IDIOPATHIC INFANTILE HYPERCALCEMIA . DESCRIPTION OF CLINICAL CASES AND REVIEW.

Vitamin D plays a central role in calcium homeostasis. Impaired degradation  of 1,25-dihydroxyvitamin D due to loss-of-function mutations in CYP24A1 leads to significant hypercalcemia, hypercalciuria,  suppressed level of parathyroid hormone (PTH),  nephrocalcinosis and nephrolithiasis.  This condition has been called Idiopathic infantile hypercalcemia.

Treatment includes low calcium diet, rehydration, furosemid,  avoidance of vitamin D supplements  and sun protection.   In severe  cases   glucocorticoids, ketoconazole,  bisphosphonates  and  hemodiafiltration may be used.

Early diagnosis of the disease allows to develop an individual plan for managing these patients to prevent the formation of kidney disease, to conduct a genetic family counseling.

Here, we describe the cohort of  patients (3  children, 2 adults)  with significant hypercalcemia due to  homo- and compound heterozygous mutations in CYP24A1, describe  the main clinical and laboratory characteristics, diagnosis, principles and foundations of the management of patients with this pathology.

idiopathic infantile hypercalcemia, hypercalciuria, suppressed parathyroid hormone, nephrocalcinosis, 24-hydroxylase, CYP24A1

1. Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011;365(5):410-421. doi: 10.1056/nejmoa1103864

2. Skalova S, Cerna L, Bayer M, et al. Intravenous pamidronate in the treatment of severe idiopathic infantile hypercalcemia. Iran J Kidney Dis. 2013;7(2):160-164.

3. Lightwood R. Idiopathic hypercalcaemia with failure to thrive-nephrocalcinosis. Paper presented at: proceedings of the royal society of medicine. London; 1952.

4. Creery RD, Neill DW. Idiopathic hypercalcaemia in infants with failure to thrive. Lancet. 1954;267(6829):110-114.

5. Rhaney K, Mitchell RG. Idiopathic hypercalcaemia of infants. Lancet. 1956;270(6931):1028-1032.

6. Hahn CN, Baker E, Laslo P, et al. Localization of the human vitamin D 24-hydroxylase gene (CYP24) to chromosome 20q13.2—>q13.3. Cytogenet Cell Genet. 1993;62(4):192-193.

7. Annalora AJ, Goodin DB, Hong WX, et al. Crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism. J Mol Biol. 2010;396(2):441-451. doi: 10.1016/j.jmb.2009.11.057

8. Deluca HF. Metabolism of vitamin D: current status. Am J Clin Nutr. 1976;29(11):1258-1270.

9. Reddy GS, Tserng KY. Calcitroic acid, end product of renal metabolism of 1,25-dihydroxyvitamin D3 through C-24 oxidation pathway. Biochemistry. 1989;28(4):1763-1769.

10. Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci. 2004;29(12):664-673. doi: 10.1016/j.tibs.2004.10.005

11. Sakaki T, Kagawa N, Yamamoto K, Inouye K. Metabolism of vitamin D3 by cytochromes P450. Front Biosci. 2005;10:119-134.

12. Jones G, Prosser DE, Kaufmann M. 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch Biochem Biophys. 2012;523(1):9-18. doi: 10.1016/j.abb.2011.11.003

13. Nesterova G, Malicdan MC, Yasuda K, et al. 1,25-(OH)2D-24 hydroxylase (CYP24A1) deficiency as a cause of nephrolithiasis. Clin J Am Soc Nephrol. 2013;8(4):649-657.doi: 10.2215/cjn.05360512

14. Tebben PJ, Milliner DS, Horst RL, et al. Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy. J Clin Endocrinol Metab. 2012;97(3):E423-427. doi: 10.1210/jc.2011-1935

15. Dinour D, Beckerman P, Ganon L, et al. Loss-of-function mutations of CYP24A1, the vitamin D 24-hydroxylase gene, cause long-standing hypercalciuric nephrolithiasis and nephrocalcinosis. J Urol. 2013;190(2):552-557. doi: 10.1016/j.juro.2013.02.3188

16. Sayer JA, Hogg P, Rice SJ, et al. Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis. OA Nephrology. 2013;1(1). doi: 10.13172/2053-0293-1-1-525

17. Meusburger E, Mundlein A, Zitt E, et al. Medullary nephrocalcinosis in an adult patient with idiopathic infantile hypercalcaemia and a novel CYP24A1 mutation. Clin Kidney J. 2013;6(2):211-215. doi: 10.1093/ckj/sft008

18. Fencl F, Blahova K, Schlingmann KP, et al. Severe hypercalcemic crisis in an infant with idiopathic infantile hypercalcemia caused by mutation in CYP24A1 gene. Eur J Pediatr. 2013;172(1):45-49. doi: 10.1007/s00431-012-1818-1