SAT-804 - Primary Hyperparathyroidism Associated with the GCM2 Y394S Variant- Report of 2 Cases

Background: Primary hyperparathyroidism (PHPT) is predominantly sporadic, though germline variants contribute to syndromic and non -syndromic familial forms. Gain-of-function variants in GCM2 have recently been implicated in both familial and sporadic PHPT. The GCM2 p.Tyr394Ser variant is reported with increased frequency in individuals of Ashkenazi Jewish ancestry. However, its penetrance and clinical significance remain uncertain, and it is currently classified as a variant of uncertain significance in ClinVar.

Case Presentation: We describe two women of Ashkenazi Jewish heritage with PHPT who were found to carry a heterozygous GCM2 c.1181A>C (p.Tyr394Ser) variant. Both had mild hypercalcemia and elevated parathyroid hormone levels. Case 1 had longstanding hypercalcemia without documented prior normocalcemia, exhibited low urinary calcium excretion and osteoporosis, and is being managed conservatively. Case 2 demonstrated acquired hypercalcemia, nephrolithiasis, and normal urinary calcium excretion, and is planning parathyroidectomy.

Discussion: Reported GCM2 variants have been associated with higher rates of multiglandular involvement, greater likelihood of persistent or recurrent hyperparathyroidism after surgery, and, in some cases, parathyroid carcinoma. Familial cases appear to demonstrate greater severity than sporadic cases.

Conclusion: These cases highlight the phenotypic variability and diagnostic challenges associated with the GCM2 p.Tyr394Ser variant. Further studies are warranted to clarify its penetrance and clinical significance in non-familial cases and in broader populations.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*