Overview Of MEN2
- Definition & Subtypes
- Autosomal dominant disorder involving medullary thyroid carcinoma (MTC) in all subtypes
- Three clinical variants:
- MEN 2A: MTC, pheochromocytoma (≈50%), primary hyperparathyroidism (≈20%), cutaneous lichen amyloidosis (≈5%)
- MEN 2B: MTC, pheochromocytoma (≈50%), mucocutaneous neuromas, intestinal ganglioneuromas (including Hirschsprung disease), skeletal abnormalities
- Familial Medullary Thyroid Cancer (FMTC): MTC only (or very minimal additional features)
- Estimated Prevalence
- ~2.5 per 100,000 in the general population
- Genetics
- Caused by germline gain-of-function mutations in the RET proto-oncogene on chromosome 10
- High penetrance for MTC
- Genotype–phenotype correlations guide prophylactic thyroidectomy timing
- Example: Codon 918 (MEN 2B) -> earliest/aggressive MTC
Medullary Thyroid Carcinoma (MTC)
- Pathophysiology & Features
- Neuroendocrine tumor arising from parafollicular C cells of the thyroid
- C cells secrete calcitonin (tumor marker); serum calcitonin correlates with tumor burden
- MTC is multicentric, often located in upper thyroid lobes (where C cells concentrate)
- ~25% of all MTC cases are heritable (MEN 2 or FMTC)
- Clinical Presentation
- Thyroid mass, cervical lymphadenopathy, or incidental imaging finding
- MEN 2B subtype: more aggressive MTC, earlier onset, metastases often found in children
- MEN 2A/FMTC: typically present in adolescence/early adulthood
- Management
- Prophylactic thyroidectomy in childhood or early adulthood, guided by RET mutation codon
- Goal: complete removal of thyroid before invasive MTC develops
- Calcitonin and carcinoembryonic antigen (CEA) are tumor markers used in postoperative follow-up
Pheochromocytoma
- Prevalence in MEN 2
- ~50% of patients with MEN 2A or 2B
- Often bilateral and multicentric
- Clinical Presentation
- May be asymptomatic initially, detected by routine screening (plasma metanephrines, urinary fractionated metanephrines)
- Symptomatic patients: episodic headache, hypertension, palpitations, diaphoresis, pallor (“the 5 P’s”)
- Management
- Preoperative α-adrenergic blockade followed by possible β-blockade if needed
- Surgical resection of involved adrenal(s); often bilateral adrenalectomy needed
Primary Hyperparathyroidism (MEN 2A only)
- Incidence
- ~20% of MEN 2A patients
- Typically multigland involvement
- Diagnosis & Treatment
- Biochemical hypercalcemia with inappropriately high parathyroid hormone (PTH)
- Surgical resection of enlarged glands (often 3.5 gland resection)
- Less common in MEN 2A than in MEN 1
MEN 2B–Specific Features
- Mucocutaneous Neuromas
- Appear on the lips, tongue, eyelids → thickened “blubbery” lips, everted eyelids
- Skeletal Deformities
- Kyphoscoliosis, lordosis, joint laxity
- Intestinal Ganglioneuromas
- Can lead to Hirschsprung disease (aganglionic megacolon)
- Aggressive MTC
- Earlier onset, often metastatic in childhood
Cutaneous Lichen Amyloidosis (MEN 2A)
- Description
- Rare, pruritic, scaly, pigmented lesion (often in the interscapular region)
- 5% of individuals with MEN 2A may have this
RET Mutations & Genotype–Phenotype Correlations
- MEN 2A / FMTC
- Commonly in cysteine codons in RET (exons 10–11, particularly codon 634)
- Risk of pheochromocytoma and MTC is high; parathyroid involvement in MEN 2A
- MEN 2B
- Usually codon 918 (p.Met918Thr) in exon 16 → most aggressive MTC
- Alternative: codon 883 in exon 15 (less common)
- Guided Prophylaxis
- Codons 918, 883, 922 → earliest prophylactic thyroidectomy (often infancy)
- Codons 611, 618, 620, 634 → removal of thyroid by age 5 years
- Codons 609, 768, 790, 791, 804, 891 → generally less aggressive MTC, thyroidectomy may be delayed (e.g., up to age 10)
Clinical Screening & Management
- Genetic Testing
- Offered to all first-degree relatives once a RET mutation is discovered in an index case
- Children with MEN 2B–associated mutations → prophylactic thyroidectomy within first 6 months of life
- Biochemical Screening
- Annual screening for pheochromocytoma (plasma or urinary metanephrines) if patient has a known “pheo-associated” RET codon
- Serum calcitonin and CEA levels for MTC
- Calcium and PTH measurements if MEN 2A to detect hyperparathyroidism
- Therapeutic Interventions
- Total thyroidectomy + central node dissection at timing based on mutation risk
- Pheochromocytoma resection after appropriate medical management
- Parathyroidectomy if needed for hyperparathyroidism