Overview Of MEN2

  • Definition & Subtypes
    • Autosomal dominant disorder involving medullary thyroid carcinoma (MTC) in all subtypes
    • Three clinical variants:
      1. MEN 2A: MTC, pheochromocytoma (≈50%), primary hyperparathyroidism (≈20%), cutaneous lichen amyloidosis (≈5%)
      2. MEN 2B: MTC, pheochromocytoma (≈50%), mucocutaneous neuromas, intestinal ganglioneuromas (including Hirschsprung disease), skeletal abnormalities
      3. 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

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

  1. 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
  2. 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
  3. Therapeutic Interventions
    • Total thyroidectomy + central node dissection at timing based on mutation risk
    • Pheochromocytoma resection after appropriate medical management
    • Parathyroidectomy if needed for hyperparathyroidism

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