An investigation into increased cases of idiopathic infantile hypercalcaemia

Abstract

Following increased presentations for idiopathic infantile hypercalcaemia (IIH) between 2011 and 2014, we hypothesized that antenatal vitamin D supplementation might be associated with increased calcaemia in infancy, and hypercalcaemia in susceptible infants. We examined the biochemical profile and response to treatment of 14 patients presenting at median age 17 days [range 5-53] managed for IIH, and the diagnostic utility of a panel of genes involved in calcium sensing or vitamin D metabolism (CASR, AP2S1, GNAll, CYP24Al). Using a laboratory-based population under the age of 6 months, we examined the trend in calcaemia, the prevalence of hyper- and hypocalcaemia, the frequency of 25 hydroxyvitamin D (25OHD) testing and levels of sufficiency over a 12 year period Biochemistry of the 14 infants was consistent with variations in vitamin D metabolism and/or calcium sensing and antenatal vitamin D supplementation was common; however no pathogenic genetic variants were identified in 9 infants studied. All infants responded to low calcium feed; however prolonged use was associated with high parathyroid hormone (PTH) and low 25OHD in most infants, despite total calcium concentrations in the upper part of the reference range. Examining separate laboratory datasets for total (n= 26765) and ionised (n=83228) calcium measurements identified increased hypercalcaemia, decreased hypocalcaemia and a gradual rise in both total and ionised calcaemia over 12 years. The frequency of 25OHD testing increased but concentrations and the number of values >50nmol/L did not. There was no correlation between paired calcium and 25OHD concentrations.Our findings suggest that single variations in the genes studied are unlikely to explain IIH in the majority of infants, despite biochemical evidence of variations in calcium sensing and/or vitamin D metabolism. The rise of PTH associated with prolonged low calcium feeds may have a deleterious effect on bone health and should be monitored closely. A contribution of antenatal vitamin D supplementation to the increase in calcaemia and hypercalcaemia observed remains plausible but was not supported by increased 25OHD concentrations. Given the broad range of calcaemia associated with 25OHD concentrations well below 50nmol/l however, we question whether an isolated 25OHD concentration is a robust marker of vitamin D action.