Multiple Endocrine Neoplasia (MEN1 and MEN2)

Risk factors

• First-degree relative with confirmed MEN1 or MEN2 mutation
• Personal history of medullary thyroid carcinoma, pheochromocytoma, or parathyroid adenoma at young age (<35)
• Multiglandular parathyroid disease at any age
• Family history of unexplained sudden death, hypertensive crisis in pregnancy, or hypercalcemia
• Pancreatic neuroendocrine tumor (gastrinoma, insulinoma) before age 50

Pathophysiology

MEN1 results from inactivating mutations in the MEN1 tumor suppressor gene, which encodes menin, a nuclear scaffolding protein involved in transcriptional regulation and DNA repair. Tumorigenesis follows the Knudson two-hit hypothesis. MEN2 results from activating (gain-of-function) mutations of the RET receptor tyrosine kinase, driving constitutive proliferative signaling in neural crest-derived tissues (parafollicular C cells, adrenal medulla, sympathetic ganglia). Specific codon mutations correlate with phenotype severity and inform timing of prophylactic thyroidectomy.

Clinical presentation

Differential diagnosis

• Sporadic primary hyperparathyroidism — Usually a single adenoma in an older adult; absence of family history and other endocrine tumors; calcium-to-creatinine clearance ratio helps exclude familial hypocalciuric hypercalcemia
• Sporadic pheochromocytoma — Unilateral, occurs later in life (>40), lacks other endocrinopathies; genetic testing still recommended given ~30% germline mutation rate
• Von Hippel-Lindau disease — Pheochromocytoma plus retinal and CNS hemangioblastomas, renal cell carcinoma, pancreatic cysts and serous cystadenomas; VHL gene mutation
• Neurofibromatosis type 1 — Pheochromocytoma plus cafe-au-lait macules, neurofibromas, axillary freckling, Lisch nodules; NF1 gene mutation
• Familial isolated hyperparathyroidism — Hyperparathyroidism without other tumors; may involve MEN1, CDC73, or CASR variants
• Zollinger-Ellison syndrome (sporadic) — Refractory peptic ulceration with elevated gastrin and secretin stimulation; 25% of gastrinomas are MEN1-associated and warrant genetic testing
• Carney complex — Cardiac myxomas, skin pigmentation (lentigines), primary pigmented nodular adrenocortical disease (Cushing syndrome), testicular tumors; PRKAR1A gene

Diagnostic workup

Diagnostic algorithm

Treatment

Complications

• Metastatic medullary thyroid carcinoma — leading cause of MEN2-related death; calcitonin doubling time predicts prognosis
• Hypertensive crisis from unrecognized pheochromocytoma during surgery, pregnancy, or anesthesia induction
• Nephrolithiasis, renal insufficiency, and bone loss from chronic hypercalcemia
• Recurrent peptic ulceration, perforation, and bleeding from gastrinoma
• Apoplexy of large pituitary adenomas, visual field loss from chiasmal compression
• Surgical hypoparathyroidism, recurrent laryngeal nerve injury after thyroidectomy or parathyroidectomy

PANCE pearls

• Always screen for and treat pheochromocytoma BEFORE thyroid or parathyroid surgery in any patient with confirmed or suspected MEN2 — failure to do so risks fatal intraoperative hypertensive crisis.
• RET codon M918T defines MEN2B and carries the highest risk; prophylactic thyroidectomy within the first year of life is recommended.
• Hyperparathyroidism in MEN1 is multiglandular at presentation — single-gland parathyroidectomy is inadequate; recurrence rates exceed 50% within 10 years.
• Gastrinoma triangle (junction of cystic and common bile ducts, neck of pancreas, junction of second and third portions of duodenum) is the most common location for MEN1-associated gastrinomas, which are often multiple and small.
• MEN2B patients often present in infancy with inability to cry tears, constipation, and feeding difficulty from intestinal ganglioneuromatosis — recognition before age 1 is critical because medullary thyroid carcinoma can metastasize within the first year of life.

References

• Endocrine Society 2012 — Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (Thakker et al., J Clin Endocrinol Metab 2012)
• ATA 2015 — Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma (Wells et al., Thyroid 2015)
• AACE/AAES 2016 — American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Disease State Clinical Review: Pheochromocytoma and Paraganglioma (Fishbein et al., Endocr Pract 2021)
• Endocrine Society 2014 — Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline (Lenders et al., J Clin Endocrinol Metab 2014)