MON-314 - Navigating Genetic Uncertainty in MEN1: Integrating Molecular, Clinical, and Familial Diagnostic Criteria

Introduction: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant hereditary tumor syndrome caused by mutations in the MEN1 gene encoding the tumor suppressor protein menin. It is characterized by primary hyperparathyroidism (PHPT), gastroenteropancreatic neuroendocrine tumors, and pituitary adenomas, with PHPT being the most common and earliest manifestation. Although more than 1,600 MEN1 gene variants have been reported, new variants are still emerging. Diagnosis can be made via three approaches: genetic testing (pathogenic/likely pathogenic MEN1 variant), clinical (≥2 cardinal MEN1-associated tumors), or familial (≥1 MEN1- in a first-degree relative).

Case: A 22-year-old male was referred for evaluation of hypercalcemia. Biochemical testing confirmed PHPT and nuclear medicine parathyroid scan suggested a right-sided parathyroid adenoma. Family history was significant for his father, who developed PHPT at a young age requiring parathyroidectomy and later diagnosed with a pituitary prolactinoma, raising strong clinical suspicion for MEN1 syndrome. Genetic testing in our patient revealed a heterozygous missense variant in exon 3 of the MEN1 gene: c.597C>G (p.His199Gln), classified as a variant of uncertain significance (VUS). This variant has not been previously reported in the literature or major variant databases (NM_130799; hg19 chr11:g.64575420).

Discussion: The VUS in MEN1 genetic testing presents a diagnostic challenge, with 25% of MEN1 variants classified as VUS. Although c.597C>G is a VUS, the patient's early-onset PHPT and strong family history strongly support a clinical diagnosis of MEN1, aligning with familial MEN1 criteria. The likelihood of identifying a pathogenic MEN1 variant in patients ranges between 29-57% while approximately 20% of patients with clinical MEN1 disease have genetic tests consistent with VUS. The diagnosis of MEN1 has critical implications for the patient and family members, given the 50% inheritance risk and the need for lifelong biochemical and radiological surveillance. Patients with genotype-positive MEN1 demonstrate younger age at diagnosis and increased frequency of recurrent parathyroid tumors and gastroenteropancreatic neuroendocrine tumors compared to genotype-negative disease. Management includes cascade genetic testing of first-degree relatives, comprehensive tumor surveillance, and potential surgical intervention for PHPT.

Conclusion: This case highlights the importance of combining genetic, clinical, and family history data for accurate MEN1 diagnosis and management. When VUS are identified in patients with clinical features, a diagnosis should be made based on clinical or familial criteria to ensure proper surveillance and counseling. Further reporting of novel variants to international databases is essential for improving interpretation and advancing understanding of MEN1.

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