A 38-year-old man presents with recurrent nephrolithiasis and hypercalcaemia. Biochemistry shows elevated PTH (120 pg/mL, normal 10–65) and serum calcium 11.2 mg/dL. On further questioning, he reports a family history of thyroid nodules and medullary thyroid carcinoma in his mother. Which investigation is most appropriate to confirm the suspected diagnosis?

Explanation

## Diagnosis: MEN 2A Syndrome This patient presents with the classic triad of MEN 2A: 1. **Primary hyperparathyroidism** (elevated PTH, hypercalcaemia, nephrolithiasis) 2. **Medullary thyroid carcinoma (MTC)** (family history in mother) 3. **Pheochromocytoma** (suspected given family pattern) ## Investigation of Choice: Serum Calcitonin + RET Mutation Testing **Key Point:** MEN 2A is caused by **germline RET proto-oncogene mutations** (chromosome 10q11.2). RET testing is the gold standard for diagnosis and family screening. **High-Yield:** Calcitonin is the most sensitive and specific marker for medullary thyroid carcinoma (C-cell hyperplasia precedes MTC). Elevated calcitonin in the presence of family history of MTC strongly suggests MEN 2A. ### Why This Combination? | Investigation | Role in MEN 2A | Sensitivity | Specificity | | --- | --- | --- | --- | | **Serum calcitonin** | Detects C-cell disease (MTC precursor) | 95% for MTC | 98% | | **RET mutation testing** | Confirms diagnosis; enables family screening | 95% | 99% | | **Parathyroid imaging** | Localizes hyperparathyroid gland | 70–80% | Moderate | | **Thyroid ultrasound** | Detects nodules but not C-cell disease | 60–70% | Low specificity | **Clinical Pearl:** In MEN 2A, **RET mutation carriers require:** 1. Annual calcitonin and CEA screening from age 5–10 2. Prophylactic thyroidectomy (usually by age 5–10) if RET+ and calcitonin elevated 3. Screening for pheochromocytoma (plasma metanephrines, abdominal imaging) 4. Screening for hyperparathyroidism (serum calcium, PTH) **Mnemonic: MEN 2A = "PTC" (Pheo, Thyroid, Calcium)** - **P**heochromocytoma (50% of cases) - **T**hyroid medullary carcinoma (100% of cases) - **C**alcium elevation (primary hyperparathyroidism, 20–30%) ## Diagnostic Algorithm ```mermaid flowchart TD A[Family Hx of MTC + Hyperparathyroidism]:::outcome --> B{Suspect MEN 2A?}:::decision B -->|Yes| C[Measure serum calcitonin]:::action C --> D{Calcitonin elevated?}:::decision D -->|Yes| E[RET proto-oncogene mutation testing]:::action D -->|No| F[Consider MEN 1 or sporadic hyperparathyroidism]:::outcome E --> G{RET mutation present?}:::decision G -->|Yes| H[Confirm MEN 2A diagnosis]:::outcome G -->|No| I[Exclude MEN 2A]:::outcome H --> J[Screen for pheochromocytoma]:::action J --> K[Prophylactic thyroidectomy planning]:::action ``` [cite:Robbins 10e Ch 24]