Which of the following genetic syndromes is associated with the HIGHEST risk of bilateral pheochromocytoma?

Explanation

## Hereditary Pheochromocytoma Syndromes and Bilateral Risk **Key Point:** Von Hippel–Lindau (VHL) syndrome carries the highest risk of bilateral pheochromocytoma (~70%), followed by MEN 2A (~50%) and NF1 (~5%). ### Genetic Syndromes Associated with Pheochromocytoma | Syndrome | Gene | Bilateral Risk | Other Features | Malignancy Risk | |----------|------|-----------------|-----------------|------------------| | **VHL** | VHL (3p25) | ~70% (highest) | Renal cysts/RCC, haemangioblastomas, pancreatic cysts | ~5% | | **MEN 2A** | RET (10q11) | ~50% | Medullary thyroid carcinoma (100%), primary hyperparathyroidism | ~5% | | **MEN 2B** | RET (10q11) | ~50% | Medullary thyroid carcinoma, mucosal neuromas, marfanoid habitus | ~5% | | **NF1** | NF1 (17q11) | ~5% | Neurofibromas, optic nerve gliomas, increased malignancy risk | ~12% | | **Familial Paraganglioma** | SDHA, SDHB, SDHD, SDHAF2 | Variable (SDHB ~70%) | Extra-adrenal paragangliomas, malignancy risk ~30–40% (SDHB) | High (SDHB) | **High-Yield:** - **VHL syndrome:** ~70% bilateral pheochromocytoma — screen all VHL patients with plasma metanephrines - **MEN 2A/2B:** ~50% bilateral — RET mutation carriers require annual biochemical screening - **NF1:** ~5% bilateral — lower risk but still screen - **SDHB mutations:** Associated with extra-adrenal paragangliomas and highest malignancy risk (~30–40%) **Clinical Pearl:** In any patient presenting with pheochromocytoma before age 40, or with bilateral disease, or with extra-adrenal paragangliomas, genetic testing is indicated. VHL and MEN 2 account for ~30% of all pheochromocytomas; SDHB mutations account for ~10%. **Mnemonic:** **VHLMN** — VHL (70% bilateral), MEN (50% bilateral), NF1 (5% bilateral), SDHB (paraganglioma, high malignancy) **Warning:** Do not confuse SDHB-associated paraganglioma (malignant, extra-adrenal, ~70% bilateral) with VHL-associated pheochromocytoma (benign, adrenal, ~70% bilateral). Both have high bilateral risk, but SDHB has much higher malignancy risk.