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Genotype-phenotype correlation in multiple endocrine neoplasia type 1
Charlita C Worthy1, Rana Tora1, Chandra N Uttarkar1
1Metabolic Diseases Branch.
JCI Insight
|February 13, 2025
Summary
Genotype-positive multiple endocrine neoplasia type 1 (MEN1) patients present differently than genotype-negative cases. Genetic testing helps predict MEN1 clinical course and metastasis risk, guiding surveillance strategies.
Area of Science:
- Endocrinology
- Genetics
- Oncology
Background:
- Multiple endocrine neoplasia type 1 (MEN1) is associated with duodenopancreatic neuroendocrine tumors (dpNETs), with significant metastatic risk.
- Accurate biomarkers are needed to predict aggressive disease in MEN1 patients.
- Clinical diagnosis of MEN1 can be challenging, with a subset lacking identifiable germline MEN1 variants.
Purpose of the Study:
- To investigate the clinical differences between genotype-positive and genotype-negative MEN1.
- To identify potential biomarkers for predicting MEN1 disease course and metastasis.
- To evaluate the role of MEN1 mosaicism and specific variant locations in disease presentation.
Main Methods:
- Retrospective analysis of 162 genotype-positive and 47 genotype-negative MEN1 patients.
- Clinical data collection from 1977 to 2022.
- Tumor analysis for MEN1 mosaicism in genotype-negative cases.
Main Results:
- Genotype-positive MEN1 patients were younger at diagnosis and showed higher frequencies of recurrent parathyroid tumors, dpNETs, and skin manifestations.
- A weighted scoring system for diagnosing genotype-positive MEN1 based on clinical features was proposed.
- Germline MEN1 variants in exons 2 and 3 correlated with a lower risk of distant metastases.
Conclusions:
- The clinical trajectory of genotype-negative MEN1 differs significantly from genotype-positive MEN1, questioning the necessity of lifelong surveillance for the former.
- MEN1 mosaicism appears to be rare.
- Genotype-specific analysis is crucial for understanding MEN1 heterogeneity and tailoring patient management.
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