Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia.

Context: Idiopathic infantile hypercalcemia (IIH) is a disorder the genetic etiology and physiological basis of which are not well understood.

Objective: The objective of the study was to describe the underlying physiology and genetic cause of hypercalcemia in an infant with severe IIH and to extend these genetic findings into an additional cohort of children with IIH.

Design: This was an inpatient study of a single patient with consanguineous parents at an academic medical center with follow-up in a specialty clinic cohort.

Patients: The patient population was one patient with severe IIH for gene discovery and physiological testing and 27 patients with idiopathic infantile hypercalcemia in the replication cohort.

Interventions: Interventions included a calcium isotopic absorption study as well as homozygosity mapping and whole-exome sequencing in a single patient followed up by gene sequencing in replication cohort.

Main Outcome Measure: Fractional absorption of calcium and genetic variants causing hypercalcemia were measured.

Results: Intestinal calcium absorption was extremely elevated (∼90%). A rare homozygous deletion in the CYP24A1 gene was found, leading to the loss of a single highly conserved amino acid. In vivo functional studies confirmed decreased 24-hydroxylase activity because the subject had undetectable levels of 24,25-dihydroxyvitamin D. No coding variants in CYP24A1 were found in the 27 additional patients with IIH.

Conclusions: Our study confirms that CYP24A1 plays a causal role in some but not all cases of IIH via markedly increased intestinal absorption of calcium, suggesting that genetic diagnosis could be helpful in a subset of IIH patients. This case demonstrates the power of an unbiased, genome-wide approach accompanied by informative physiological studies to provide new insights into human biology.