Genotype-phenotype correlation in multiple endocrine neoplasia type 1.

Abstract

Background: 80% of patients with multiple endocrine neoplasia type 1 (MEN1) develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom, 15% to 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 lifetime. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥ 2 primary endocrine tumors (pituitary, parathyroid and pancreas) or ≥ 1 primary endocrine tumor(s) with a positive family history. 10-30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants.

Methods: Retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977-2022.

Results: Compared to 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 novel 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 have a reduced risk of distant metastases.

Conclusions: The clinical course of genotype-negative MEN1 is distinct from genotype-positive disease raising uncertainty about the benefits of lifetime surveillance inpatients with genotype-negative disease. MEN1 mosaicism is rare.

Trial registration:

Clinicaltrials: gov NCT04969926.

Funding: Intramural Research Program of NIDDK (ZIA DK043006-46).