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Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2

Cornelis J Lips, MD, PhD
Douglas W Ball, MD
Section Editor
Marc K Drezner, MD
Deputy Editor
Jean E Mulder, MD


Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder with an estimated prevalence of 1 per 30,000 in the general population. MEN2 is subclassified into two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B). Within MEN2A, there are four variants: classical MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HD), and familial medullary thyroid cancer (FMTC) (table 1) [1].

The genetic defect in these disorders involves the RET proto-oncogene on chromosome 10. MEN2A and 2B are inherited in an autosomal dominant pattern with very high penetrance. In both syndromes, there is an occurrence of multicentric tumor formation in all organs where the RET proto-oncogene is expressed. The thyroid, parathyroid, and adrenal glands are at risk for developing tumors that may reduce life expectancy and quality of life. The excellent prognosis for medullary thyroid cancer (MTC) diagnosed at its earliest stage underscores the importance of early diagnosis for sporadic and hereditary MTC [2].

This topic will review the clinical manifestations, diagnosis, and evaluation of MEN2. The genetics and treatment of this disorder are discussed separately. Sporadic MTC is also discussed separately.

(See "Classification and genetics of multiple endocrine neoplasia type 2".)

(See "Approach to therapy in multiple endocrine neoplasia type 2".)

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Literature review current through: Nov 2017. | This topic last updated: May 15, 2017.
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  1. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25:567.
  2. Frank-Raue K, Rondot S, Raue F. Molecular genetics and phenomics of RET mutations: Impact on prognosis of MTC. Mol Cell Endocrinol 2010; 322:2.
  3. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994; 6:70.
  4. Mulligan LM, Ponder BA. Genetic basis of endocrine disease: multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 1995; 80:1989.
  5. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994; 367:375.
  6. Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993; 2:851.
  7. Raue F, Frank-Raue K, Grauer A. Multiple endocrine neoplasia type 2. Clinical features and screening. Endocrinol Metab Clin North Am 1994; 23:137.
  8. Parthemore JG, Bronzert D, Roberts G, Deftos LJ. A short calcium infusion in the diagnosis of medullary thyroid carcinoma. J Clin Endocrinol Metab 1974; 39:108.
  9. Verga U, Ferrero S, Vicentini L, et al. Histopathological and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 14:393.
  10. Wolfe HJ, Delellis RA. Familial medullary thyroid carcinoma and C cell hyperplasia. Clin Endocrinol Metab 1981; 10:351.
  11. Albores-Saavedra JA, Krueger JE. C-cell hyperplasia and medullary thyroid microcarcinoma. Endocr Pathol 2001; 12:365.
  12. Siqueira DR, Ceolin L, Ferreira CV, et al. Role of RET genetic variants in MEN2-associated pheochromocytoma. Eur J Endocrinol 2014; 170:821.
  13. Imai T, Uchino S, Okamoto T, et al. High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. Eur J Endocrinol 2013; 168:683.
  14. Thosani S, Ayala-Ramirez M, Palmer L, et al. The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 2013; 98:E1813.
  15. Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metab 2013; 98:E336.
  16. Rowland KJ, Chernock RD, Moley JF. Pheochromocytoma in an 8-year-old patient with multiple endocrine neoplasia type 2A: implications for screening. J Surg Oncol 2013; 108:203.
  17. Utiger RD. Medullary thyroid carcinoma, genes, and the prevention of cancer. N Engl J Med 1994; 331:870.
  18. Kinlaw WB, Scott SM, Maue RA, et al. Multiple endocrine neoplasia 2A due to a unique C609S RET mutation presents with pheochromocytoma and reduced penetrance of medullary thyroid carcinoma. Clin Endocrinol (Oxf) 2005; 63:676.
  19. Pigny P, Cardot-Bauters C, Do Cao C, et al. Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation? Eur J Endocrinol 2009; 160:227.
  20. Pomares FJ, Cañas R, Rodriguez JM, et al. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma. Clin Endocrinol (Oxf) 1998; 48:195.
  21. Toledo RA, Wagner SM, Coutinho FL, et al. High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. J Clin Endocrinol Metab 2010; 95:1318.
  22. Neumann HP, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 1993; 329:1531.
  23. Webb TA, Sheps SG, Carney JA. Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2. Am J Surg Pathol 1980; 4:121.
  24. Evans DB, Lee JE, Merrell RC, Hickey RC. Adrenal medullary disease in multiple endocrine neoplasia type 2. Appropriate management. Endocrinol Metab Clin North Am 1994; 23:167.
  25. Lips CJ, Minder WH, Leo JR, et al. Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2a (Sipple's syndrome) in a large family in the Netherlands. Diagnostic and therapeutic implications. Am J Med 1978; 64:569.
  26. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19:565.
  27. Schuffenecker I, Virally-Monod M, Brohet R, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine. J Clin Endocrinol Metab 1998; 83:487.
  28. O'Riordain DS, O'Brien T, Grant CS, et al. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery 1993; 114:1031.
  29. Raue F, Kraimps JL, Dralle H, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med 1995; 238:369.
  30. Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988; 318:478.
  31. Snow KJ, Boyd AE 3rd. Management of individual tumor syndromes. Medullary thyroid carcinoma and hyperparathyroidism. Endocrinol Metab Clin North Am 1994; 23:157.
  32. Pausova Z, Soliman E, Amizuka N, et al. Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 1996; 81:2711.
  33. Eng C, Clayton D, Schuffenecker I, et al. 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.
  34. Vierhapper H, Rondot S, Schulze E, et al. Primary hyperparathyroidism as the leading symptom in a patient with a Y791F RET mutation. Thyroid 2005; 15:1303.
  35. Heath H 3rd, Sizemore GW, Carney JA. Preoperative diagnosis of occult parathyroid hyperplasia by calcium infusion in patients with multiple endocrine neoplasia, type 2a. J Clin Endocrinol Metab 1976; 43:428.
  36. Gagel RF, Levy ML, Donovan DT, et al. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med 1989; 111:802.
  37. Kousseff BG, Espinoza C, Zamore GA. Sipple syndrome with lichen amyloidosis as a paracrinopathy: pleiotropy, heterogeneity, or a contiguous gene? J Am Acad Dermatol 1991; 25:651.
  38. Wong CK, Lin CS. Friction amyloidosis. Int J Dermatol 1988; 27:302.
  39. Robinson MF, Furst EJ, Nunziata V, et al. Evidence for a neurologic defect in the men 2A/cutaneous lichen amyloidosis syndrome. Bone 1992; 17:91.
  40. Verga U, Fugazzola L, Cambiaghi S, et al. Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol (Oxf) 2003; 59:156.
  41. Schuchardt A, D'Agati V, Larsson-Blomberg L, et al. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 1994; 367:380.
  42. Pachnis V, Mankoo B, Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 1993; 119:1005.
  43. Avantaggiato V, Dathan NA, Grieco M, et al. Developmental expression of the RET protooncogene. Cell Growth Differ 1994; 5:305.
  44. Ceccherini I, Romei C, Barone V, et al. Identification of the Cys634-->Tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis. J Endocrinol Invest 1994; 17:201.
  45. Hofstra RMW, Stelwagen T, Stulp RP. RET mutations in MEN 2 associated diseases. Am J Hum Genet 1994; 55:A60.
  46. Rothberg AE, Raymond VM, Gruber SB, Sisson J. Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid 2009; 19:651.
  47. Bütter A, Gagné J, Al-Jazaeri A, et al. Prophylactic thyroidectomy in pediatric carriers of multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma: mutation in C620 is associated with Hirschsprung's disease. J Pediatr Surg 2007; 42:203.
  48. Fialkowski EA, DeBenedetti MK, Moley JF, Bachrach B. RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. J Pediatr Surg 2008; 43:188.
  49. Moore SW, Zaahl M. Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 "Janus" genetic variation. J Pediatr Surg 2010; 45:393.
  50. Wells SA Jr, Dilley WG, Farndon JA, et al. Early diagnosis and treatment of medullary thyroid carcinoma. Arch Intern Med 1985; 145:1248.
  51. O'Riordain DS, O'Brien T, Crotty TB, et al. Multiple endocrine neoplasia type 2B: more than an endocrine disorder. Surgery 1995; 118:936.
  52. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86:5658.
  53. Lips CJ, Höppener JW, Thijssen JH. Medullary thyroid carcinoma: role of genetic testing and calcitonin measurement. Ann Clin Biochem 2001; 38:168.
  54. Lips CJ, Landsvater RM, Höppener JW, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994; 331:828.
  55. Hernández G, Simó R, Oriola J, Mesa J. False-positive results of basal and pentagastrin-stimulated calcitonin in non-gene carriers of multiple endocrine neoplasia type 2A. Thyroid 1997; 7:51.
  56. Cupisti K, Wolf A, Raffel A, et al. Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution's experience over 20 years. Ann Surg 2007; 246:815.
  57. Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine. Clin Endocrinol (Oxf) 1998; 48:265.
  58. Sosa JA, Tuggle CT, Wang TS, et al. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab 2008; 93:3058.
  59. Kebebew E, Greenspan FS, Clark OH, et al. Extent of disease and practice patterns for medullary thyroid cancer. J Am Coll Surg 2005; 200:890.
  60. Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 2006; 107:2134.
  61. Lips CJ, Höppener JW, Van Nesselrooij BP, Van der Luijt RB. Counselling in multiple endocrine neoplasia syndromes: from individual experience to general guidelines. J Intern Med 2005; 257:69.
  62. Bae SJ, Kim DJ, Kim JY, et al. A rare extracellular D631Y germline mutation of the RET proto-oncogene in two Korean families with multiple endocrine neoplasia 2A. Thyroid 2006; 16:609.
  63. Dourisboure RJ, Belli S, Domenichini E, et al. Penetrance and clinical manifestations of non-hotspot germline RET mutation, C630R, in a family with medullary thyroid carcinoma. Thyroid 2005; 15:668.
  64. Learoyd DL, Gosnell J, Elston MS, et al. Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf) 2005; 63:636.
  65. Quayle FJ, Fialkowski EA, Benveniste R, Moley JF. Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 2007; 142:800.
  66. Peppa M, Boutati E, Kamakari S, et al. 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 2008; 159:767.
  67. Bethanis S, Koutsodontis G, Palouka T, et al. A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A. Hormones (Athens) 2007; 6:152.
  68. Mian C, Barollo S, Zambonin L, et al. Characterization of the largest kindred with MEN2A due to a Cys609Ser RET mutation. Fam Cancer 2009; 8:379.
  69. Pinna G, Ghiani M, Mariotti S. Asymptomatic bilateral adrenal pheochromocytoma in a patient with a germline V804M mutation in the RET proto-oncogene. Clin Endocrinol (Oxf) 2008; 68:836.
  70. Jackson MB, Guttenberg M, Hedrick H, Moshang T Jr. Multiple endocrine neoplasia type 2A in a kindred with C634Y mutation. Pediatrics 2005; 116:e468.
  71. Kraimps JL, Denizot A, Carnaille B, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World J Surg 1996; 20:808.
  72. Kudo T, Miyauchi A, Ito Y, et al. Serum calcitonin levels with calcium loading tests before and after total thyroidectomy in patients with thyroid diseases other than medullary thyroid carcinoma. Endocr J 2011; 58:217.
  73. Colombo C, Verga U, Mian C, et al. Comparison of calcium and pentagastrin tests for the diagnosis and follow-up of medullary thyroid cancer. J Clin Endocrinol Metab 2012; 97:905.
  74. Mian C, Perrino M, Colombo C, et al. Refining calcium test for the diagnosis of medullary thyroid cancer: cutoffs, procedures, and safety. J Clin Endocrinol Metab 2014; 99:1656.
  75. Herrmann BL, Schmid KW, Goerges R, et al. Calcitonin screening and pentagastrin testing: predictive value for the diagnosis of medullary carcinoma in nodular thyroid disease. Eur J Endocrinol 2010; 162:1141.
  76. Doyle P, Düren C, Nerlich K, et al. Potency and tolerance of calcitonin stimulation with high-dose calcium versus pentagastrin in normal adults. J Clin Endocrinol Metab 2009; 94:2970.
  77. Daniels GH. Screening for medullary thyroid carcinoma with serum calcitonin measurements in patients with thyroid nodules in the United States and Canada. Thyroid 2011; 21:1199.
  78. Milone F, Ramundo V, Chiofalo MG, et al. Predictive value of pentagastrin test for preoperative differential diagnosis between C-cell hyperplasia and medullary thyroid carcinoma in patients with moderately elevated basal calcitonin levels. Clin Endocrinol (Oxf) 2010; 73:85.
  79. Karges W, Dralle H, Raue F, et al. Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation. Exp Clin Endocrinol Diabetes 2004; 112:52.