Key features of
Abstract
The CYP24A1 gene encodes 1,25-hydroxyvitamin-D3-24-hydroxylase, a key enzyme responsible for the catabolism of active vitamin D (1,25-dihydroxyvitamin D3). Loss-of-function mutations in CYP24A1 lead to increased levels of active vitamin D metabolites. Clinically, two distinct phenotypes have been recognised from this: infants with CYP24A1 mutations present with infantile idiopathic hypercalcaemia, often precipitated by prophylactic vitamin D supplementation. A separate phenotype of nephrolithiasis, hypercalciuria and nephrocalcinosis often presents in adulthood. CYP24A1 mutations should be suspected when a classical biochemical profile of high active vitamin D metabolites, high or normal serum calcium, high urine calcium and low parathyroid hormone is detected. Successful treatment with fluconazole, a P450 enzyme inhibitor, has been shown to be effective in individuals with CYP24A1 mutations. Although CYP24A1 mutations are rare, early recognition can prompt definitive diagnosis and ensure treatment is commenced.
Keywords
- CYP24A1
- vitamin D
- hypercalcaemia
- idiopathic infantile hypercalcaemia
- nephrolithiasis
1. Introduction
The supplementation of formula milk with vitamin D3 (cholecalciferol) prompted a rise in infants presenting with symptomatic hypercalcaemia in the United Kingdom during the 1950s [1]. While this public health initiative was proving highly successful in preventing rickets, for the small cohort of infants presenting with failure to thrive, dehydration and nephrocalcinosis, the consequences of their hypercalcaemia were at times fatal. A diagnosis of idiopathic infantile hypercalcaemia was given to many in this cohort. The apparent increased susceptibility of this minority group to vitamin D toxicity prompted research into a genetic predisposition. Fifty-nine years later,
More recently,
2. CYP24A1 and the vitamin D pathway
The crucial role of vitamin D in calcium and phosphate homeostasis means excessive levels of its active form can precipitate symptomatic hypercalcaemia. The activation of vitamin D takes place in two stages. The first stage takes place in the liver: vitamin D3 is converted to 25-hydroxyvitamin D3, a reaction catalysed by 25-hydroxylase (
The inactivation of vitamin D metabolites relies upon two pathways which both include steps catalysed by 1,25-hydroxyvitamin-D3-24-hydroxylase;
2.1. Phenotypes
2.1.1. Idiopathic infantile hypercalcaemia
The first recognised phenotype of
2.1.2. Adult nephrolithiasis
Hypercalciuria is the most common cause of calcium-containing kidney stones. The recognition that 40–45% of patients with idiopathic hypercalciuria have at least one relative with nephrolithiasis implicates a genetic predisposition in many cases [4].
Clinical features | Biochemical profile |
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Idiopathic infantile hypercalcaemia:
|
|
2.1.3. Investigation
In patients with
2.2. CYP24A1 variants
Several different loss-of-function mutations have now been identified within the
Year mutation reported | Age at presentation | Phenotype | Reference | |
---|---|---|---|---|
2011 | 6 months | IIH | A475fsX490 homozygote | Schlingmann et al. [2] |
2011 | 6 months | IIH | delE143 and E151X | Schlingmann et al. [2] |
2011 | Asymptomatic | Identified on family screening |
delE143 and E151X | Schlingmann et al. [2] |
2011 | 8 months | IIH | L409S and R396W | Schlingmann et al. [2] |
2011 | Asymptomatic | Identified on family screening |
L409S and R396W | Schlingmann et al. [2] |
2011 | 11 months | IIH | delE143 and R159Q | Schlingmann et al. [2] |
2011 | 7 months | IIH | E322K and R396W | Schlingmann et al. [2] |
2011 | 3.5 months | IIH | E322K and R396W | Schlingmann et al. [2] |
2011 | 7 weeks | IIH | R396W homozygote | Schlingmann et al. [2] |
2011 | 5 weeks | IIH | Complex deletion | Schlingmann et al. [2] |
2012 | 10 months | IIH | Homozygous delE143 | Dauber et al. [10] |
2012 | 44 years | Intermittent hypercalcaemia, hypercalciuria, nephrolithiasis |
2 canonical intron-exon splice junction mutations (IVS5 +1G>A and IVS6 -2A>G) |
Tebben et al. [11] |
2013 | 4 months | IIH | Homozygous R396W | Fencl et al. [12] |
2013 | 9 years | Nephrocalcinosis, nephrolithiasis | Homozygous delE143 | Dinour et al. [4] |
2013 | 19 years | Nephrolithiasis, nephrocalcinosis, bladder calcification | Compound heterozygous L409S and W268X |
Dinour et al. [4] |
2013 | 13 years | Nephrolithiasis, nephrocalcinosis, hypercalcaemia, hypercalciuria | Compound heterozygous L409S and W268X |
Dinour et al. [4] |
2013 | 9 years | Nephrocalcinosis, hypercalciuria | Compound heterozygous delE143 and L148P |
Nesterova et al. [5] |
2013 | 25 years | Nephrolithiasis, hypercalcaemia, hypercalciuria | Compound heterozygous delE143 and L409S |
Nesterova et al. [5] |
2013 | 4.5 months | IIH | Homozygous R396W | Skalova et al. [13] |
2013 | 3 months | IIH followed by adult presentation with nephrocalcinosis, CKD, hypercalcaemia and hypercalciuria | Homozygous W210R | Meusburger et al. [14] |
2014 | ~20 years | Nephrolithiasis, hypercalcaemia, hypercalciuria | Homozygous delE143 | Jacobs et al. [15] |
2015 | 10 years | Nephrolithiasis, hypercalcaemia, hypercalciuria | Homozygous delE143 | Sayers et al. [7] |
2015 | 45 years | Nephrocalcinosis, hypercalcaemia, hypercalciuria | Compound heterozygous G469Afs*22 and P21R |
Figueres et al. [19] |
2015 | 32 years | Nephrolithiasis, nephrocalcinosis, hypercalcaemia, hypercalciuria | Compound heterozygous L409S and R157W |
Figueres et al. [19] |
2015 | 28 days | IIH | Compound heterozygous R157W and M374T |
Figueres et al. [19] |
2015 | 2 months | IIH | Compound heterozygous L409S and R396W |
Figueres et al. [19] |
2015 | 6 months | IIH | Homozygous L409S | Figueres et al. [19] |
2015 | 2 months | IIH | Compound heterozygous R396W and R396G |
Figueres et al. [19] |
2015 | 6 months | IIH | Compound heterozygous delE143 and L409S |
Figueres et al. [19] |
2015 | 1 day | Hypercalcaemia, apnoea | Heterozygous M374T | Molin et al. [6] |
2015 | 3 days | Infection, hypercalcaemia, suppressed PTH |
Heterozygous M374T | Molin et al. [6] |
2015 | 11 days | Prematurity, hypercalcaemia, suppressed PTH |
Heterozygous G322A | Molin et al. [6] |
2015 | 4 days | Prematurity, hypercalcaemia, suppressed PTH |
Heterozygous R439C | Molin et al. [6] |
2015 | 13 days | Small for gestational age, hypercalcaemia, suppressed PTH |
Heterozygous M374T | Molin et al. [6] |
2015 | 24 years | Hypercalcaemia, suppressed PTH, nephrocalcinosis, CKD |
Homozygous delE143 | Jobst-Schwan et al. [3] |
2015 | Asymptomatic | Identified on family screening |
Homozygous delE143 | Jobst-Schwan et al. [3] |
2015 | 26 years | Nephrocalcinosis, hypercalcaemia, hypercalciuria | Homozygous delE143 | Tray et al. [16] |
2015 | 21 years | Nephrocalcinosis, nephrolithiasis, hypercalcaemia | Heterozygous delE143 and R396W | Tray et al. [16] |
2015 | 5 months | IIH | Compound heterozygous R396W and W134G |
Dinour et al. [17] |
2015 | 9 months | IIH | Compound heterozygous G315X and W134G |
Dinour et al. [17] |
2015 | 5 months | IIH | Homozygous delE143 | Dinour et al. [17] |
2015 | 35 years | Nephrolithiasis, nephrocalcinosis and hypercalcaemia during pregnancy |
Homozygous delE143 | Dinour et al. [17] |
2.3. Treatment
2.4. Evidence for genetic heterogeneity of idiopathic infantile hypercalcaemia
Since the discovery of
3. Conclusions
Overall,
References
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