Abstract
Disclosure: J. Bacchetta: None. C. Jacobsen: None. T. Kubota: None. Autosomal dominant hypocalcemia type 1 (ADH1) and type 2 (ADH2) are rare disorders caused by activating variants of the CASR and GNA11 genes, respectively. The calcium-sensing receptor (CaSR) plays a critical role in calcium homeostasis by signaling parathyroid hormone (PTH) secretion and urinary calcium (uCa) reabsorption in response to variations in blood calcium. The CaSR signals by coupling to G-proteins, including GNA11-encoded Gα11. The CLARIFY disease monitoring study [NCT05227287] is an ongoing global, multicenter, longitudinal, observational study to characterize disease burden, management, and progression in children and adults with ADH1/2 over a 5-year period. Of 25 pediatric participants (birth to <18y) enrolled (Mar 2022 to Jun 2024), 22 were diagnosed with ADH1 and 3 with ADH2; 64% are females. Median age at enrollment was 9 years (IQR 5-13). Median age at hypocalcemia presentation and ADH1/2 diagnosis were 0.8 years (IQR 0.0-3.0) and 1.0 year (IQR 0.5-3.0), respectively. Family history of ADH1/2 was reported in 64% of participants. 16 unique CASR and 2 unique GNA11 variants were present, with CASR E767K (3) and F788C (3) the most frequent. Treatment regimen varied at baseline (Day 1 study visit): 32% (8) were on Ca and active vitamin D, 24% (6) on Ca alone, 8% (2) on active vitamin D alone, 20% (5) on PTH replacement, 20% (5) on magnesium, 12% (3) on thiazide diuretics, 12% (3) on potassium, 12% (3) on phosphate binder, 32% (8) on cholecalciferol, and 20% (5) without treatment. At baseline, 92% (23) had hypocalcemia (0-<1y <8.4 mg/dL; 1-17y <8.6 mg/dL), 83% (20) had low iPTH (<15 pg/mL), 84% (21) had hyperphosphatemia (0-<1y >7.8 mg/dL; 1-12y >6.0 mg/dL; 13-17y >4.8 mg/dL), 8% (2) had hypomagnesemia (<1.5 mg/dL), and 84% (21) had normal total 25-OH Vitamin D (20-50 ng/mL). 32% (6) of 19 participants with 24hr uCa collected were hypercalciuric (>4 mg/kg/day); and 0% of 5 participants with spot urine collections had Ca/Cr above the aged-defined reference range (7-18mo <0.60 mg/mg; 19mo – 6y <0.41 mg/mg; adults <0.21 mg/mg). Baseline eGFR by Schwartz equation was 117±25 mL/min/1.73m² (range: 69-175). Common (proxy) self-reported ADH1-related comorbidities were seizures (36%), nephrocalcinosis (32%), dental abnormalities (20%), and long QT syndrome (16%). This study represents the largest pediatric cohort of ADH1/2 described to date. Persistent hypocalcemia and hypercalciuria, along with the high prevalence of comorbidities, highlights the ongoing medical need in this population. Long-term prospective data are needed to better understand disease progression and burden of ADH1/2. Presentation: Monday, July 14, 2025