Multiple endocrine neoplasia type 2 (MEN2)
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A 25-year-old woman presents with a thyroid nodule. Biopsy shows medullary thyroid carcinoma. Calcitonin is markedly elevated. Genetic testing reveals a RET pathogenic variant. Her 5-year-old son tests positive for the same variant and is referred for prophylactic thyroidectomy.
AD; RET proto-oncogene (gain-of-function)
- Genotype-phenotype correlation determines management
- Specific RET codon variants predict disease severity and timing
Subtypes:
| Feature | MEN2A (~95%) | MEN2B (~5%) |
|---|---|---|
| MTC | Nearly 100% | Nearly 100% (earlier, more aggressive) |
| Pheochromocytoma | ~50% | ~50% |
| Parathyroid hyperplasia | 20-30% | Rare |
| Mucosal neuromas | No | Yes (lips, tongue, eyelids) |
| Marfanoid habitus | No | Yes |
| Intestinal ganglioneuromatosis | No | Yes |
- Medullary thyroid carcinoma (MTC): nearly 100%; arises from parafollicular C cells; calcitonin is the tumor marker
- Pheochromocytoma: bilateral in ~50%; screen before any surgery
- Prophylactic thyroidectomy based on RET variant:
- Highest risk (M918T/MEN2B): thyroidectomy within first 6 months of life
- High risk (C634R): thyroidectomy by age 5
- Moderate risk: thyroidectomy can be guided by calcitonin levels
- RET genetic testing
- Calcitonin and CEA for MTC screening
- Plasma/urine metanephrines and catecholamines for pheochromocytoma
- Always screen for pheochromocytoma BEFORE surgery
- Risk-stratified prophylactic thyroidectomy
- Annual biochemical screening for pheochromocytoma
- Calcium/PTH monitoring for hyperparathyroidism (MEN2A)
- Genetic testing of at-risk family members
"Piter Pan's papa pheels thyr'd and mucousy": MEN1 = Pituitary, pancreas, parathyroid. MEN2A = parathyroid, pheo, thyroid. MEN2B = pheo, thyroid, mucosal neuromas.
Mutations in RET are associated with ThyRoid cancer: RET is a proto-oncogene (gain-of-function), unlike most cancer predisposition genes which are tumor suppressors (loss-of-function). 50% of MEN2B occurs de novo.