A 38-year-old man from rural Rajasthan presents with recurrent nephrolithiasis and severe headaches. On examination, blood pressure is 165/105 mmHg. Serum calcium is 11.2 mg/dL (normal 8.5–10.2), and PTH is elevated at 120 pg/mL. Imaging reveals a 1.8 cm left adrenal mass. A 24-hour urine metanephrine is elevated at 450 μg (normal <400). Upper GI endoscopy shows a 0.8 cm gastric ulcer. Which of the following is the most likely diagnosis?

## Clinical Diagnosis: MEN 2A Syndrome ### Key Clinical Features Present **Key Point:** The patient demonstrates the classic triad of MEN 2A: **pheochromocytoma** (hypertension, elevated 24-hour urine metanephrines, adrenal mass), **primary hyperparathyroidism** (elevated calcium, elevated PTH, nephrolithiasis), and the clinical context strongly favors MEN 2A over MEN 1. ### Differential Diagnosis of MEN Syndromes | Feature | MEN 1 | MEN 2A | MEN 2B | |---------|-------|--------|--------| | **Parathyroid involvement** | Hyperplasia (95%) | Hyperplasia (20–30%) | Rare (<5%) | | **Pheochromocytoma** | Rare (2–3%) | Common (50%) | Common (50%) | | **GEP-NETs / Gastrinoma** | Common (60–70%) | Rare | Absent | | **Medullary thyroid cancer** | Absent | Present (100%) | Present (100%) | | **Mucosal neuromas** | Absent | Absent | Present (100%) | | **Gene** | MENIN (chr 11q13) | RET proto-oncogene | RET proto-oncogene | ### Why This Is MEN 2A 1. **Pheochromocytoma** — occurs in ~50% of MEN 2A patients and is a defining feature. The adrenal mass with elevated urine metanephrines is a hallmark finding. 2. **Primary hyperparathyroidism** — occurs in 20–30% of MEN 2A patients; elevated calcium and PTH with nephrolithiasis fits this component. 3. **Gastric ulcer** — in this context, the ulcer is most likely a peptic ulcer secondary to stress or incidental finding, NOT a gastrinoma-driven GEP-NET. The stem does not confirm elevated fasting gastrin or Zollinger-Ellison syndrome. 4. **Pheochromocytoma in MEN 1 is exceedingly rare (2–3%)** — making MEN 1 a far less likely diagnosis when pheochromocytoma is a prominent feature. 5. **Absence of mucosal neuromas** — rules out MEN 2B. **High-Yield:** The combination of **pheochromocytoma + primary hyperparathyroidism** in a middle-aged patient is the classic presentation of **MEN 2A** (Sipple syndrome). Pheochromocytoma is common in MEN 2A (50%) but rare in MEN 1 (2–3%) — this distinction is the key discriminator. ### Pathophysiology MEN 2A is caused by gain-of-function mutations in the **RET proto-oncogene** (chromosome 10q11.2), which encodes a receptor tyrosine kinase. This leads to: - Medullary thyroid carcinoma (virtually 100% penetrance — may be subclinical at this stage) - Pheochromocytoma (~50%) - Parathyroid hyperplasia/adenoma (~20–30%) **Clinical Pearl:** Always screen MEN 2A patients for medullary thyroid carcinoma (calcitonin levels, RET mutation testing) even if not clinically apparent. Pheochromocytoma must be excluded BEFORE any surgical intervention for thyroid or parathyroid disease. ### Mnemonic for MEN 2A — "Sipple's 3 P's": - **P**heochromocytoma - **P**arathyroid hyperplasia - **P**apillary/medullary thyroid cancer (medullary) [cite: Robbins & Cotran Pathologic Basis of Disease, 10e, Ch 24; Harrison's Principles of Internal Medicine, 21e, Ch 384]