A novel likely pathogenetic variant p.(Cys235Arg) of the MEN1 gene in multiple endocrine neoplasia type 1 with multifocal glucagonomas

Abstract

Purpose Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine syndrome caused by pathogenic variants in MEN1 tumor suppressor gene. Diagnosis is commonly based on clinical criteria and confirmed by genetic testing. The objective of the present study was to report on a MEN1 case characterized by multiple pancreatic glucagonomas, with particular concern on the possible predisposing genetic defects. Methods While conducting an extensive review of the most recent scientific evidence on the unusual glucagonoma familial forms, we analyzed the MEN1 gene in a 35-year-old female with MEN1, as well as her son and daughter, using Sanger and next-generation sequencing (NGS) approaches. We additionally explored the functional and structural consequences of the identified variant using in silico analyses. Results NGS did not show any known pathogenic variant in the tested regions. However, a new non-conservative variant in exon 4 of MEN1 gene was found in heterozygosity in the patient and in her daughter, resulting in an amino acid substitution from hydrophobic cysteine to hydrophilic arginine at c.703T > C, p.(Cys235Arg). This variant is absent from populations databases and was never reported in full papers: its characteristics, together with the high specificity of the patient’s clinical phenotype, pointed toward a possible causative role. Conclusion Our findings confirm the need for careful genetic analysis of patients with MEN1 and establish a likely pathogenic role for the new p.(Cys235Arg) variant, at least in the rare subset of MEN1 associated with glucagonomas.

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance

“…Also, duodeno-pancreatic NETs affect between 30% and 80% of MEN1 families. Unless non-functioning (which is reported in 60–70% in some studies), almost half of them are gastrinomas (of note, hypergastrinemia-related Zollinger–Ellison syndrome should be taken into consideration [ 92 ]), and approximately one-third is represented by insulinomas; glucagonomas [ 93 ] and cystic pancreatic adenomas have been described, as well [ 94 , 95 ]. Overall, the clinical MEN1 onset is typically between the age of 20 and 25 years, while 95% of affected patients present neuroendocrine manifestations before the age of 50 [ 96 ].…”