MEN2 is caused by germline gain-of-function pathogenic variants in the RET proto-oncogene, which encodes a receptor tyrosine kinase critical to multiple developmental signaling pathways. The assertional relationship between RET variants and MEN2 is deterministic. In cases of simplex MTC (no known family history), approximately 6 to 7% of individuals are found to harbor a germline RET variant. Penetrance of specific RET pathogenic variants is incomplete, with incidence of MTC, pheochromocytoma, and parathyroid disease varying by MEN2 phenotype and specific variant. Genotype-specific risk stratification guides surveillance timing and prophylactic interventions. The inheritance pattern documented in GeneReviews is consistent with autosomal dominant transmission, though this field is absent from the structured packet data.

Clinical diagnostic criteria for MEN2 have been published and are subtype-specific. MEN2A is suspected in individuals with one or more of the characteristic endocrine tumors: MTC, pheochromocytoma, or parathyroid adenoma/hyperplasia. FMTC is suspected in families with multiple members diagnosed with MTC in the absence of pheochromocytoma or parathyroid disease. MEN2B is suspected in individuals with the distinctive facial features, mucosal neuromas, marfanoid habitus, and MTC. The principal biochemical marker is plasma calcitonin, which is elevated in MTC and CCH. Stimulated calcitonin testing using intravenous calcium administration is used for provocative assessment. The diagnosis is confirmed by molecular genetic testing identifying a heterozygous germline gain-of-function pathogenic variant in RET. Molecular genetic testing is recommended in all individuals with clinical diagnosis due to genotype-specific surveillance and treatment implications. Biochemical evaluation at diagnosis includes plasma CEA, plasma free metanephrines or 24-hour urine fractionated metanephrines, and serum calcium with parathyroid hormone.

Prophylactic thyroidectomy is the primary preventive intervention for individuals with an identified germline RET pathogenic variant; timing is guided by the specific variant's risk category. Thyroidectomy before progression to invasive MTC offers the best oncologic outcomes. For established MTC, surgical resection including neck nodal dissection is the primary treatment. For persistent, recurrent, or metastatic MTC, systemic therapy with tyrosine kinase inhibitors is used; vandetanib and cabozantinib are approved kinase inhibitors in this indication. RET-selective inhibitors selpercatinib and pralsetinib are documented in GeneReviews as now approved for RET-driven MTC. Pheochromocytoma is managed with surgical resection, with perioperative alpha-blockade to prevent hypertensive crisis. Primary hyperparathyroidism is managed surgically based on the extent of glandular involvement.

MEN2 prognosis is strongly influenced by stage at detection and the specific RET variant. Approximately 50% of individuals who undergo total thyroidectomy and neck nodal dissection develop recurrent disease. When MTC is identified biochemically before clinical manifestation — through genetic screening of at-risk family members — outcomes are substantially better than in those presenting with symptomatic disease. The availability of RET-selective inhibitors has improved outcomes for individuals with metastatic or progressive disease. Pheochromocytoma, although rarely metastatic in MEN2, carries lethal potential if unrecognized. The near-universal biochemical penetrance of RET variants (all carriers show MTC evidence by age 35 without thyroidectomy) underscores the importance of early genetic diagnosis.

Multikinase inhibitors including sorafenib, sunitinib, and regorafenib are under investigation in clinical trials for MTC. National Comprehensive Cancer Network and American Thyroid Association guidelines recognize RET-selective inhibitors as having expanded therapeutic options for individuals who fail standard treatment. Ongoing registry and natural history studies include NCT01793168 (Coordination of Rare Diseases at Sanford) and NCT03050268 (Familial Investigations of Childhood Cancer Predisposition at St. Jude Children's Research Hospital). Genetic epidemiology research is characterizing the spectrum of RET variants and their phenotypic consequences across different ethnic populations, including an active study on neuroendocrine neoplasms in Mexican patients (NCT06523582).