Genotype-phenotype correlation in multiple endocrine neoplasia type 1

Abstract

BACKGROUND. Among patients with multiple endocrine neoplasia type 1 (MEN1), 80% develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom 15%–25% die of metastasis. There is a need to identify biomarkers to predict aggressive disease. MEN1 genotype affords an attractive possibility as a biomarker, as it remains constant during life. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥2 primary endocrine tumors (pituitary, parathyroid, and pancreas) or ≥1 primary endocrine tumor with a positive family history. From 10% to 30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants. METHODS. This was a retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977 to 2022. RESULTS. Compared with patients with genotype-negative disease, patients with genotype-positive disease were younger at diagnosis and had an increased frequency of recurrent parathyroid tumors, dpNETs, and angiofibromas or collagenomas. We propose a weighted scoring system to diagnose genotype-positive MEN1 based on clinical characteristics. No evidence of MEN1 mosaicism was seen in 30 tumors from 17 patients with genotype-negative MEN1. Patients with germline MEN1 variants in exons 2 and 3 had a reduced risk of distant metastases. CONCLUSION. The clinical course of genotype-negative MEN1 is distinct from genotype-positive disease, raising uncertainty about the benefits of lifetime surveillance in patients with genotype-negative disease. MEN1 mosaicism is rare.