Bone Abstracts

Defects in 24-hydroxylation caused by vitamin D-hydroxylase (CYP24A1) loss-of-function mutations lead to decreased degradation of 1,25(OH)₂D and the syndrome of idiopathic infantile hypercalcemia. Affected individuals show increased sensitivity to vitamin D and may develop severe hypercalcemia and hypercalciuria, even with small doses of vitamin D.

Presenting: The objective of the study was to investigate the gene expression profile in peripheral blood of a 4-month-old boy with a compound heterozygous CYP24A1 mutation suffering from idiopathic infantile hypercalcemia in contrast to his family members and to healthy controls.

A 4-month-old boy was first diagnosed with hypercalcemia, highly increased 25-hydroxyvitamin D (25(OH)D) levels, and symptoms of acute renal failure at the Department for Pediatrics and Adolescent Medicine including dehydration, lethargy and reported problems in gaining weight.

A compound heterozygous mutation of p.R396W und p.R439C was identified in the CYP24A1 gene. Whole blood gene expression analysis was used for the first time to identify changes in the mRNA profile of relevant calcium and vitamin D metabolism genes, depending on the mutation status in the patient and the family members compared to healthy controls. Therefore, RNA was isolated from whole blood samples using the PAXgene RNA system (BD, PreAnalytix). We were able to show significantly decreased gene expressions for the CYP24A1 gene in the mother and the patient as well as decreased expressions of the calcium sensing receptor (CASR) in the brother, father and the infant. Significantly decreased CYP27A1 as well as vitamin D receptor (VDR) expressions were found only in peripheral blood from the patient in contrast to his family members and to healthy controls.

Heterozygous CYP24A1 mutations might cause different clinical symptoms depending on the gene expression status. Although the mother and brother showed the same p.R396W, and the father the same p.R439C CYP24A1 mutation, only the patient developed severe symptoms. A classic vitamin D intoxication has been characterized in the infant with significantly decreased VDR as well as CYP27A1 gene expressions. In parallel to DNA and potential epigenetic diagnostics, RNA expression from whole blood could help to characterize specific changes in these patients.

Disclosure: The authors declared no competing interests.