Endocrinology · Endocrine Neoplasia Syndromes
The facts most likely to be tested
MEN2 is caused by an activating germline mutation in the RET proto-oncogene.
MEN2A is characterized by the triad of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia.
MEN2B presents with medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and a marfanoid habitus.
Patients with pheochromocytoma must undergo alpha-blockade before beta-blockade to prevent hypertensive crisis.
Medullary thyroid carcinoma originates from parafollicular C-cells and secretes calcitonin.
Prophylactic thyroidectomy is the definitive management for all patients with RET mutations due to the high risk of MTC.
Pheochromocytoma must be ruled out via plasma free metanephrines or 24-hour urine fractionated metanephrines prior to any surgical intervention for thyroid disease.
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A 28-year-old male presents for evaluation of a neck mass. Physical examination reveals a firm, non-tender thyroid nodule and multiple small mucosal neuromas on the tongue and lips. He has a tall, thin frame with long, slender fingers and joint hypermobility. His blood pressure is 165/95 mmHg, and he reports episodic headaches and palpitations.
What is the most likely diagnosis and the most appropriate next step in management?
MEN2B; screen for pheochromocytoma with plasma free metanephrines before thyroidectomy.
The patient's marfanoid habitus and mucosal neuromas are pathognomonic for MEN2B, which carries a high risk of pheochromocytoma; failure to screen for and treat a pheochromocytoma prior to surgery can lead to a fatal hypertensive crisis.
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Etiology / Epidemiology
Autosomal dominant RET proto-oncogene mutation. MEN2A includes MTC, pheochromocytoma, and hyperparathyroidism.
Clinical Manifestations
Palpable thyroid nodule (MTC), episodic hypertension (pheochromocytoma), and nephrolithiasis (hyperparathyroidism).
Diagnosis
Genetic testing for RET mutation is definitive. Screen for pheochromocytoma with plasma free metanephrines.
Treatment
Prophylactic thyroidectomy is mandatory. Never operate on pheochromocytoma before alpha-blockade.
Prognosis
MTC is the primary cause of mortality. 100% penetrance of MTC in untreated carriers.
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Epidemiology & Etiology
MEN2 is an autosomal dominant disorder caused by a gain-of-function mutation in the RET proto-oncogene. MEN2A accounts for >90% of cases, characterized by the triad of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia. MEN2B presents with MTC, pheochromocytoma, and mucosal neuromas or marfanoid habitus.
Pertinent Anatomy
The thyroid C-cells are the origin of MTC, located in the superior-posterior thyroid lobes. Adrenal medullary chromaffin cells are the site of pheochromocytoma. Parathyroid glands are typically involved in MEN2A, leading to hypercalcemia.
Pathophysiology
The RET mutation leads to constitutive activation of tyrosine kinase receptors, driving uncontrolled cellular proliferation. MTC arises from calcitonin-secreting C-cells, which serve as a tumor marker. Pheochromocytomas cause episodic catecholamine excess, while parathyroid hyperplasia results in autonomous PTH secretion.
Clinical Manifestations
Patients often present with a hard, fixed thyroid nodule. Pheochromocytoma manifests as the classic triad of episodic headache, sweating, and tachycardia. Red flag: hypertensive crisis triggered by anesthesia or surgery. MEN2B patients exhibit marfanoid habitus and ganglioneuromatosis of the GI tract.
Diagnosis
Genetic testing for RET mutation is the gold standard for diagnosis in asymptomatic family members. Biochemical screening includes plasma free metanephrines for pheochromocytoma and serum calcium/PTH for hyperparathyroidism. Serum calcitonin levels are used to monitor MTC recurrence.
Treatment
Prophylactic thyroidectomy is the definitive management, performed in early childhood based on specific RET mutation risk levels. Alpha-blockade (e.g., phenoxybenzamine) must be initiated at least 10-14 days prior to any surgery to prevent hypertensive crisis during pheochromocytoma resection. Beta-blockers are added only after adequate alpha-blockade.
Prognosis
Early detection and prophylactic surgery are curative for MTC. Annual screening for pheochromocytoma and hyperparathyroidism is required for life. Metastatic MTC carries a poor prognosis, necessitating systemic therapy with tyrosine kinase inhibitors.
Differential Diagnosis
MEN1: associated with pituitary, parathyroid, and pancreatic tumors
Medullary Thyroid Carcinoma (sporadic): lacks RET mutation and associated endocrine tumors
Pheochromocytoma (sporadic): lacks thyroid or parathyroid involvement
Hyperparathyroidism (primary): usually sporadic adenoma, not associated with MTC
Marfan Syndrome: lacks mucosal neuromas and endocrine tumors