Multiple Endocrine Neoplasia Type 2

Rare familial cancer syndrome caused by mutations in the RET proto-oncogene; there is an association with medullary thyroid cancer and phaeochromocytoma

Aetiology

  • Autosomal dominant RET gene mutation - 10q
    • Classic proto-oncogene

Pathophysiology

  • RET mutations affect specific cysteine residues
  • Mutations result in activation of receptor tyrosine kinase
  • Clear phenotype/genotype correlation
  • High frequency of de novo mutations for MEN2B (i.e. absent familiy history)

MEN2 subtypes

MEN2a (Sipple syndrome)
  • Accounts for the majority of MEN2 cases (90-95%), describes the combination of medullary thyroid cancer in association with phaechromocytoma and parathyroid tumours
  • Phaeochromocytoma may be bilateral and occur at extra-adrenal sites
  • Linked to germline gain of function mutation in RET oncogene - several variants
MEN2b
  • MTC and pheochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibres, intestinal autonomic ganglion dysfunction
  • Also linked to a germline mutation in RET oncogene - distinct from 2A mutations and almost always activating point mutation in the catalytic domain of the encoded enzyme

MEN2 and medullary thyroid cancer

  • MTC typically first manifestation in MEN2
  • Major cause of premature morbidity and mortality
  • Importance of early detection of those at risk through RET mutation testing
  • Clinical presentations are typically associated with metastatic disease and poor outcomes
    • Neck mass
    • Diarrhoea and flushing (metastatic disease)
    • Ectopic ACTH and Cushing

Pheochromocytoma and primary hyperparathyroidism in MEN2

  • Pheochromocytoma occurs in 40-50% of MEN2 patients but dependent on genotype
    • May occur in children and are frequently bilateral
    • Typically benign but associated with morbidity and mortality if not recongnised and treated
    • Pheochromocytoma diagnosis based on elevatedurinary or plasma metanephrines
    • Management - surgical with appropriate pre-operative management
  • Primary hyperparathyroidism occurs in ~30% of MEN2 patients
    • Management - surgical removal of enlarged/overactive parathyroid glands

Clinical presentation

  • Patients may present with symptoms related to MTC, hyperparathyroidism, or phaeochromocytoma