Sipple syndrome

**Definition:** Sipple syndrome = Multiple Endocrine Neoplasia type 2A (MEN2A). Classic triad: (1) medullary thyroid carcinoma (MTC, ~100% penetrance), (2) pheochromocytoma (~50%), (3) primary hyperparathyroidism from parathyroid hyperplasia (~20-30%).

**Genetics/Pathophysiology:** - Autosomal dominant; gain-of-function germline mutation of the RET proto-oncogene (chr 10q11), a receptor tyrosine kinase. The most common mutations are in cysteine codons of the extracellular domain (e.g., codon 634) and cause constitutive activation. - Contrast with loss-of-function RET mutations, which cause Hirschsprung disease. Some families have both. - MTC arises from parafollicular C cells (neural crest derived) and secretes calcitonin. Tumors stain for amyloid (calcitonin-derived), which appears as Congo red-positive apple-green birefringence. - Pheochromocytoma arises from adrenal medulla chromaffin cells and secretes catecholamines. It is often bilateral in MEN2.

**Clinical features:** - MTC: thyroid nodule, neck mass, and possible diarrhea (calcitonin/prostaglandins/VIP). Elevated calcitonin and CEA. Usually the first manifestation, and it is multifocal and bilateral. - Pheochromocytoma: episodic headache, palpitations, diaphoresis, and hypertension (the "5 Ps": pressure, pain, perspiration, palpitations, pallor). - Hyperparathyroidism: hypercalcemia ("stones, bones, groans, psychiatric overtones"), with elevated PTH.

**Diagnosis:** Serum calcitonin, plasma free or urinary fractionated metanephrines, calcium/PTH, and RET germline testing. Screen relatives.

**Management:** - **Prophylactic total thyroidectomy** in RET mutation carriers. Timing depends on the mutation risk category (earliest for codon 918/MEN2B and 634). - **Pheochromocytoma:** Always rule out and treat it BEFORE any other surgery. Give an alpha-blocker first (phenoxybenzamine), then a beta-blocker, then adrenalectomy. Starting a beta-blocker first causes unopposed alpha stimulation and a hypertensive crisis. - Parathyroid: resection of the involved glands. - Vandetanib/cabozantinib (RET tyrosine kinase inhibitors) for advanced MTC. Selpercatinib/pralsetinib are selective RET inhibitors.

**Key associations/distinctions (high-yield):** - **MEN2A (Sipple):** MTC + pheochromocytoma + parathyroid hyperplasia. Variants include cutaneous lichen amyloidosis and Hirschsprung disease. - **MEN2B (MEN3):** MTC + pheochromocytoma + mucosal neuromas + marfanoid habitus, with NO hyperparathyroidism. Usually RET codon M918T, and it is more aggressive. - **MEN1 (Wermer):** the 3 Ps: Pituitary, Parathyroid, Pancreas (gastrinoma, insulinoma). It is caused by a MEN1 (menin) tumor suppressor mutation on chr 11. - Mnemonic: MEN2A has "2 As" = Adrenal and thyroid/parathyroid... (Sipple = "Sip" a drink with the 2A "calcium" for the parathyroid.)

**Exam pearl:** A patient with a thyroid mass, high calcitonin, and episodic hypertension has MEN2A until proven otherwise. Check metanephrines before thyroid surgery.