Comparison of Pediatric Stone-Formers with and without mutations in Soluable Adenylate Cyclase

Abstract Purpose Two-thirds of children with urolithiasis have hypercalciuria. Recently, a candidate gene for absorptive hypercalciuria (AH) was mapped to chromosome 1q23.3-24 in the adult population. In adults, the presence of up to 6 identified base substitutions in the soluble adenylate cyclase gene (sAC) was associated with a 2.2- to 3.5-fold increased risk for AH. We screened a pediatric population of stone formers for sAC sequence variations. Material and Methods Pediatric patients with stone disease were offered study participation if they met the following criteria: family history of stones; hypercalciuria (urine calcium/creatinine ratio > 0.21 mg/mg creatinine or 24 hour calcium excretion > 4 mg/kg/day); and/or calcium stones on stone analysis. Serum laboratories, spot and 24-hour urine, and bone mineral density (BMD) were collected. Patients were excluded for metabolic conditions predisposing to stone disease. Probands were genotyped for 6 previously identified base substitutions in the sAC gene. Comparisons were made between probands with and without sAC substitutions using Fisher's exact test. Results Of 46 children recruited, sAC substitutions were identified in 19 (41%). Clinical parameters were similar in patients with and without substitutions: positive family history in 14/17 (82%) vs. 21/27 (78%); hypercalciuria in 13/19 (68%) vs. 22/27 (82%); and mean number of stone events 2.1 vs. 2.8. Overall, 5/16 (31%) had abnormal BMD (age-adjusted Z-scores Conclusions Of 46 pediatric stone formers, 31% had abnormal BMD scores, and 41% of probands had sAC gene base changes previously identified in adults to increase risk for stones and osteoporosis. This warrants further investigation for potential genetic screening and therapeutic interventions to prevent pediatric stone formation and long-term osteoporotic risk.