Multiple endocrine neoplasia type 4 (MEN4)

MEN4 is a rare autosomal dominant multiglandular endocrine neoplasia syndrome that clinically overlaps with but presents with a milder phenotype and a later age at onset. Primary hyperparathyroidism is the hallmark and most frequent first manifestation, usually presenting in adulthood and at a later age than in MEN1. Hyperparathyroidism in MEN4 is often caused by a single parathyroid adenoma, although the evidence base is limited and multi-gland involvement also occurs. Pituitary adenomas occur in approximately 23% of affected individuals, most commonly secreting growth hormone or ACTH, while functionally inactive adenomas also occur. Gastro-entero-pancreatic and duodenal neuroendocrine tumours are described but rare, and additional reported manifestations include adrenocortical and thyroid lesions.

MEN4 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the familial CDKN1B pathogenic variant.

The diagnosis of MEN4 is established in a proband with suggestive clinical and biochemical findings (primary hyperparathyroidism and/or pituitary adenoma, often in combination with additional endocrine tumours) by identification of a heterozygous germline pathogenic variant in CDKN1B on molecular genetic testing. No formal consensus clinical diagnostic criteria for MEN4 have been established; the molecular finding distinguishes MEN4 from and other monogenic causes of multiglandular endocrine tumour predisposition.

Main differential diagnoses include:

• : with multi-gland parathyroid involvement, higher penetrance of primary hyperparathyroidism (over 90%) and substantially more frequent gastro-entero-pancreatic neuroendocrine tumours; MEN1
• Familial isolated hyperparathyroidism (FIHP): isolated familial primary hyperparathyroidism without pituitary, pancreatic or other endocrine tumours; lacks the multiglandular endocrine spectrum that defines MEN4; MEN1, CDC73, CASR, GCM2

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic CDKN1B 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.

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