Novel germline likely pathogenic frameshift variant of the MEN1 gene contributes to multiple endocrine neoplasia type 1: a case report with review of literature.

Abstract

A 46-year-old man with a family history of multiple endocrine neoplasia type 1 (MEN1) presented with recurrent hypoglycemic episodes and was referred to our hospital. Based on hypoglycemia, endogenous hyperinsulinemia, and imaging findings revealing masses in the head, body, and tail of the pancreas, insulin-producing neuroendocrine neoplasms (NENs) or insulinomas were strongly suspected. A selective arterial calcium stimulation test supported this diagnosis. Additional biochemical and imaging studies suggested the presence of normocalcemic primary hyperparathyroidism (PHPT), a thymic NEN, and a prolactinoma. The patient subsequently underwent distal pancreatectomy for the pancreatic body and tail masses, enucleation of the pancreatic head mass, extended thymectomy, and subtotal parathyroidectomy. Histopathological evaluation confirmed the diagnoses of insulinoma, thymic NEN, and normocalcemic PHPT. He continued medical treatment with the dopamine receptor agonist cabergoline for the prolactinoma. Genetic testing revealed a novel heterozygous likely pathogenic frameshift MEN1 variant, c.1078del (p.Ile360Serfs*8). Based on a previous study, this variant (located within the JunD-interacting domain of the transcript Menin) has been proposed to impair the repression of JunD-mediated transcription and may contribute to aggressive tumors such as thymic NENs, which have high recurrence rates, metastatic potential, and high mortality risk. Although the specific pathological significance of this variant in tumorigenesis remains unclear, this case suggests a need for increased awareness and cautious surveillance of aggressive manifestations, including thymic lesions, in individuals harboring this variant.