Clinical and Pathological Features of Patients with Multiple Endocrine Neoplasia Type 1: A Long-Term Comparative Analysis Between Exon 2 and Other Mutations in the MEN1 Gene

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited syndrome characterized by primary hyperparathyroidism (PHPT), duodenopancreatic neuroendocrine tumors (DP-NET), pituitary NET (Pit-NET) and other endocrine neoplasms. Reliable genotype–phenotype correlations remain limited, and the clinical relevance of MEN1 exon 2 variants is still uncertain. Methods and aim: This monocentric retrospective cohort included genetically confirmed MEN1 patients followed at the University of Naples Federico II from January 1992 to April 2025. Eligible patients carried a pathogenic MEN-1 variant involving a single exon and had at least 36 months of follow-up. Clinical, biochemical, radiological, histopathological, genetic, and treatment data were reviewed to compare patients carrying exon 2 variants (Ex2) with those carrying variants in other exons (OtherEx) in order to evaluate mean age at diagnosis (TD) and aggressiveness of MEN-1 manifestations in these two groups. Results: Sixty patients were included: 21 Ex2 and 39 OtherEx. Follow-up was comparable between groups (133 +/− 47.7 vs. 128 +/− 50.0 months). PHPT, Pit-NET, and DP-NET had similar prevalence. DP-NET metastases were more frequent in Ex2 than OtherEx patients (4/21, 19.0% vs. 1/39, 2.6%; OR 8.94, 95% CI 0.93–86.09; p = 0.0465). When the analysis was restricted to patients who developed DP-NET, metastatic disease occurred in 4/16 Ex2 patients (25.0%) and 1/30 OtherEx patients (3.3%; OR 9.67, 95% CI 0.98–95.68; p = 0.0430). Mean DP-NET progression-free survival was numerically shorter in Ex2 patients, without statistical significance (99.6 vs. 121.6 months; p = 0.27), and DP-NET-related deaths occurred only in the Ex2 group. Additional exploratory signals included male-specific adrenal adenomas among Ex2 patients and exon 7-related bone impairment. Conclusions: This long-term MEN1 cohort suggests that exon 2 variants may identify patients with similar DP-NET prevalence but greater metastatic propensity. Because of the number of metastatic events, these findings require validation in larger multicenter cohorts.