Background: A female infant was admitted to hospital due to failure to thrive. She presented hypercalcemia (4.09 mmol/L, normal range: 2.2-2.65 mmol/L), high 25-hydroxyvitamin D (283 nmol/L, normal range: 75-250 nmol/L), 1,25-dihydroxyvitamin D in the upper normal range, and low parathyroid hormone. Vitamin D intoxication was suspected. The patient had received routine rickets prophylaxis. Methods: Williams-Beuren syndrome was genetically excluded. Sequencing of CYP24A1 showed 2 mutations: c.443T>C and c.1186C>T. Results: The patient's clinical status improved after intravenous rehydration, cessation of supplementation, and on a low-calcium diet. 25-Hydroxyvitamin D concentrations normalized within days, while 1,25-dihydroxyvitamin D remained in the upper normal range. We also investigated our patient's bone health. Conclusion: The patient was hospitalized initially on suspicion of vitamin D intoxication but proved to be a case of compound heterozygosity. Data on the long-term clinical and biochemical evolution of patients with idiopathic infantile hypercalcemia are sparse. Our follow-up showed seasonal variations of vitamin D and calcium parameters, with no influence on kidney function or bone health for the investigated period.

Lightwood R, Stapleton T: Idiopathic hypercalcaemia in infants. Lancet 1953;265:255-256.
Fanconi G: Chronic disorders of calcium and phosphate metabolism in children. Schweiz Med Wochenschr 1951;81:908-913.
Pober BR: Williams-Beuren syndrome. N Engl J Med 2010;362:239-252.
Martin ND, Snodgrass GJ, Cohen RD: Idiopathic infantile hypercalcaemia - a continuing enigma. Arch Dis Child 1984;59:605-613.
Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, Misselwitz J, Klaus G, Kuwertz-Bröking E, Fehrenbach H, Wingen AM, Güran T, Hoenderop JG, Bindels RJ, Prosser DE, Jones G, Konrad M: Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med 2011;365:410-421.
Labuda M, Lemieux N, Tihy F, Prinster C, Glorieux FH: Human 25-hydroxyvitamin D 24-hydroxylase cytochrome P450 subunit maps to a different chromosomal location than that of pseudovitamin D-deficient rickets. J Bone Miner Res 1993;8:1397-1406.
Sakaki T, Sawada N, Komai K, Shiozawa S, Yamada S, Yamamoto K, Ohyama Y, Inouye K: Dualmetabolic pathway of 25-hydroxyvitamin D3 catalyzed by human CYP24. Eur J Biochem 2000;267:6158-6165.
Dauber A, Nguyen TT, Sochett E, Cole DE, Horst R, Abrams SA, Carpenter TO, Hirschhorn JN: Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia. J Clin Endocrinol Metab 2012;97:E268-E274.
O'Keeffe DT, Tebben PJ, Kumar R, Singh RJ, Wu Y, Wermers RA: Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect. Osteoporos Int 2016;27:3121-3125.
Nesterova G, Malicdan MC, Yasuda K, Sakaki T, Vilboux T, Ciccone C, Horst R, Huang Y, Golas G, Introne W, Huizing M, Adams D, Boerkoel CF, Collins MT, Gahl WA: 1,25-(OH)2D-24 hydroxylase (CYP24A1) deficiency as a cause of nephrolithiasis. Clin J Am Soc Nephrol 2013;8:649-657.
Sayers J, Hynes AM, Rice SJ, Hogg P, Sayer JA: Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis. OA Nephrology 2013;1:6.
Molin A, Baudoin R, Kaufmann M, Souberbielle JC, Ryckewaert A, Vantyghem MC, Eckart P, Bacchetta J, Deschenes G, Kesler-Roussey G, Coudray N, Richard N, Wraich M, Bonafiglia Q, Tiulpakov A, Jones G, Kottler ML: CYP24A1 mutations in a cohort of hypercalcemic patients: evidence for a recessive trait. J Clin Endocrinol Metab 2015;100:E1343-E1352.
Streeten EA, Zarbalian K, Damcott CM: CYP24A1 mutations in idiopathic infantile hypercalcemia. N Engl J Med 2011;365:1741-1742; author reply 1742-1743.
Jacobs TP, Kaufman M, Jones G, Kumar R, Schlingmann KP, Shapses S, Bilezikian JP: A lifetime of hypercalcemia and hypercalciuria, finally explained. J Clin Endocrinol Metab 2014;99:708-712.
Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, Kranz B, Pronicka E, Ciara E, Akcay T, Bulus D, Cornelissen EA, Gawlik A, Sikora P, Patzer L, Galiano M, Boyadzhiev V, Dumic M, Vivante A, Kleta R, Dekel B, Levtchenko E, Bindels RJ, Rust S, Forster IC, Hernando N, Jones G, Wagner CA, Konrad M: Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J Am Soc Nephrol 2016;27:604-614.
Rodd C, Goodyer P: Hypercalcemia of the newborn: etiology, evaluation, and management. Pediatr Nephrol 1999;13:542-547.
Huang J, Coman D, McTaggart SJ, Burke JR: Long-term follow-up of patients with idiopathic infantile hypercalcaemia. Pediatr Nephrol 2006;21:1676-1680.
Pronicka E, Rowińska E, Kulczycka H, Lukaszkiewicz J, Lorenc R, Janas R: Persistent hypercalciuria and elevated 25-hydroxyvitamin D3 in children with infantile hypercalcaemia. Pediatr Nephrol 1997;11:2-6.
Figueres ML, Linglart A, Bienaime F, Allain-Launay E, Roussey-Kessler G, Ryckewaert A, Kottler ML, Hourmant M: Kidney function and influence of sunlight exposure in patients with impaired 24-hydroxylation of vitamin D due to CYP24A1 mutations. Am J Kidney Dis 2015;65:122-126.
Yu WS, Chan KY, Yu FW, Ng BK, Lee KM, Qin L, Lam TP, Cheng JC: Bone structural and mechanical indices in adolescent idiopathic scoliosis evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Bone 2014;61:109-115.
Bacchetta J, Boutroy S, Vilayphiou N, Ranchin B, Fouque-Aubert A, Basmaison O, Cochat P: Bone assessment in children with chronic kidney disease: data from two new bone imaging techniques in a single-center pilot study. Pediatr Nephrol 2011;26:587-595.
Määttä M, Macdonald HM, Mulpuri K, McKay HA: Deficits in distal radius bone strength, density and microstructure are associated with forearm fractures in girls: an HR-pQCT study. Osteoporos Int 2015;26:1163-1174.
Cools M, Goemaere S, Baetens D, Raes A, Desloovere A, Kaufman JM, De Schepper J, Jans I, Vanderschueren D, Billen J, De Baere E, Fiers T, Bouillon R: Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: a cross-sectional study. Bone 2015;81:89-96.
Ketha H, Kumar R, Singh RJ: LC-MS/MS for identifying patients with CYP24A1 mutations. Clin Chem 2016;62:236-242.
Masuda S, Prosser DE, Guo Y-D, Kaufmann M, Jones G: Generation of a homology model for the human cytochrome P450, CYP24A1, and the testing of putative substrate binding residues by site-directed mutagenesis and enzyme activity studies. Arch Biochem Biophys 2007;460:177-191.
Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 1988;16:1215.
Hochberg Z, Bereket A, Davenport M, Delemarre-Van de Waal HA, De Schepper J, Levine MA, Shaw N, Schoenau E, van Coeverden SC, Weisman Y, et al: Consensus development for the supplementation of vitamin D in childhood and adolescence. Horm Res 2002;58:39-51.
Deutsche Gesellschaft für Ernährung e.V. (DGE), Österreichische Gesellschaft für Ernährung (ÖGE), Schweizerische Gesellschaft für Ernährungsforschung (SGE), Schweizerische Vereinigung für Ernährung (SVE): Referenzwerte für die Nährstoffzufuhr, 1. Auflage, 5. Korrigierter Nachdruck. Umschau Braus, Germany, 2013.
Schlingmann KP, Glenville J: CYP24A1 mutations in idiopathic infantile hypercalcemia. N Engl J Med 2011;365:1741-1743.
Han H, Segal AM, Seifter JL, Dwyer JT: Nutritional management of kidney stones (nephrolithiasis). Clin Nutr Res 2015;4:137-152.
Grant MP, Cavanaugh A, Breitwieser GE: 14-3-3 proteins buffer intracellular calcium sensing receptors to constrain signaling. PLoS One 2015;10:e0136702.
Rubin RM, Dempster DW, Sliney J Jr, Zhou H, Nickolas TL, Stein EM, Dworakowski E, Dellabadia M, Ives R, McMahon DJ, Zhang C, Silverberg SJ, Shane E, Cremers S, Bilezikian JP: PTH(1-84) administration reverses abnormal bone-remodeling dynamics and structure in hypoparathyroidism. J Bone Miner Res 2011;26:2727-2736.
Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G: Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev 2016;96:365-408.
Shima M, Tanaka H, Norman AW, Yamaoka K, Yoshikawa H, Takaoka K, Ishizuka S, Seino Y: 23(S),25(R)-1,25-dihydroxyvitamin D3-26,23-lactone stimulates murine bone formation in vivo. Endocrinology 1990;126:832-836.
Seo EG, Einhorn TA, Norman AW: 24R,25-dihydroxyvitamin D3: an essential vitamin D3 metabolite for both normal bone integrity and healing of tibial fracture in chicks. Endocrinology 1997;138:3864-3872.
St-Arnaud R: CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24. J Steroid Biochem Mol Biol 2010;121:254-256.
St-Arnaud R: Targeted inactivation of vitamin D hydroxylases in mice. Bone 1999;25:127-129.
McTaggart SJ, Craig J, MacMillan J, Burke JR: Familial occurrence of idiopathic infantile hypercalcemia. Pediatr Nephrol 1999;13:668-671.
Dinour D, Beckerman P, Ganon L, Tordjman K, Eisenstein Z, Holtzman EJ: Loss-of-function mutations of CYP24A1, the vitamin D 24-hydroxylase gene, cause long-standing hypercalciuric nephrolithiasis and nephrocalcinosis. J Urol 2013;190:552-557.
Stapleton T, MacDonald WB, Lightwood R: The pathogenesis of idiopathic hypercalcemia in infancy. Am J Clin Nutr 1957;5:533-542.
Mizusawa Y, Burke JR: Prednisolone and cellulose phosphate treatment in idiopathic infantile hypercalcaemia with nephrocalcinosis. J Paediatr Child Health 1996;32:350-352.
Bereket A, Erdogan T: Oral bisphosphonate therapy for vitamin D intoxication of the infant. Pediatrics 2003;111:899-901.
Nguyen M, Boutignon H, Mallet E, Linglart A, Guillozo H, Jehan F, Garabedian M: Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment. J Pediatr 2010;157296-302.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.