MON-782 Heterogeneous Intra- and Inter-Syndromic Severity in Hereditary Primary Hyperparathyroidism

Abstract Disclosure: R. Halperin: None. L. Tripto Shkolnik: None. G. Goldinger: None. N. Peshes-Yaloz: None. A. Tirosh: None. Primary hyperparathyroidism (PHPT) is a prevalent endocrine disease, with up to 10% risk for genetic predisposition. The GCM2 gene p.Y394S pathogenic variant (PV), found mostly in Ashkenazi Jews, leads to an autosomal dominant disorder of familial isolated hyperparathyroidism. We aimed to compare the biochemical phenotype of patients with various hereditary PHPT. Methods In this prospective study, we included patients that underwent next generation sequencing due to a diagnosis of neuroendocrine neoplasms, suspected multiple endocrine neoplasia syndromes or PHPT. We compared demographic, clinical and biochemical parameters, and surgical outcome data between pathogenic variant carriers vs. non-carriers. Results A total of 380 patients underwent genetic analysis, of them sixty patients diagnosed with PHPT (63.3% females, mean age at diagnosis 45.1±2.1 years). Eleven (18.3% of those with PHPT) carried a PV in a PHPT-relevant gene: four patients had MEN1 PV (6.7%), five - GCM2 (8.33%) and two - CDKN1B gene PV. Age at diagnosis, serum and urinary calcium levels were comparable between carriers and non-carriers. However, number of parathyroid glands involved was significantly higher in the carriers vs. non-carriers group (p = 0.011), with a trend toward increased rate of recurrence in the carrier group (p = 0.06). Twelve (3.75%) patients evaluated for other clinical diagnoses were found to carry a PV in PHPT-related genes: six in GCM2, three in CDKN1B, two in MEN1 and one in RET. In the entire cohort, eleven patients, all of Jewish ancestry, carried the GCM2 p.Y394S PV, of them seven (63.6%) had PHPT. Clinical presentation was various, most patients with GCM2-related PHPT had a mild disease. However, one patient had post-surgical recurrence and another patient presented with hypercalcemic crisis at the age of 32 with a three-generation history of PHPT, and a maternal grandfather deceased due to hypercalcemic crisis at the age of 47. In contrast, three GCM2 PV carriers did not develop hypercalcemia until their evaluation at the ages of 51, 59 and 81 years. Conclusion Based on a large cohort of patients with hereditary PHPT, we report various biochemical phenotypes in patients with the p.Y394S GCM2 PV, ranging between absence of hypercalcemia in adulthood, and hypercalcemic crisis at a young age. Presentation: Monday, July 14, 2025