Multiple endocrine neoplasia (MEN) indicates a group of familial syndromes characterized by the simultaneous occurrence of tumors in more than one endocrine organ. MEN patients develop tumors of the pancreas, parathyroid, pituitary, adrenal, and thyroid glands, together with various neuroendocrine tumors (NETs) of the respiratory and gastrointestinal tracts. These syndromes are inherited as autosomal dominant traits with high penetrance. There are three recognized MEN syndromes: MEN type 1 (MEN1), MEN2, and MEN4. Each of these syndromes has a specific tumor spectrum and is caused by germline mutation of a different gene: MEN1 patients carry loss-of-function mutations in the MEN1 tumor suppressor gene; MEN2 is associated with activating changes in the RET proto-oncogene; and MEN4 is caused by mutations in CDKN1B encoding the cell cycle inhibitor p27Kip1 (p27).

MEN4 is the most recently discovered syndrome. CDKN1B was identified as susceptibility gene for multiple endocrine tumors based on studies of a rat strain displaying a MEN1-like tumors spectrum (MENX syndrome). MENX-affected rats were found to carry a spontaneous germline inactivating mutation in Cdkn1b. To date only 19 patients with germline CDKN1B mutations have been reported in the literature. The most recurrent MEN4-associated clinical manifestations are primary hyperparathyroidism (1°HPT) and pituitary adenomas. MENX and MEN4 syndromes mostly resemble MEN1; hence they were initially referred to as MEN1-like. This review will focus on the phenotypic features and the genetics of MENX and MEN4 syndromes and will briefly address the role of CDKN1B in tumorigenesis.