Endocrine Abstracts

Background: The fourth type of Multiple Endocrine Neoplasia (MEN) is a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in CDKN1B. However, due to the small number of cases documented in literature, the peculiar clinical features of MEN4 are still largely unknown, and clear indications about the clinical management of these patients are currently lacking. In order to enlarge our knowledge on MEN4 and to better typify the clinical features of this syndrome, we present two more patients with a germline CDKN1B mutation developing MEN features and perform a review of the current literature about MEN4.

Case presentation: The first case is a man who was diagnosed with a metastatic ileal G2-NET at the age of 34. Genetic analysis revealed the mutation p.I119T (c.356T>C) of CDKN1B. This variant is classified as of uncertain significance according to 2015 ACMG guidelines and has been previously reported in association to early-onset pituitary adenoma. The patient was screened for pituitary and parathyroid disease without any pathological findings. The second report is a 76-year-old woman with a multifocal pancreatic G1-NET. Genetic analysis identified the CDKN1B mutation c.482C>G (p.S161C). The variant is of first description in literature in association to MEN4. It is located into the C-terminal RhoA binding domain, potentially affecting cell motility. However, in silico analysis supports that this missense variant does not alter protein structure/function and it has been currently classified as a variant of uncertain significance. Pituitary and parathyroid function resulted normal as well.

Review of literature: To date, twenty-three different mutations of CDKN1B have been described in literature in association to MEN4, including fifty-seven carriers. Forty-two of these subjects developed at least one endocrine neoplasm, while involvement of multiple endocrine organs was detected in seventeen of them. Primary hyperparathyroidism results the most frequent endocrine neoplasm (75%), followed by pituitary adenoma (≈40%) and neuroendocrine tumors (≈20%). In general, MEN 4 seems a variant with later onset, less penetrance, and milder clinical features than MEN1.

Conclusions: MEN4 patients might need a different and personalized approach in clinical management. For hyperparathyroidism, since recurrence and/or multiple parathyroids involvement appears to be rare, a less aggressive surgical approach than in MEN1 could be justified. Therefore, MEN4 carriers should be screened for neuroendocrine tumors and pituitary adenomas. Larger case series are still necessary to clarify the peculiar features of MEN4 and to establish a specific diagnostic and therapeutic standard.