Successful Treatment with Ketoconazole for Autosomal Recessive Infantile Hypercalcemia in an Adult with Kidney Stones and Severe Nephrocalcinosis

Introduction: Presentation of autosomal recessive infantile hypercalcemia can vary from severe cases in the first months of life to later findings in adulthood. Classically, there is hypercalcemia associated with hypercalciuria, nephrocalcinosis, and stone formation. Treatment, however, can be challenging. Here, we present a case with successful treatment of hypercalciuria with ketoconazole. Case Description: 31-year-old woman with significant past medical history of nephrocalcinosis and kidney stones since age 2 with multiple urological interventions. A prior 24-hour urine collection had shown significant hypercalciuria (461 mg/24 h). Multiple stone analyses showed predominantly calcium phosphate stone composition (80-90% component). Prior genetic testing had initially shown a mutation of CYP24A1 (c.1186C>T [p.R396W]) at that time classified as known variant of uncertain significance, now reclassified as pathogenic. Reanalysis results almost a decade later also showed a new heterozygous intronic variant in CYP24A1 (c.544-17G>A). She was referred to a dedicated kidney stone nephrology clinic for a second opinion. 24-hour urine collection was repeated, showing: hypercalciuria of 656 mg (<200 mg), hyperphosphaturia of 1,360 mg (600-1,200 mg), hypocitraturia of 208 mg (>550 mg), in 24 h. Serum calcium levels have ranged from 8.6-10.9 mg/dL in the last 5 years. She had previously been treated with thiazides and thiazide-like diuretics. She was started on Ketoconazole 200 mg three times a day, aiming to block 1-25 hydroxy Vitamin D. A repeat 24-hour urine collection after 6 months of treatment showed significant improvement in calciuria to 169 mg and phosphaturia to 786 mg, in 24 h. The patient has not had recurrent kidney stone episodes. Discussion: Kidney stones have many different etiologies including hypercalcemia and hypercalciuria which, as in this patient, may be caused by a genetic etiology. In this case, a mutation in CYP24A1 causes hypercalcemia mainly by inability to produce normal 24 hydroxylase which, under normal conditions, decrease the amount of active vitamin D (1-25 hydroxy Vit D). This decreased degradation of calcitriol causes hypercalcemia which may lead to hypercalciuria. Using a potent CYP inhibitor, such as ketoconazole for our patient, can be an effective treatment option for these patients