Endocrine Abstracts

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by germline mutations of MEN1 gene, without genotype–phenotype correlation. It is defined as the occurrence of two or more primary neuroendocrine tumors (parathyroid, enteropancreatic, pituitary), or the occurrence of one of the MEN1-associated tumors in family members of a patient with a clinical diagnosis of MEN1. Multiple parathyroid tumors with hyperparathyroidism are the most common manifestation with highest penetrance between 40 to 50 years, followed by pancreatic neuroendocrine tumors. Our patient, 49 years old, had a family history positive for hyperparathyroidism, gastrinoma, pancreatic and adrenal tumor, (his brother), pancreatic tumor, subcutaneous lipomas, (his father), prolactinoma, (his daughter). He was diagnosed with primary hyperparathyroidism at 37 years, submitted in 2013 to parathyroidectomy that revealed three adenomas. In 2014, he was diagnosed with nonfunctioning pituitary macroadenoma. In 2015, an abdominal computed tomography scan revealed pancreatic tumors and bilateral adrenal adenomas which proved nonfunctional at biochemical evaluation. In 2021, IRM showed the gastric wall thickening and superior digestive endoscopy was performed. Gastric biopsy documented gastric neuroendocrine tumor grade 1. He then developed carcinoid syndrome and elevated levels of chromogranin A (>2800 ng/ml), serotonin (535.3 ng/ml), and 5-hydroxyindoleacetic acid (17.83 mg/24 h). Functional imaging (99mTcEDDA/HYNIC-TOC SPECT/CT) revealed gastric and pancreatic tumor with high expression of somatostatin receptors, with secondary lymph node and liver involvement, and a faint uptake in the middle ear. To rule out the existence of a phenocopy of this syndrome we analyzed MEN1 gene by Sanger sequencing. Genetic analysis showed the occurrence of a new heterozygous mutation by the insertion of two nucleotides in exon 3 of MEN1 gene at the position c.520_521insCA, resulting in a frame shift mutation (H174Pfs*12). This mutation is predicted as pathogenic and disease causing (MutationTaster). One previous report identified a pathogenic missense mutation at the same position, but in our case the alteration is different and not described yet.

We report a patient with a novel mutation in MEN1 gene presenting with primary hyperparathyroidism, a nonfunctioning pituitary macroadenoma, bilateral nonfunctioning adrenal adenomas, neuroendocrine gastric and pancreatic tumors with liver metastases, and middle ear neuroendocrine tumor. A higher risk of aggressive tumor phenotypes has been described in relation to frameshift and non-sense mutations, predominantly associated with aggressive gastroenteropancreatic neuroendocrine tumors (GEP NETs). Patients with aggressive phenotypes and genetically confirmed MEN1 should be carefully followed up in a multidisciplinary approach, preferably at 3 months interval for long-term.