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