CYP24A1 and SLC34A1 Pathogenic Variants Are Uncommon in a Canadian Cohort of Children with Hypercalcemia or Hypercalciuria

2021 ◽  
pp. 1-9
Author(s):  
Isabelle Rousseau-Nepton ◽  
Glenville Jones ◽  
Karlpiet Schlingmann ◽  
Martin Kaufmann ◽  
Caroline S. Zuijdwijk ◽  
...  
Keyword(s):  
Late Onset ◽  
Loss Of Function ◽  
Cascade Screening ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Cascade Testing ◽  
Pathogenic Variants ◽  
Liquid Chromatography Tandem Mass ◽  
25 Hydroxyvitamin D ◽  
Idiopathic Infantile Hypercalcemia

<b><i>Objectives:</i></b> Biallelic pathogenic variants in <i>CYPA24A1</i> and <i>SLC34A1</i> are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of <i>CYP24A1</i> or <i>SLC34A1</i> variants in children with early hypercalcemia or late-onset hypercalciuria. <b><i>Method:</i></b> Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D<sub>3</sub> to 24,25-dihydroxyvitamin D<sub>3</sub>, (25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub>), an elevation pathognomonic for the loss of function of the <i>CYP24A1</i> enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. <b><i>Results:</i></b> Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in <i>CYP24A1.</i> Four <i>CYP24A1</i> pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No <i>SLC34A1</i> pathogenic variants were detected. <b><i>Conclusion:</i></b> In Canada, pathogenic variants in <i>CYP24A1</i> appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> ratio is an excellent tool for screening for biallelic pathogenic variants in <i>CYP24A1</i>. We confirm that cascade testing is important for these variants.

scholarly journals A Case Report of Compound Heterozygous CYP24A1 Mutations Leading to Nephrolithiasis Successfully Treated with Ketoconazole

2017 ◽  
Vol 7 (3) ◽  
pp. 167-171 ◽  
Author(s):  
Emma Davidson Peiris ◽  
Raghav Wusirika
Keyword(s):  
Vitamin D ◽  
Treatment Options ◽  
Elevated Serum ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Idiopathic Infantile Hypercalcemia

CYP24A1 is an enzyme that inactivates vitamin D. Loss-of-function mutations in this enzyme are rare but have been linked with idiopathic infantile hypercalcemia as well as adult-onset nephrocalcinosis and nephrolithiasis. Genetic testing for this mutation should be considered in the presence of calciuria, elevated serum calcium, elevated 1,25-dihydroxyvitamin D, and suppressed parathyroid hormone. We present a case with these lab findings as well as an elevated 25-hydroxyvitamin D/24,25-dihydroxyvitamin D ratio in whom compound heterozygous CYP24A1 mutations were found. His hypercalciuria resolved and 1,25-vitamin D level improved with ketoconazole treatment. We suggest that it is clinically important to identify patients with this phenotype as testing and treatment options are available which could reduce progression to chronic kidney disease in this population.

1,25-DIHYDROXYCHOLECALCIFEROL IN HYPOPHOSPHATAEMIC OSTEOMALACIA PRESENTING IN ADULTS

1978 ◽  
Vol 88 (2) ◽  
pp. 408-416 ◽  
Author(s):  
G. Offermann ◽  
G. Delling ◽  
M. R. Haussler
Keyword(s):  
Late Onset ◽  
Bone Mineralization ◽  
Urinary Calcium ◽  
Primary Defect ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Hydroxyproline Excretion ◽  
Dose Dependent ◽  
Hypophosphataemic Osteomalacia

ABSTRACT The effects of exogenous 1,25-dihydroxycholecalciferol (1,25(OH)2D3) in two adults with late-onset hypophosphataemic osteomalacia were studied. In the presence of elevated 25-hydroxyvitamin D levels 1,25(OH)2D3 improved intestinal 17Ca absorption and increased urinary calcium, phosphate and hydroxyproline excretion. Hypophosphataemia, parathyroid hormone and bone mineralization were not significantly affected. The rise of the 1,25-dihydroxyvitamin D concentrations was dose dependent. The results indicate that the impaired renal phosphate conservation - the primary defect in this disorder - is not corrected by exogenous 1,25-dihydroxycholecalciferol.

scholarly journals Vitamin D upregulates the macrophage complement receptor immunoglobulin in innate immunity to microbial pathogens

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Annabelle G. Small ◽  
Sarah Harvey ◽  
Jaspreet Kaur ◽  
Trishni Putty ◽  
Alex Quach ◽  
...  
Keyword(s):  
Vitamin D ◽  
Innate Immunity ◽  
Surface Expression ◽  
Microbial Pathogens ◽  
Cell Surface Expression ◽  
Complement Receptor ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Multistep Process ◽  
25 Hydroxyvitamin D

AbstractVitamin D deficiency remains a global concern. This ‘sunshine’ vitamin is converted through a multistep process to active 1,25-dihydroxyvitamin D3 (1,25D), the final step of which can occur in macrophages. Here we demonstrate a role for vitamin D in innate immunity. The expression of the complement receptor immunoglobulin (CRIg), which plays an important role in innate immunity, is upregulated by 1,25D in human macrophages. Monocytes cultured in 1,25D differentiated into macrophages displaying increased CRIg mRNA, protein and cell surface expression but not in classical complement receptors, CR3 and CR4. This was associated with increases in phagocytosis of complement opsonised Staphylococcus aureus and Candida albicans. Treating macrophages with 1,25D for 24 h also increases CRIg expression. While treating macrophages with 25-hydroxyvitamin D3 does not increase CRIg expression, added together with the toll like receptor 2 agonist, triacylated lipopeptide, Pam3CSK4, which promotes the conversion of 25-hydroxyvitamin D3 to 1,25D, leads to an increase in CRIg expression and increases in CYP27B1 mRNA. These findings suggest that macrophages harbour a vitamin D-primed innate defence mechanism, involving CRIg.

scholarly journals Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

2016 ◽  
Vol 37 (5) ◽  
pp. 521-547 ◽  
Author(s):  
Peter J. Tebben ◽  
Ravinder J. Singh ◽  
Rajiv Kumar
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Elevated Serum ◽  
Diagnosis And Treatment ◽  
Vitamin D Metabolites ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Stone Formers ◽  
25 Hydroxyvitamin D

AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

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