Multiple endocrine neoplasia type 2A
Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant RET-mutation syndrome causing medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism. First-line treatment is total thyroidectomy for medullary thyroid carcinoma and surgical resection of pheochromocytoma, always after preoperative alpha-then-beta adrenergic blockade if pheochromocytoma coexists.
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What this article covers
- Overview
Definition: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant syndrome caused by germline activating mutation of the REarranged during Transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase.
- Epidemiology
Rarity: MEN2A is a rare syndrome, though it accounts for a meaningful minority of all medullary thyroid carcinoma, since 25% or more of MTC arises from germline RET mutations across the type 2A and 2B spectrum (collectively MEN2).
- Risk factors
Germline RET mutation: an inherited or de novo activating mutation of the RET proto-oncogene is both necessary and sufficient to confer syndrome risk.
- Pathophysiology
RET gain-of-function: RET encodes a receptor tyrosine kinase normally activated by glial-derived neurotrophic factor family ligands; a germline activating mutation causes constitutive…
- Clinical features
Diagnostic core feature: the defining clinical pattern is two or more of medullary thyroid carcinoma, pheochromocytoma, or parathyroid adenoma/hyperplasia occurring in one patient or across close relatives.
- Differential diagnosis
Multiple endocrine neoplasia type 2B (MEN2B): medullary thyroid carcinoma and pheochromocytoma overlap, but MEN2B is distinguished by the absence of hyperparathyroidism and the presence of mucosal…
- Diagnosis
Diagnostic criteria: MEN2A is diagnosed clinically by two or more of medullary thyroid carcinoma, pheochromocytoma, or parathyroid adenoma/hyperplasia in one person or close relatives, and confirmed…
- Management
First, if pheochromocytoma is present, treat it before any other surgery: phenoxybenzamine 10 mg PO twice daily, titrated up over 10-14 days before surgery to a seated blood pressure of 130/80 mm Hg…
- Complications
Metastatic medullary thyroid carcinoma: MTC can spread to cervical lymph nodes, lung, liver, and bone; persistently elevated or rising calcitonin after surgery signals recurrent or metastatic disease.
- Prognosis
MTC prognosis depends on stage at resection: medullary thyroid carcinoma detected and resected while confined to the thyroid, before nodal or distant spread, carries a substantially better prognosis…
- Prevention
Cascade genetic testing: once a familial RET mutation is identified, test first-degree relatives so carriers can be identified before symptomatic disease develops.
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Related articles
- Medullary thyroid carcinoma
Medullary thyroid carcinoma is a neuroendocrine tumor of the parafollicular C cells that secretes calcitonin and is familial (RET-mutant, part of MEN2A or MEN2B) in about 25% of cases. First-line treatment is total thyroidectomy with central neck lymph node dissection, with any coexisting pheochromocytoma resected first, followed by lifelong levothyroxine replacement and calcitonin/CEA surveillance; selpercatinib, a RET kinase inhibitor, is used for unresectable or metastatic RET-mutant disease.
- Primary hyperparathyroidism
Primary hyperparathyroidism is autonomous PTH oversecretion, most often from a solitary parathyroid adenoma, producing hypercalcemia with an elevated or inappropriately normal PTH and low or low-normal phosphorus. Most patients are asymptomatic and identified on routine labs; parathyroidectomy is curative and is first-line for symptomatic disease or when specific biochemical, skeletal, or renal criteria are met, while observation with annual monitoring suffices for mild, asymptomatic disease.
- Multiple endocrine neoplasia type 1
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor-suppressor syndrome causing parathyroid, pancreatic, and pituitary tumors, the '3 Ps.' First-line treatment is organ-specific: parathyroidectomy for hyperparathyroidism, dopamine agonists for prolactinoma, and surgical resection or acid suppression for pancreatic neuroendocrine tumors.
- Multiple endocrine neoplasia type 2B
Multiple endocrine neoplasia type 2B is an autosomal dominant RET proto-oncogene disorder producing early, aggressive medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and a marfanoid habitus, without the parathyroid disease seen in MEN2A. First-line treatment is prophylactic total thyroidectomy at the earliest safe age, with pheochromocytoma resected first if both lesions are present, after alpha blockade.