A 42-year-old man with a family history of medullary thyroid carcinoma presents to the emergency department with acute severe headache, chest tightness, and blood pressure 210/130 mmHg. His 24-hour urine metanephrines are markedly elevated at 8.5 nmol/L. Abdominal imaging reveals bilateral adrenal masses (2.5 cm left, 1.8 cm right). Serum calcium is 10.2 mg/dL (normal 8.5–10.5). What is the most likely underlying genetic syndrome, and what is the recommended screening for this patient's first-degree relatives?

Explanation

## Clinical Clues Pointing to MEN-2A **Key Point:** The combination of **bilateral pheochromocytoma + family history of medullary thyroid carcinoma (MTC)** is pathognomonic for MEN-2A syndrome. ## MEN-2A Syndrome Overview MEN-2A is an autosomal-dominant syndrome caused by **RET proto-oncogene mutations** (chromosome 10q11.2). It is characterized by the triad: 1. **Medullary thyroid carcinoma (MTC)** — present in >95% of carriers; often the first manifestation 2. **Pheochromocytoma** — occurs in 50% of MEN-2A patients; bilateral in 70% of cases 3. **Primary hyperparathyroidism** — occurs in 20–30%; may present with hypercalcemia or kidney stones **High-Yield:** Bilateral pheochromocytoma is rare in sporadic disease (~10%) but common in MEN-2A (~70% of MEN-2A pheo patients have bilateral disease). ## Why This Patient Has MEN-2A | Feature | This Patient | MEN-2A Pattern | | --- | --- | --- | | **Bilateral adrenal masses** | Yes (2.5 + 1.8 cm) | 70% bilateral | | **Family history of MTC** | Yes (first-degree relative) | Autosomal dominant | | **Elevated metanephrines** | Yes (8.5 nmol/L) | 50% of MEN-2A | | **Serum calcium** | Normal (10.2) | Hyperparathyroidism in 20–30% | ## Screening Relatives: RET Testing & Calcitonin **Clinical Pearl:** All first-degree relatives of MEN-2A patients must undergo: 1. **RET proto-oncogene DNA sequencing** — identifies carriers of the mutation; if positive, prophylactic thyroidectomy is recommended (usually before age 5–10 years) 2. **Serum calcitonin (fasting and stimulated with pentagastrin or calcium gluconate)** — detects early MTC; elevated calcitonin is the earliest biochemical marker of MTC in MEN-2A 3. **24-hour urine metanephrines** — screens for pheochromocytoma (annually after age 8) 4. **Serum calcium and PTH** — screens for hyperparathyroidism **Mnemonic:** **RET-MEN-2A** — **RET** mutation causes **MEN-2A** (Medullary, Endocrine, Neoplasia). ## Why Not the Other Syndromes? ```mermaid flowchart TD A[Bilateral pheochromocytoma<br/>+ Family hx MTC]:::outcome --> B{Which syndrome?}:::decision B -->|MEN-1| C[Prolactinoma, parathyroid<br/>adenoma, pancreatic NET]:::outcome B -->|MEN-2A| D[MTC + pheo + hyperPTH<br/>RET mutation]:::outcome B -->|Familial pheo| E[SDHA/SDHB/SDHD<br/>Unilateral or extra-adrenal]:::outcome B -->|VHL| F[Hemangioblastoma, RCC<br/>Usually unilateral pheo]:::outcome D -->|CORRECT| G[RET testing +<br/>calcitonin screening]:::action ``` **High-Yield:** MEN-1 does NOT include MTC (it has prolactinoma and parathyroid adenoma); VHL and familial SDHA pheo rarely present with MTC family history.