A 42-year-old woman from Delhi presents to the endocrinology clinic for evaluation of hypertension (BP 164/102 mmHg) and episodic palpitations with diaphoresis. Plasma metanephrines are markedly elevated. On examination, she has a firm, non-tender thyroid nodule. TSH is normal, but fine-needle aspiration cytology (FNAC) shows C-cell hyperplasia and focal medullary thyroid carcinoma (MTC). Serum calcium is 10.8 mg/dL and PTH is 78 pg/mL (normal 15–65). Her 16-year-old daughter has been found to have elevated calcitonin (45 pg/mL; normal <10) on routine screening. What is the most likely diagnosis?

Explanation

## Diagnosis: MEN 2A Syndrome ### Clinical Triad Present **Key Point:** MEN 2A is defined by the **3 M's**: **M**edullary thyroid carcinoma (MTC), **M**ultiple endocrine neoplasias (parathyroid hyperplasia), and **M**ultiple pheochromocytomas. This patient demonstrates all three cardinal features: | Feature | Clinical Finding | Mechanism | |---------|------------------|----------| | **Medullary Thyroid Carcinoma** | C-cell hyperplasia with focal MTC; elevated calcitonin in daughter | RET proto-oncogene gain-of-function mutation (chromosome 10q11.2) | | **Pheochromocytoma** | Elevated plasma metanephrines; episodic palpitations, diaphoresis, hypertension | Bilateral adrenal medullary hyperplasia/adenoma (50% of MEN 2A patients) | | **Primary Hyperparathyroidism** | Serum calcium 10.8, PTH 78 (mildly elevated) | Parathyroid hyperplasia (20–30% of MEN 2A patients) | ### Pathophysiology **High-Yield:** MEN 2A is caused by **activating mutations in the RET proto-oncogene** (chromosome 10q11.2). RET encodes a receptor tyrosine kinase: 1. Gain-of-function mutation → constitutive RET activation 2. Uncontrolled proliferation of **neural crest–derived cells** (C-cells, adrenal medulla, parathyroid) 3. **C-cell hyperplasia is the precursor lesion** to MTC (present in nearly 100% of MEN 2A carriers by age 50) ### Diagnostic Criteria & Genetic Counseling **Mnemonic: "RET = Rare Endocrine Tumors"** - **RET mutation** is the molecular hallmark - **E**ndocrine hyperplasia precedes malignancy - **T**hyroid C-cells are the primary target **Clinical Pearl:** The daughter's elevated calcitonin (45 pg/mL) indicates **C-cell hyperplasia/early MTC**, confirming familial inheritance. Genetic testing for RET mutations is indicated in all first-degree relatives. ### MEN 2A vs. MEN 2B vs. fMTC | Feature | MEN 2A | MEN 2B | fMTC | |---------|--------|--------|------| | **MTC** | Yes (95%) | Yes (100%) | Yes (100%) | | **Pheochromocytoma** | Yes (50%) | Yes (50%) | No | | **Hyperparathyroidism** | Yes (20–30%) | **No** | No | | **Mucosal neuromas** | No | **Yes (100%)** | No | | **Marfanoid habitus** | No | **Yes** | No | | **RET codon** | 609, 611, 618, 620, 634 | 918 (M918T), 883 | 609, 611, 618, 620, 634 | ### Management **Urgent actions:** 1. **Thyroidectomy:** Total thyroidectomy recommended for all RET mutation carriers (ideally before age 5–10 in MEN 2A; earlier in MEN 2B) 2. **Pheochromocytoma screening:** 24-hour urine metanephrines, plasma metanephrines, imaging (CT/MRI abdomen) annually 3. **Parathyroid screening:** Serum calcium, PTH annually; consider parathyroidectomy if symptomatic or biochemically significant hyperparathyroidism 4. **Genetic testing:** RET sequencing in the proband and all first-degree relatives 5. **Calcitonin monitoring:** In the daughter, escalating calcitonin levels warrant earlier thyroidectomy [cite:Robbins 10e Ch 24; Harrison 21e Ch 438]