A 42-year-old woman with hypertension and a family history of medullary thyroid carcinoma is found to have a 2.2 cm right adrenal mass on imaging. Plasma free metanephrines are 1.8 times the upper limit of normal (borderline elevated). A repeat plasma metanephrine measurement 1 week later is normal. What is the most appropriate next step?

Explanation

## Clinical Context: Familial Pheochromocytoma Syndrome **Key Point:** This patient has a **borderline elevated** plasma metanephrine (normalized on repeat testing) AND a significant family history of medullary thyroid carcinoma (MTC). This constellation strongly suggests **Multiple Endocrine Neoplasia type 2 (MEN2)**, a RET proto-oncogene–driven syndrome. ## MEN2 Syndromes & Associated Tumors | Syndrome | RET Mutation | Pheochromocytoma | Medullary Thyroid Ca | Primary Hyperparathyroidism | Mucosal Neuromas | | --- | --- | --- | --- | --- | --- | | **MEN2A** | Germline RET | 50% | 100% | 20–30% | Absent | | **MEN2B** | Germline RET | 50% | 100% | Rare | Present | | **Familial Medullary Thyroid Ca (FMTC)** | Germline RET | Rare | 100% | Absent | Absent | **High-Yield:** The presence of MTC in a first-degree relative + adrenal mass in the proband = **presumed MEN2 until proven otherwise**, regardless of biochemical borderline results. ## Management Algorithm for Suspected MEN2 ```mermaid flowchart TD A[Adrenal mass + FHx MTC]:::outcome --> B{Biochemical confirmation of pheo?}:::decision B -->|Borderline/Normal| C[Still suspect MEN2]:::action B -->|Clearly elevated| C C --> D[Genetic testing: RET proto-oncogene]:::action D --> E{RET mutation present?}:::decision E -->|Yes| F[Confirm MEN2 diagnosis]:::outcome F --> G[Thyroid screening: ultrasound + calcitonin]:::action F --> H[Parathyroid screening: serum calcium/PTH]:::action F --> I[Ophthalmology: pheochromocytoma-specific eye exam if MEN2B]:::action E -->|No| J[Sporadic adrenal mass]:::outcome J --> K[Standard surveillance]:::action ``` ## Why Genetic Testing is Mandatory Here 1. **Family history of MTC is a red flag** — MTC is the hallmark of MEN2, not sporadic pheochromocytoma 2. **Borderline biochemistry does NOT exclude pheochromocytoma** in a hereditary syndrome; some MEN2 patients have mild catecholamine excess 3. **RET mutation status determines lifelong surveillance and screening** for other MEN2 tumors 4. **Medullary thyroid carcinoma requires early intervention** — prophylactic thyroidectomy is often recommended before age 10 in RET mutation carriers **Clinical Pearl:** In hereditary pheochromocytoma (MEN2, NF1, SDH mutations), the adrenal mass may be smaller and biochemical abnormalities more subtle than in sporadic cases. Family history is often the strongest clue. **Warning:** Do NOT dismiss borderline metanephrines in a patient with a strong family history of MTC. Genetic testing takes precedence over repeat biochemistry in this scenario. [cite:Harrison 21e Ch 405]