Multiple endocrine neoplasia type 4

Multiple endocrine neoplasia type 4 (MEN4), also known as MEN1-like syndrome or MENX, is a rare hereditary tumor syndrome caused by germline mutations in the CDKN1B gene, which encodes the cyclin-dependent kinase inhibitor p27Kip1. MEN4 was first described in 2006 and represents the most recently identified member of the multiple endocrine neoplasia family of syndromes. It shares significant clinical overlap with multiple endocrine neoplasia type 1 (MEN1) but occurs in patients who do not carry MEN1 gene mutations. MEN4 primarily affects the endocrine system, with patients developing tumors in multiple endocrine glands. The most commonly reported features include primary hyperparathyroidism (due to parathyroid adenomas or hyperplasia), pituitary adenomas (most frequently growth hormone-secreting or non-functioning adenomas), and, less commonly, neuroendocrine tumors of the pancreas, adrenal glands, or other organs. Patients may present with symptoms related to hormone overproduction, such as elevated calcium levels causing kidney stones, bone loss, fatigue, and muscle weakness from hyperparathyroidism, or visual disturbances and hormonal imbalances from pituitary tumors. Because MEN4 is extremely rare, with only a limited number of cases reported worldwide, management strategies are largely extrapolated from experience with MEN1. Treatment typically involves surgical removal of affected glands and tumors, along with medical management of hormonal excess. Regular biochemical and imaging surveillance of at-risk endocrine organs is recommended for mutation carriers. Genetic testing for CDKN1B mutations should be considered in patients with MEN1-like clinical features who test negative for MEN1 mutations. Long-term follow-up is essential due to the risk of developing additional endocrine tumors over time.

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