Familial Hypocalciuric Hypercalcemia as a Misnomer: Limitations of 24-Hour Urine Calcium and Calcium:Creatinine Clearance Ratios for Identifying Germline Mutations in Patients with Primary Hyperparathyroidism.

Abstract

Familial hypocalciuric hypercalcemia (FHH) can mimic primary hyperparathyroidism (PHPT), yet commonly used 24-hour urine calcium (UCa) and calcium:creatinine clearance ratio (CCCR) thresholds may not reliably identify patients with FHH before parathyroidectomy. We retrospectively reviewed a prospectively maintained single-institution database of adults undergoing initial or reoperative parathyroidectomy for presumed PHPT from January 2012 through December 2023. Patients required concurrent 24-hour urine calcium and creatinine measurements and serum calcium and creatinine within 30 days for inclusion in the study. Patients were stratified by UCa (<100, 100-199, ≥200 mg/24h) and CCCR (<1.0%, 1.00-1.99%, ≥2.0%). Spearman's rho assessed correlation between UCa and CCCR. Of 1,599 patients, 126 (7.8%) had UCa <100, 348 (21.7%) had 100-199, and 1,125 (70.4%) had ≥200 mg/24h. CCCR correlated weakly with UCa among patients with UCa <100 (ρ=0.47) and ≥200 (ρ=0.58). Genetic testing was performed in 254 (15.9%) patients; 20 had pathogenic variants or variants of uncertain significance. Three had pathogenic FHH-associated mutations (2 CASR, 1 AP2S1), with UCa/CCCR values of 326 mg/1.24%, 334 mg/1.83%, and 240 mg/1.00%, respectively. Conventional UCa and CCCR thresholds may fail to identify patients with pathogenic FHH-associated variants. Germline genetic testing should be considered in patients evaluated for PHPT and parathyroidectomy without previously documented normocalcemia or other evidence of acquired hypercalcemia.