FaCD Online Syndrome Fact Sheet

Last updated: 14 Jan 2010

Name: Multiple Endocrine Neoplasia, type 2A

Synonym: MEN2A, Sipple disease, incl MEN2C

Mode of Inheritance: AD

Genes

RET, mapped to 10q11.2

Tumor features

C-cell hyperplasia
paraganglioma, chromaffin (extra-adrenal pheochromocytoma)
parathyroid adenoma
pheochromocytoma
thyroid cancer, medullary

Tumor features (possible)

gastrointestinal stromal tumor (GIST)
thyroid cancer, papillary

Non-tumor features

cutaneous lichen amyloidosis
Hirschsprung disease
hyperparathyroidism

Comment

This disorder is characterized [4] by medullary thyroid carcinoma, hyperparathyroidism(20-30 % of cases; caused by multifocal parathyroid hyperplasia/adenoma)[1] and pheochromocytomas[2,3](50-70 % of cases, bilateral in 70 % of those; malignant in 4% of cases). In very rare cases extra-adrenal pheochromocytomas / head and neck patragangliomas have been observed in MEN2A[13].

In some families with MEN 2A, cutaneous lichen amyloidosis and Hirschsprung disease occurs[5;6]. Approximately 50 % of the MEN 2A gene carriers will have presented with symptoms by the age of 55 and 90 % of gene carriers will be detected by biochemical screening before age 30[7]. Not all RET mutations carry the same risk of developing the different parts of the MEN2 tumor spectrum. Age of onset and risk of tumor types and other manifestations depend on genotype[16], see also familial medullary thyroid cancer and MEN2B.

Several reports on papillary thyroid cancer in MEN2 have been made. In one MEN 2A family reported by Decker[8] 2 patients developed papillary thyroid carcinoma (1 of them multifocal) in addition to medullary thyroid carcinoma. Scopsi et al.[9] also reviewed the possible occurrence of papillary thyroid cancer in MEN2A and patients with pheochromocytoma in general. Other authors have observed papillary thyroid cancer in MEN2A as well[10,11], or have observed sporadic combinations of medullary and non-medullary thyroid cancer[12]. In a large family with the V804M mutation, consisting of one hundred and seven family members, medullary and simultaneous papillary thyroid carcinomas (40%), rare primary hyperparathyroidism, and no pheochromocytomas were observed. This lead the authors to coin the name MEN2C[14]. A case of a gastrointestinal stromal tumor in MEN2A has been reported[15].

Links

eMedicine info on MEN 23 1 08

References

[1] Raue F, Kraimps JL, Dralle H, Cougard P, Proye C, Frilling A, Limbert E, Llenas LF, Niederle B. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Int Med 1995; 238:369-373.
[2] Casanova S, Rosenberg-Bourgin M, Farkast D, Calmettes C, Feingold N, Heshmati HM, Cohen R, Conte-Devoix B, Gaillausseau PJ, Houdent C, Bigornet JC, Boiteau V, Caron J, Modigliani E. Phaechromocytoma in multiple endocrine neoplasia type 2A: survey of 100 cases. Clin Endocrinol 1993; 38:531-537.
[3] Modigliani E, Vasen HM, Raue K, Dralle H, Frilling A, Gheri RG, Brandi ML, Limbert E, Niederle B, Forgas L, Rosenberg-Bourgin M, Calmettes C. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. J Int Med 1995; 238:363-367.
[4] Ball DW. Clinical manifestations of multiple endocrine neoplasia type 2. In: Nelkin BD, editor. Genetic Mechanisms in Multiple Endocrine Neoplasia Type 2. Georgetown: R G Landes Co, 1996: 1-20.
[5] Hofstra RMW, Sijmons RH, Stelwagen T, Stulp RP, Kousseff BG, Lips CJM, Steijlen PM, VanVoorstVader PC, Buys CHCM. RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia. J Invest Dermatol 107[2], 215-218. 1996. Ref Type: Journal (Full)
[6] Sijmons RH, Hofstra RMW, Wijburg FA, Links TP, Zwierstra RP, Vermey A, Aronson DC, Tan-Sindhunata G, Brouwers-Smalbraak GJ, Maas SM, Buys CHCM. Oncological implications of RET gene mutations in Hirschsprung's disease. Gut 1998; 43:542-547.
[7] Ponder BAJ, Ponder MA, Coffey R, Pembrey ME, Gagel RF, Telenius-Berg M, Semple P, Easton DF. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 1988; 1(8582):397-401.
[8] Decker RA. Expression of papillary thyroid carcinoma in multiple endocrine neoplasia type 2A. Surgery 1993; 114(6):1059-1063.
[9] Scopsi L, Cozzaglio L, Collini P, Gullo M, Bongarzone I, Giarola M, Radice P, Gennari L. Concurrent pheochromocytoma, paraganglioma, papillary thyroid carcinoma, and desmoid tumor: A case report with analyses at the molecular level. Endocr Pathol 9[1], 79-90. 1998. Ref Type: Journal (Full)
[10] Giacomelli L, Guerriero G, Falvo L, Altomare V, Chiesa C, Ferri S, Stio F. Simultaneous occurrence of medullary carcinoma and papillary microcarcinoma of thyroid in a patient with MEN 2A syndrome. report of a case. Tumori 2007 Jan-Feb; 93(1):109-11.
[11] Kösem M, Kotan C, Algün E, Topal C. Simultaneous occurrence of papillary intrafollicular and microcarcinomas with bilateral medullary microcarcinoma of the thyroid in a patient with multiple endocrine neoplasia type 2A: report of a case. Surgery today 2002; 32(7):623-8.
[12] Younes N, Shomaf M, Al Hassan L. Simultaneous medullary and papillary thyroid carcinoma with lymph node metastasis in the same patient: case report and review of the literature. Asian journal of surgery 2005; 28(3):223-6.
[13] Boedeker CC, Erlic Z, Richard S, Kontny U, Gimenez-Roqueplo AP, Cascon A, Robledo M, de Campos JM, van Nederveen FH, de Krijger RR, Burnichon N, Gaal J, Walter MA, Reschke K, Wiech T, Weber J, Rückauer K, Plouin PF, Darrouzet V, Giraud S, Eng C, Neumann HP. Head and Neck Paragangliomas in Von Hippel-Lindau Disease and Multiple Endocrine Neoplasia Type 2. J Clin Endocrinol Metab. 2009 Mar 31. [Epub ahead of print]
[14] Shifrin AL, Xenachis C, Fay A, Matulewicz TJ, Kuo YH, Vernick JJ. One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome--MEN 2C? Surgery. 2009 Dec;146(6):998-1005.
[15] Malek R, McCarthy-Keith D, Levens ED, Merino MJ, DeCherney AH, Weinstein LS. A gastrointestinal stromal tumor in a patient with multiple endocrine neoplasia type 2A and metastatic medullary thyroid cancer to the ovaries. Endocr Pract. 2008 Oct;14(7):898-901.
[16] Raue F, Frank-Raue K. Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens). 2009 Jan-Mar;8(1):23-8.