What is MEN2?

MEN2 is a rare inherited syndrome characterized by medullary thyroid cancer (MTC), pheochromocytomas, and (in MEN2A) primary hyperparathyroidism. It is caused by mutations in the RET gene.

Genetics:

• RET Proto-Oncogene Mutation: Autosomal dominant (50% transmission risk)
• High Penetrance: Nearly 100% develop MTC
• Three Subtypes: MEN2A (most common), MEN2B (most aggressive), Familial MTC only (FMTC)

MEN2A (95% of MEN2):

Clinical Features:

• Medullary Thyroid Cancer (MTC) (100%): Develops in childhood/early adulthood; often first manifestation
• Pheochromocytomas (50%): Bilateral in 50%; benign in 95%; secrete catecholamines
• Primary Hyperparathyroidism (20-30%): Multiglandular hyperplasia
• Cutaneous Lichen Amyloidosis (Rare): Itchy skin patches on upper back
• Hirschsprung Disease (Rare): Congenital megacolon

MEN2B (5% of MEN2 - Most Aggressive):

• MTC (100%): Develops in infancy; very aggressive
• Pheochromocytomas (50%)
• Mucosal Neuromas (100%): Bumpy lips, tongue—pathognomonic
• Marfanoid Habitus: Tall, thin, long limbs
• GI Issues: Constipation, megacolon
• NO Hyperparathyroidism
• Requires Earliest Thyroidectomy (Infancy)

Diagnosis & Screening:

• Genetic Testing: RET mutation confirmsdiagnosis; screen all at-risk family members
• Biochemical Screening (Annual for Mutation Carriers):
  • Calcitonin: Marker for MTC (elevated → MTC present or developing)
  • Plasma/Urine Metanephrines: Screen for pheochromocytoma (BEFORE any surgery)
  • Calcium, PTH: Screen for hyperparathyroidism (MEN2A)
• Imaging: Neck ultrasound (thyroid), adrenal CT/MRI if biochemistry positive

Management:

Medullary Thyroid Cancer (MTC):

• Prophylactic Total Thyroidectomy: CURATIVE if done before MTC develops
  • MEN2A: Age 5 years (or earlier if elevated calcitonin)
  • MEN2B: Within first year of life (preferably 6-12 months)
• Lifelong Thyroid Hormone Replacement (Levothyroxine)
• Monitor Calcitonin & CEA: Lifelong (detect recurrence)

Pheochromocytoma:

• Always Screen BEFORE Thyroid Surgery: Undiagnosed pheochromocytoma can cause fatal hypertensive crisis during anesthesia
• Treatment: Surgical removal (adrenalectomy)
  • If bilateral: Consider cortical-sparing adrenalectomy to preserve adrenal function
• Alpha-Blockade Pre-Op: Phenoxybenzamine, doxazosin

Hyperparathyroidism (MEN2A):

• Surgery: Subtotal parathyroidectomy (remove 3.5 glands) if symptomatic

Prognosis:

• Excellent if MTC Prevented: Prophylactic thyroidectomy before MTC develops is curative
• MEN2B: Poorer prognosis (aggressive MTC); early thyroidectomy critical
• Pheochromocytomas: Usually benign; excellent prognosis with surgery
• Family Screening Essential: Identify mutation carriers early