ABSTRACT

Multiple Endocrine Neoplasia Type 4 (MEN4) (OMIM #610755) has many similarities with MEN1, but is caused by germline mutations in CDKN1B. MEN4 is less common than MEN1. Clinical manifestations of MEN4 encompass: primary hyperparathyroidism, pituitary adenomas. and gastroenteropancreatic neuroendocrine neoplasms. In line with MEN1 other neoplasms may occur. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Multiple Endocrine Neoplasia Type 4 (MEN4) (OMIM #610755) was initially named MENX and was first described in rats (1-3). MEN4 is caused by germline mutations in CDKN1B (Cdkn1b in rats), a tumor suppression gene encoding for the protein p27Kip1 (commonly referred to as p27 or as KIP1). The CDKN1B gene is located on chromosome 12p13.1 (4). p27 is a member of the cyclin-dependent kinase inhibitor (CDKI) family which regulates the cell cycle (5, 6). Germline mutations in CDKN1B lead to reduced expression of p27, thereby resulting in uncontrolled cell cycle progression. To date, most of the reported human mutations were missense. These mutations were deemed pathogenic due to their in vivo or in vitro effects on the function of p27. In humans, two CDKI families were identified: the INK4a/ARF and Cip/Kip family (7). Natalia Pellegata and colleagues reported in 2006 a three-generation family with apparently MEN1-related tumors, but turned out to become the first reported cases of MEN4 in humans (2). The incidence of CDKN1B mutations in patients with a MEN1-related phenotype is likely to be in the range of 1-4% (8-10). MEN4 screening is recommended for all patients with a MEN1-related phenotype without the presence of a MEN1 gene mutation. All first-degree relatives of patients with MEN4 should be offered genetic testing (11-13).

CLINICAL FEATURES OF MEN4

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