Multiple endocrine neoplasia (MEN) syndromes

The estimated prevalence of is 1/10,000 to 1/100,000 and of approximately 1/35,000. is comparatively rare and likely underdiagnosed.

Three genes underlie the recognised MEN syndromes. The most common cause is MEN type 1 (MEN1). MEN type 2 (RET) includes MEN2A and MEN2B. MEN type 4 is caused by pathogenic variants in CDKN1B.

The MEN syndromes are inherited in an autosomal dominant manner, and this pattern applies to all currently recognised subtypes, including the three MEN2 phenotypes (MEN2A, MEN2B and FMTC). A proportion of cases arise de novo: approximately 10% of individuals with MEN1 carry a de novo MEN1 pathogenic variant, as do roughly 5% to 9% of individuals with MEN2A and about 50% of individuals with MEN2B.

Molecular genetic testing of MEN1, RET and CDKN1B establishes the subtype where an MEN syndrome is clinically suspected. A defined germline pathogenic variant clarifies the genetic aetiology, distinguishes the subtypes whose surveillance differs, and provides the basis for predictive testing of at-risk relatives.

Main differential diagnoses include:

• Isolated primary hyperparathyroidism: parathyroid tumour without other MEN features; CDC73, CASR, GNA11, AP2S1, GCM2
• Isolated or familial phaeochromocytoma and paraganglioma: catecholamine-secreting tumours; SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, MAX
• : phaeochromocytoma with renal and central nervous system tumours; VHL

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying which MEN subtype is present and providing a basis for genetic counselling.
• A confirmed result supports subtype-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.

• Giusti F, Marini F, Brandi ML. Multiple endocrine neoplasia type 1. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .
• Eng C, Plitt G. Multiple endocrine neoplasia type 2. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .
• Brock P, Kirschner L. Multiple endocrine neoplasia type 4. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .