MEN4 and CDKN1B mutations: the latest of the MEN syndromes

Abstract

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor gene MEN1 MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not have MEN1 mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressor CDKN1B The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations in CDKN1B were also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role for CDKN1B as a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

Keywords: CDKN1B; MEN1; MEN4; multiple endocrine neoplasia; neuroendocrine tumors; p27.

Figure 1

A pathway depicting the alterations in p27 expression in MEN1 and/or MEN4 that lead to tumorigenesis. Menin, encoded by MEN1, regulates the expression of p27 by forming a transcriptional activation complex with methyltransferase (MLL2) and RNA polymerase II (Pol III). Menin inactivation (MEN1 mutation) leads to decreased p27 expression. Mutations in CDKN1B, either solely or with MEN1 as a second germline hit, leads to a greater decrease in expression of p27 protein, triggering neoplasia.

Figure 2

The variable clinical phenotypes of MENs. ^*Recent case of Cushing Disease reported in MEN2B ^**Pheochromocytomas have been described in mouse models of MEN4 ^***On case of metastatic papillary thyroid carcinoma

Figure 3

An approach to screening in MEN4. Index cases, or individuals with MEN1-like features and negative MEN1 testing should be offered genetic counseling and testing for MEN4 (CDKN1B). Screening should also be offered to a first-degree relative with or without MEN1 features. The identification of a germline CDKN1B mutation should prompt periodic clinical, biochemical, and radiological screening for MEN4.