEN2) is a rare genetic disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism. MEN2 is an autosomal dominant syndrome caused by mutations in the RET proto-oncogene. In the vast majority of patients, the mutations are localized in exons 10, 11 and 13–15 of the RET gene. Rare variants located in exon 8 were recently identified but their clinical significance remains unclear. DESIGN AND METHODS: We studied two sisters presenting with pheochromocytoma as the first tumor. One of the sisters was diagnosed with a right pheochromocytoma at the age of 44 and at age 53 she developed an invasive left pheochromocytoma with no other endocrine neoplasia. The other sister was diagnosed with a left pheochromocytoma at age 50 and at age 64 she had a right phemochromocytoma and MTC. Neither of the two sisters presented evidence of primary hyperparathyroidism. Mutations of the RET proto-oncogene were investigated by DNA sequencing. RESULTS: We detected a germline missense variant in RET exon 8 (p.Cys531Arg) in both sisters. The p.Cys531Arg variant was not present in a third 50-year-old sister who has remained to date clinically unaffected. CONCLUSION: This is the first case showing the p.Cys531Arg variant in RET exon 8 co-segregating with family members affected by a syndrome reminiscent of MEN2A. Our results suggest that this variant has a specific genotype-phenotype correlation as it is associated with the development of pheochromocytoma before the onset of MTC.
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Krampitz GW, Norton JA, 2014 RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma Cancer 120: 1920–1931.
Hoff AO, Cote GJ, Gagel RF, 2000 Multiple Endocrine Neoplasias. Ann Rev Physiol 62: 377–411.
Pellegata N, 2012 MENX and MEN4. Clinics 67: Supp 1: 13–18.
Georgitsi M, Raitila A, Karhu A, 2007 Germline CD-KNlB/p27Kipl Mutation in Multiple Endocrine Neoplasia. J Clin Endocrinol Metab 92: 3321–3325.
Weinstein L, 2007 Gs Mutations in Fibrous Dysplasia and McCune-Albright Syndrome. J Bone Miner Res 21: 120–124.
Raue F, Frank-Raue K, 2009 Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens) 8: 23–28.
Romei C, Pardi E, Cetani F, Elisei R, 2012 Genetic and Clinical Features of Multiple Endocrine Neoplasia Type 1 and 2 — Review Article. J Oncol 2012: 705036.
Hansford JR, Mulligan LM, 2000 Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J Med Genet 37: 817–827.
Machens A, Dralle Henning, 2012 Multiple endocrine neoplasia type 2: achivements and current challenges. Clinics 67: Supp 1: 113–118.
Eng C, Clayton D, Schuffenecker I, et al, 1996 The relationship between specific RET Proto-oncogene mutations and disease phenotype in Multile Endocrine Neoplasia Type 2. JAMA 276: 1575–1579.
Pachnis V, Mankoo B, Costantini F, 1993 Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119: 1005–1017.
Gardner E, Papi L, Easton DF, et al, 1993 Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2. Hum Mol Genet 2: 241–246.
Santoro M, Carlomagno F, Romano A, et al, 1995 Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267: 381–383.
Takahashi M, Cooper G, 1987 ret Transforming Gene Encodes a Fusion Protein Homologous to Tyrosine Kinases. Mol Cell Biol 7: 1378–1385.
Wagner S, Zhu S, Nicolescu A, 2012 Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2. Clinics 67: Suppl 1: 77–84.
Songyang Z, Carraway KL, Eck MJ, et al, 1995 Catalytic specificity of protein-tyro sine kinases is critical for selective signalling. Nature 373: 536–539.
Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS), 2010 The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 39: 775–783.
Puñales MK, Graf H, Gross JL, Maia AL, 2003 RET Codon 634 Mutations in Multiple Endocrine Neoplasia Type 2: Variable Clinical Features and Clinical Outcome. J Clin Endocrinol Metab 88: 2644–2649.
Muzza M, Cordella D, Bombled J, et al, 2010 Four novel germline variants in exons 8 and 11 display an oncogenic potencial in vitro. Eur J Endoc 162: 771–777.
Toledo SP, Lourenço DM Jr, Santos MA, Tavares MR, Toledo RA, Correia-Deur JE, 2009 Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma. Clinics 64: 699–706.
Komminoth P, Roth J, Schröder S, Saremaslani P, Heitz PU, 1995 Overlaping expression of immuno-histochemical markers and synaptophysin mRNA in pheochromocytomas and adrenocortical carcinomas. Implication for the differential diagnosis of the adrenal gland tumors. Lab Invest 72: 424–431.
Tessitore A, Sinisi AA, Pasquali D, et al, 1999 ANovel Case of Multiple Endocrine Neoplasia Type 2A Associated with Two de Novo Mutations of the RET Protooncogene. J Clin Endocrinol Metab 84: 3522–3527.
Pigny P, Bauters C, Wemeau JL, et al, 1999 A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma. J Clin Endocrinol Metab 84: 1700–1704.
Niccoli-Sire P, Murat A, Rohmer V, et al, 2003 When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations? Surgery 134: 1029–1036.
Fazioli F, Piccinini G, Appolloni G, et al, 2008 A new germline point mutation in Ret exon 8 (Cys515Ser) in a family with medullary thyroid carcinoma. Thyroid 18: 775–782.
Da Silva AM, Maciel RM, Da Silva MR, Toledo SR, De Carvalho MB, Cerutti JM, 2003 A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab 88: 5438–5443.
Kaldrymides P, Mytakidis N, Anagnostopoulos T, et al, 2006 A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening. Clin Endocrinol 64: 561–566.
Bethanis S, Koutsodontis G, Palouka T, et al, 2007 A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A. Hormones (Athens) 6: 152–156.
Peppa M, Boutati E, Kamakari S, et al, 2008 Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene. Eur J Endocrinol 159: 767–771.
Sarika HL, Papathoma A, Garofalaki M, et al, 2012 High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in Greece. Clin Endocr 77: 857–862.
Castro MR, Thomas BC, Richards ML, Zhang J, Morris JC, 2013 Multiple Endocrine Neoplasia Type 2A Due to an Exon 8 (G533C) Mutation in a Large North American Kindred. Thyroid 23: 1547–1552.
Margraf RL, Durtschi JD, Stephens JE, Perez M, Voelkerding KV, 2012 Determination of RET Sequence Variation in an MEN2 Unaffected Cohort Using Multiple-Sample Pooling and Next-Generation Sequencing. J Thyroid Res 2012: 318232.
Asai N, Iwashita T, Matsuyama M, Takahashi M, 1995 Mechanism of activation of the ret ptoto-oncogene bu multiple endocrine neoplasia 2A mutations. Mol Cel Biol 15: 1613–1619.
Kashuk CS, Stone EA, Grice EA, et al, 2005 Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence. Proc Natl Acad Sci U S A 102: 8949–8954.
Machens A, Lorenz K, Dralle H, 2013 Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metab 98: E336–345.
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Martins, A.F., Martins, J.M., do Vale, S. et al. A rare missense variant in RET exon 8 in a Portuguese family with atypical multiple endocrine neoplasia type 2A. Hormones 15, 435–440 (2016). https://doi.org/10.14310/horm.2002.1691
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DOI: https://doi.org/10.14310/horm.2002.1691