A 52-year-old man with a family history of medullary thyroid carcinoma presents with recurrent episodes of severe hypertension (200/115 mmHg), headache, and diaphoresis. Plasma free metanephrines are markedly elevated. Abdominal imaging reveals a 2.5 cm right adrenal mass. Genetic testing shows a RET proto-oncogene mutation. Which of the following is the most likely syndromic association, and what additional screening should be performed?

Explanation

## Syndromic Pheochromocytoma: MEN2A ### Clinical Recognition of MEN2A **Key Point:** RET proto-oncogene mutations define MEN2A, which presents with the triad of medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism. ### Diagnostic Features in This Case | Feature | Clinical Finding | Significance | |---------|------------------|---------------| | **Genetic mutation** | RET proto-oncogene | Pathognomonic for MEN2A/MEN2B | | **Family history** | Medullary thyroid carcinoma | Suggests hereditary syndrome | | **Catecholamine excess** | Elevated plasma free metanephrines | Pheochromocytoma component | | **Adrenal imaging** | Single 2.5 cm right adrenal mass | Unilateral in ~50% of MEN2A cases | ### MEN2A Screening Protocol **High-Yield:** All RET mutation carriers require lifelong surveillance: 1. **Thyroid surveillance** (highest cancer risk) - Annual serum calcitonin and carcinoembryonic antigen (CEA) - Annual thyroid ultrasound - Prophylactic total thyroidectomy recommended in childhood (age 5–10) for high-risk RET mutations 2. **Pheochromocytoma screening** - Annual plasma free metanephrines or 24-hour urine metanephrines - **Bilateral adrenal imaging** (pheochromocytomas are bilateral in ~50% of MEN2A cases) - Imaging at diagnosis, then every 2–3 years 3. **Parathyroid screening** - Serum calcium and PTH annually - Parathyroid imaging if hypercalcemia detected **Clinical Pearl:** Pheochromocytomas in MEN2A are often **bilateral and benign**, unlike sporadic pheochromocytomas. Bilateral adrenalectomy may be required, necessitating lifelong glucocorticoid and mineralocorticoid replacement. ### Mnemonic for MEN2A **MEN2A = "M"edullary thyroid carcinoma + "E"xtra-adrenal pheochromocytoma + "N"eck (hyperparathyroidism)** - Medullary thyroid carcinoma (100%) - Pheochromocytoma (50%) - Primary hyperparathyroidism (20–30%) ### Why This Is NOT the Other Syndromes **Neurofibromatosis type 1 (NF1):** - Associated with pheochromocytoma in ~5% of cases - Caused by NF1 gene mutations (not RET) - Presents with café-au-lait spots, neurofibromas, optic nerve gliomas - No medullary thyroid carcinoma association **Familial paraganglioma syndrome:** - Caused by mutations in SDH genes (SDHA, SDHB, SDHD, SDHAF2) - Presents with extra-adrenal paragangliomas (carotid body, jugular, mediastinal) - No thyroid or parathyroid involvement **Von Hippel–Lindau (VHL) disease:** - Caused by VHL gene mutations - Presents with renal cysts, hemangioblastomas, pancreatic neuroendocrine tumors - Pheochromocytomas occur in ~10% (usually benign) - No medullary thyroid carcinoma [cite:Harrison 21e Ch 397]