Clinical and Outcome Comparison of Genetically Positive Vs. Negative Patients in a Large Cohort of Suspected Familial Hypocalciuric Hypercalcemia

Abstract

Abstract Objective Biochemical suspicion of familial hypocalciuric hypercalcemia (FHH) might provide with a negative (FHH-negative) or positive (FHH-positive) genetic result. Understanding the differences between both groups may refine the identification of those who need genetic evaluation, aid management decisions and prospective surveillance. We aimed to compare FHH-positive and FHH-negative patients, and to identify predictive variables for FHH-positive cases. Design Retrospective, national multi-centre study of patients with suspected FHH and genetic testing of the CASR, AP2S1 and/or GNA11 genes. Methods Clinical, biochemical, radiological and treatment data were collected. We established a prediction model for the identification of FHH-positive cases by logistic regression analysis and area under the ROC curve (AUROC) was estimated. Results We included 73 index cases, of which 37 (50.7%) had a pathogenic variant. FHH-positive cases were younger (p = 0.023), reported more frequently a positive family history (p < 0.001), presented higher magnesium (p < 0.001) and lower parathormone levels (p < 0.001) and were less often treated for hypercalcemia (p = 0.017) in comparison to FHH-negative cases. Magnesium levels showed the highest AUROC (0.788, 95%CI: 0.659–0.892). The multivariate analysis revealed that family history, parathormone and magnesium levels, were independent predictors of a positive genetic result. The predictive model showed an AUROC of 0.881 (95%CI: 0.770–0.957). Conclusions The combination of magnesium, parathormone levels and a positive family history offered a good diagnostic accuracy to predict a positive genetic result. The inclusion of magnesium measurement in the routine evaluation of patients with suspected FHH might provide a more personalized approach in the decision-making process for ordering a genetic examination.