Childhood Cancer Genomics (PDQ®)–Health Professional Version

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Multiple Endocrine Neoplasia Syndromes

The most salient clinical and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 4.

Table 4. Multiple Endocrine Neoplasia (MEN) Syndromes with Associated Clinical and Genetic Alterations

Syndrome	Clinical Features/Tumors		Genetic Alterations
MEN type 1: Werner syndrome[1]	Parathyroid		11q13 (MEN1 gene)
	Pancreatic islets:	Gastrinoma	11q13 (MEN1 gene)
		Insulinoma
		Glucagonoma
		VIPoma
	Pituitary:	Prolactinoma	11q13 (MEN1 gene)
		Somatotrophinoma
		Corticotropinoma
	Other associated tumors (less common):	Carcinoid: bronchial and thymic	11q13 (MEN1 gene)
		Adrenocortical
		Lipoma
		Angiofibroma
		Collagenoma
MEN type 2A: Sipple syndrome	Medullary thyroid carcinoma		10q11.2 (RETgene)
	Pheochromocytoma
	Parathyroid gland
MEN type 2B	Medullary thyroid carcinoma		10q11.2 (RETgene)
	Pheochromocytoma
	Mucosal neuromas
	Intestinal ganglioneuromatosis
	Marfanoid habitus

Multiple endocrine neoplasia type 1 (MEN1) syndrome (Werner syndrome): MEN1 syndrome is an autosomal dominant disorder characterized by the presence of tumors in the parathyroid, pancreatic islet cells, and anterior pituitary. Diagnosis of this syndrome should be considered when two endocrine tumors listed in Table 4 are present.
A study documented the initial symptoms of MEN1 syndrome occurring before age 21 years in 160 patients.[2] Of note, most patients had familial MEN1 syndrome and were followed up using an international screening protocol.
1. Primary hyperparathyroidism. Primary hyperparathyroidism, the most common symptom, was found in 75% of patients, usually only in those with biological abnormalities. Primary hyperparathyroidism diagnosed outside of a screening program is extremely rare, most often presents with nephrolithiasis, and should lead the clinician to suspect MEN1.[2,3]
2. Pituitary adenomas. Pituitary adenomas were discovered in 34% of patients, occurred mainly in females older than 10 years, and were often symptomatic.[2]
3. Pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors were found in 23% of patients. Specific diagnoses included insulinoma, nonsecreting pancreatic tumor, and Zollinger-Ellison syndrome. The first case of insulinoma occurred before age 5 years.[2]
4. Malignant tumors. Four patients had malignant tumors (two adrenal carcinomas, one gastrinoma, and one thymic carcinoma). The patient with thymic carcinoma died before age 21 years from rapidly progressive disease.
Germline mutations of the MEN1 gene located on chromosome 11q13 are found in 70% to 90% of patients; however, this gene has also been shown to be frequently inactivated in sporadic tumors.[4] Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.[5]
It is recommended that screening for patients with MEN1 syndrome begin by the age of 5 years and continue for life. The number of tests or biochemical screening is age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography of the abdomen every 1 to 3 years.[6]
Multiple endocrine neoplasia type 2A (MEN2A) and multiple endocrine neoplasia type 2B (MEN2B) syndromes:
A germline activating mutation in the RET oncogene (a receptor tyrosine kinase) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN2A and MEN2B syndromes.[7-9]
- MEN2A: MEN2A is characterized by the presence of two or more endocrine tumors (refer to Table 4) in an individual or in close relatives.[10] RET mutations in these patients are usually confined to exons 10 and 11.
- MEN2B: MEN2B is characterized by medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, pheochromocytomas, mucosal neuromas, and ganglioneuromas.[10-12] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of mutations in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[13] Patients also have medullated corneal nerve fibers, distinctive faces with enlarged lips, and an asthenic Marfanoid body habitus.
  A pentagastrin stimulation test can be used to detect the presence of medullary thyroid carcinoma in these patients, although management of patients is driven primarily by the results of genetic analysis for RET mutations.[13,14]
Guidelines for genetic testing of suspected patients with MEN2 syndrome and the correlations between the type of mutation and the risk levels of aggressiveness of medullary thyroid cancer have been published.[14,15]
Familial Medullary Thyroid Carcinoma: Familial medullary thyroid carcinoma is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET mutations in exons 10, 11, 13, and 14 account for most cases.
The most-recent literature suggests that this entity should not be identified as a form of hereditary medullary thyroid carcinoma that is separate from MEN2A and MEN2B. Familial medullary thyroid carcinoma should be recognized as a variant of MEN2A, to include families with only medullary thyroid cancer who meet the original criteria for familial disease. The original criteria includes families of at least two generations with at least two, but less than ten, patients with RET germline mutations; small families in which two or fewer members in a single generation have germline RET mutations; and single individuals with a RET germline mutation.[14,16]

Table 5. Clinical Features of Multiple Endocrine Neoplasia Type 2 (MEN2) Syndromes

MEN2 Subtype	Medullary Thyroid Carcinoma	Pheochromocytoma	Parathyroid Disease
MEN2A	95%	50%	20% to 30%
MEN2B	100%	50%	Uncommon

(Refer to the PDQ summary on Unusual Cancers of Childhood Treatment for information about the treatment of childhood MEN syndromes.)

References

Thakker RV: Multiple endocrine neoplasia--syndromes of the twentieth century. J Clin Endocrinol Metab 83 (8): 2617-20, 1998. [PUBMED Abstract]
Goudet P, Dalac A, Le Bras M, et al.: MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab 100 (4): 1568-77, 2015. [PUBMED Abstract]
Romero Arenas MA, Morris LF, Rich TA, et al.: Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg 49 (4): 546-50, 2014. [PUBMED Abstract]
Farnebo F, Teh BT, Kytölä S, et al.: Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 83 (8): 2627-30, 1998. [PUBMED Abstract]
Field M, Shanley S, Kirk J: Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 43 (4): 219-29, 2007. [PUBMED Abstract]
Thakker RV: Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 24 (3): 355-70, 2010. [PUBMED Abstract]
Sanso GE, Domene HM, Garcia R, et al.: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 94 (2): 323-30, 2002. [PUBMED Abstract]
Alsanea O, Clark OH: Familial thyroid cancer. Curr Opin Oncol 13 (1): 44-51, 2001. [PUBMED Abstract]
Fitze G: Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg 14 (6): 375-83, 2004. [PUBMED Abstract]
Puñales MK, da Rocha AP, Meotti C, et al.: Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid 18 (12): 1261-8, 2008. [PUBMED Abstract]
Skinner MA, DeBenedetti MK, Moley JF, et al.: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 31 (1): 177-81; discussion 181-2, 1996. [PUBMED Abstract]
Brauckhoff M, Gimm O, Weiss CL, et al.: Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 28 (12): 1305-11, 2004. [PUBMED Abstract]
Sakorafas GH, Friess H, Peros G: The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15 (4): 871-84, 2008. [PUBMED Abstract]
Waguespack SG, Rich TA, Perrier ND, et al.: Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 7 (10): 596-607, 2011. [PUBMED Abstract]
Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009. [PUBMED Abstract]
Wells SA Jr, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015. [PUBMED Abstract]