Multiple endocrine neoplasia type 2 (MEN2)

The estimated prevalence is 1/35,000.

Heterozygous germline pathogenic variants in RET underlie MEN2 in >98% of probands. RET (10q11.21) encodes a receptor tyrosine kinase, and MEN2-associated variants act through gain of function. The subtypes correlate broadly with variant location: MEN2A and FMTC are associated chiefly with extracellular cysteine codons (commonly 609, 611, 618, 620, 630, or 634), whereas MEN2B is associated with the intracellular substitution p.Met918Thr (codon 918). By contrast, inactivating (loss-of-function) RET variants are associated with Hirschsprung disease ().

Main differential diagnoses include:

• Sporadic MTC: unifocal, later onset, no C-cell hyperplasia; somatic RET variants only
• Hereditary paraganglioma-phaeochromocytoma syndrome: head and neck paragangliomas alongside phaeochromocytoma; SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX, TMEM127
• : phaeochromocytoma with CNS haemangioblastomas, clear cell renal carcinoma, pancreatic neuroendocrine tumours; VHL

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic RET variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Eng C, Plitt G. Multiple endocrine neoplasia type 2. 1999 Sep 27 [updated 2023 Aug 10]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301434.
• Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. doi:10.1089/thy.2014.0335. PMID:.
• Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET mutation consortium analysis. JAMA. 1996;276(19):1575-9. PMID:.