Family History Predicts Primary Hyperparathyroidism Regardless of Genetic Predisposition

Primary hyperparathyroidism (PHPT) has a known genetic predisposition in only 10% of cases. We aimed to identify predictors of PHPT occurrence in carriers and noncarriers of a pathogenic variant (PV) in PHPT-related genes.

A prospective study of patients who underwent genetic assessment for PHPT or suspected endocrine neoplasia syndrome. Demographics, clinical, biochemical, and genetic findings were compared between patients with and without PHPT.

Overall, 249 patients were included, of whom 31.7% had PHPT. Sixty-five (26.1%) carried PV in PHPT-related genes, mainly the GCM2 p.Y394S PV (7%) and multiple endocrine neoplasia type 1 (MEN1) (4%). PV rate in patients with PHPT was 38.0% (MEN1 14%, GCM2 p.Y394S 11%). Patients with PHPT and a family history of PHPT were younger at diagnosis (Diagnosis age < 40 years, 50.0% vs 38.1%, P= .03), had a higher risk of recurrence (25.0% vs 6.3%, P= .04), and of osteoporotic fractures (P< .001). MEN1 and GCM2 PV carriers had more glands involved vs non-carriers (MEN1: 2.0 ± 1.3 vs 0.9 ± 0.3, P= .005; GCM2: 2.00 ± 1.00 vs 1.3 ± 1.0, P= .001). GCM2 PV carriers had a wide clinical spectrum, from no PHPT (47%), mild PHPT, to hypercalcemic crisis at a young age. In multivariable analysis, family history predicted PHPT occurrence (odds ratio 6.1, 95% confidence interval 1.9-24.9, P= .002) independently of PV carrier status.

Family history is a strong predictor of PHPT, regardless of genetic testing results, suggesting unrecognized genetic or epigenetic factors. GCM2 p.Y394S is relatively common and has variable phenotypes, emphasizing its importance in the genetic evaluation of patients with PHPT.