Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases

Abstract

Idiopathic infantile hypercalcemia (IIH) is a mineral metabolism disorder characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. The periodical increase in incidence of IIH, which occurred in the twentieth century in the United Kingdom, Poland, and West Germany, turned out to be a side effect of rickets over-prophylaxis. It was recently discovered that the condition is linked to two genes, CYP24A1 and SLC34A1. The aim of the study was to search for pathogenic variants of the genes in adult persons who were shortlisted in infancy as IIH caused by “hypersensitivity to vit. D”. All persons were found to carry mutations in CYP24A1 or SLC34A1, nine and two persons respectively. The changes were biallelic, with one exception. Incidence of IIH in Polish population estimated on the basis of allele frequency of recurrent p.R396W CYP24A1 variant, is 1:32,465 births. It indicates that at least a thousand homozygotes and compound heterozygotes with risk of IIH live in the country. Differences in mechanism of developing hypercalcemia indicate that its prevention may vary in both IIH defects. Theoretically, vit. D restriction is a first indication for CYP24A1 defect (which disturbs 1,25(OH)2D degradation) and phosphate supplementation for SLC34A1 defect (which impairs renal phosphate transport). In conclusion, we suggest that molecular testing for CYP24A1 and SLC34A1 mutations should be performed in each case of idiopathic hypercalcemia/hypercalciuria, both in children and adults, to determine the proper way for acute treatment and complications prevention.

Hypercalcemic Disorders in Children

“…In addition, some patients may later develop hypercalciuria and be at risk of developing renal stone disease and osteoporosis, such that long‐term surveillance is recommended for these patients . IIH is an autosomal recessive disorder, and two types of IIH (IIH1 and IIH2) are recognized, and are due to homozygous, or compound heterozygous mutations of the CYP24A1 and SLC34A1 genes …”

Outcome of a public consultation on the Draft Scientific Opinion of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on the update of the tolerable upper intake level for vitamin D for infants

“…Special attention was paid to inborn errors of metabolism with regard to vitamin D intake (Pronicka et al, 2017). Special attention was paid to inborn errors of metabolism with regard to vitamin D intake (Pronicka et al, 2017).…”

“…The Panel notes that the paper mentioned in the comment received (Pronicka et al, 2017) discusses the mutations in CYP24A1 and SLC34A1 but not SLC12A1 as mentioned in the comment received. Section 1.7.3. of the Scientific Opinion (on effects of genotypes on metabolism of vitamin D) has been expanded as follows:…”

“…Such mutations, in both homozygous or compound heterozygous patients are associated with hypersensitivity to vitamin D in prophylactic doses (10-12.5 µg/day) or in extremely high bolus doses (15 mg repeatedly) and have also been associated with nephrolithiasis and nephrocalcinosis (Jones et al, 2012;Jones et al, 2017). The frequency of IIH due to CYP24A1 mutations in Poland has been calculated to be 1:32,465 births and the frequency of mutations of CYP24A1 in the Polish population to be 1.11% (Pronicka et al, 2017).…”

“…There is an added concern about the consequences of vitamin D intake in the setting of inborn errors of metabolism; although rare, the precise prevalence is uncertain (Pronicka et al, 2017) i. If the lower threshold is chosen, then the UL should remain at 25μg daily ( • Vitamin D toxicity The evidence about the relationship between vitamin D intake and adverse health outcomes (hypercalcaemia, hypercalciuria, growth retardation, and soft tissue calcification) from trials and observational studies was deemed inadequate to derive the UL for infants (see lines 117-121).…”