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Abstract
Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant syndrome characterized by the presence of a medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. MEN2A arises due to germline missense mutations of the RET proto-oncogene. Specific RET mutations correlate with the onset of age and the aggressiveness of a medullary thyroid carcinoma. However, the clinical presentation varies even within families, where patients carry the same mutation. Recently, it has been reported that polymorphisms of RET may have a modifier effect on the presentation. We experienced a case of 42-year-old man, whose bilateral pheochromocytoma and medullary thyroid carcinoma were incidentally found. Genetic testing detected a mutation in codon 634 (C634R) and a polymorphism in codon 691 (G691S) of the RET proto-oncogene. His mother, younger brother and his only son had the same mutation and polymorphism. We report this case with a review of the literature about RET gene polymorphisms.
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Fig. 1
Adrenal CT scan shows huge mass in both adrenal glands (A). I-131 MIBG scan shows bilateral adrenal uptake with no evidence of metastasis (B). Ultrasound sonogram shows heterogeneous hyperechogenic solid nodules with dense calcification and posterior acoustic shadowing in the both thyroid (C).
Fig. 2
Histologic features of pheochromocytoma (A). It shows predominantly alveolar (zellballen) arrangement tumor cells and the prominent capillary network around each group of cells. The tumor cells show granular and basophilic cytoplasm. Cellular and nuclear pleomorphism is indistinct (H&E stain, ×400). Histologic features of the medullary thyroid carcinoma (B). The tumor shows predominantly solid growth pattern and is intersected by fibrous and amyloid deposits. Tumor cells contain round to oval, regular nuclei with coarse chromatin (H&E stain, ×400).
References
1. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Mulligan LM. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996. 276:1575–1579.
2. Robledo M, Gil L, Pollan M, Cebrian A, Ruiz S, Azanedo M, Benitez J, Menarguez J, Rojas JM. Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res. 2003. 63:1814–1817.
3. Lesueur F, Cebrian A, Robledo M, Niccoli-Sire P, Svensson KA, Pinson S, Leyland J, Whittaker J, Pharoah PD, Ponder BA. Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A. Cancer Res. 2006. 66:1177–1180.
4. Kim HY, Lee JY, Kim SB, Lee KW, Seo JA, Oh JH, Kim SG, Choi KM, Baik SH, Choi DS, Kim NH. A Case of Multiple endocrine neoplasia 2A with germ line mutation of RET gene. J Korean Soc Endocrinol. 2003. 18:481–488.
5. Kim NH, Kim JH, Nam JH, Park JP, Park JE, Choi YS, Park YH. A family of multiple endocrine neoplasia type 2A associated with a C618R mutation in RET proto-oncogene. Korean J Med. 2006. 70:448–454.
6. Kim IJ, Kang HC, Park JH, Ku JL, Lee JS, Kwon HJ, Yoon KA, Heo SC, Yang HY, Cho BY, Kim SY, Oh SK, Youn YK, Park DJ, Lee MS, Lee KW, Park JG. RET oligonucleotide microarray for the detection of RET mutations in multiple endocrine neoplasia type 2 syndromes. Clin Cancer Res. 2002. 8:457–463.
7. Chung YJ, Kim HH, Kim HJ, Min YK, Lee MS, Lee MK, Kim KW, Ki CS, Kim JW, Chung JH. RET proto-oncogene mutations are restricted to codon 634 and 618 in Korean families with multiple endocrine neoplasia 2A. Thyroid. 2004. 14:813–818.
8. Kim JE, Kim BJ, Kim SH, Kim KA, Chung JH, Lee MS, Lee MG, Kim KW. Small medullary thyroid cancer detected by genetic mutation screening in MEN IIa family. J Korean Soc Endocrinol. 1998. 13:230–239.
9. Kim JK, Chung HW, Seo HS, Kim DJ, Chung SS, Song YD, Kwon KH, Jin YM, Lee MK, Lim SK, Kim IJ, Kang HC, Park JH, Park JG. A case of papillary thyroid carcinoma combined with multiple endocrine neoplasia type 2A. J Korean Soc Endocrinol. 2002. 17:730–738.
10. Kim TY, Hwang JK, Moon MK, Park YJ, Park DJ, Kim SY, Lee HK, Yoon YK, Cho BY. A case of multiple endocrine neoplasia type 2B associated with a M918T mutation in RET proto-oncogene. J Korean Soc Endocrinol. 2003. 18:85–93.
11. Yang HY, Park YJ, Kwon HJ, Choe KJ. Germline mutation of RET gene in a multiple endocrine neoplasia type 2A (MEN2A) family. J Korean Cancer Assoc. 1999. 31:867–875.
12. Kim SW, Kim TY, Park YJ, Kim WB, Shin CS, Park DJ, Park KS, Kim SY, Cho BY, Lee HK. Early detection of medullary thyroid cancer by screening of the RET proto-oncogene germ line point mutation in family members affected with hereditary medullary thyroid cancer. J Korean Soc Endocrinol. 2001. 16:54–64.
13. Kim YK, Kim JW, Ahn SM, Song KE, Jung SH, Kim DJ, Chung YS, Lee KW, Kim CH, Hong JH, Jeong SY, Kim HJ. A case of familial medullary thyroid carcinoma with a E768D mutation in RET proto-oncogene. J Korean Soc Endocrinol. 2005. 20:375–380.
14. Lee KD, Mun HS, Kim JY, Chung H, Choi SH, Ha NW, Uchino S. Analysis of RET gene point mutation in a family with familial medullary thyroid carcinoma. Korean J Otolaryngol - Head Neck Surg. 2004. 47:904–910.
15. Kim SW, Lee KD, Kim JY, Moon HS, Kim YR, Park YH, Lee KS. Analysis of RET gene point mutation in a family with multiple endocrine neoplasia type 2A. Korean J Otolaryngol - Head Neck Surg. 2007. 50:529–536.
16. Laken SJ, Petersen GM, Gruber SB, Oddoux C, Ostrer H, Giardiello FM, Hamilton SR, Hampel H, Markowitz A, Klimstra D, Jhanwar S, Winawer S, Offit K, Luce MC, Kinzler KW, Vogelstein B. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet. 1997. 17:79–83.
17. Baumgartner-Parzer SM, Lang R, Wagner L, Heinze G, Niederle B, Kaserer K, Waldhausl W, Vierhapper H. Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005. 90:6232–6236.
18. Plaza-Menacho I, Burzynski GM, de Groot JW, Eggen BJ, Hofstra RM. Current concepts in RET-related genetics, signaling and therapeutics. Trends Genet. 2006. 22:627–636.
19. Yip L, Lee JE, Shapiro SE, Waguespack SG, Sherman SI, Hoff AO, Gagel RF, Arens JF, Evans DBL. Surgical management of hereditary pheochromocytoma. J Am Coll Surg. 2004. 198:525–523.
20. Reincke M, Allolio B, Wurth G, Winkelmann W. The hypothalamic-pituitary-adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone. J Clin Endocrinol Metab. 1993. 77:151–156.
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