Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Etiology of hypocalcemia in infants and children

Thomas Carpenter, MD
Section Editor
Joseph I Wolfsdorf, MB, BCh
Deputy Editor
Alison G Hoppin, MD


A narrow range of extracellular calcium concentrations provides for cell stability and survival and is maintained by an intricate homeostatic system. The etiology of hypocalcemia can be related to failure of a component of this system, such as deficiency of or resistance to parathyroid hormone (PTH) or vitamin D, or a defect of the calcium-sensing receptor (CaSR).

The etiology and pathogenesis of hypocalcemia in the infant and child, and a brief summary of calcium homeostasis will be presented here. An approach to determining the cause of hypocalcemia is presented separately. (See "Diagnostic approach to hypocalcemia".)

Treatment of hypocalcemia is covered in the following topic reviews:

Hypocalcemia due to hypoparathyroidism (see "Hypoparathyroidism")

Hypocalcemia in neonates (see "Neonatal hypocalcemia")


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Jan 4, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Gallo S, Comeau K, Sharma A, et al. Redefining normal bone and mineral clinical biochemistry reference intervals for healthy infants in Canada. Clin Biochem 2014; 47:27.
  2. Parkinson DB, Thakker RV. A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet 1992; 1:149.
  3. Shaw NJ, Haigh D, Lealmann GT, et al. Autosomal recessive hypoparathyroidism with renal insufficiency and developmental delay. Arch Dis Child 1991; 66:1191.
  4. Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S. A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroidism. J Clin Endocrinol Metab 1999; 84:3792.
  5. Günther T, Chen ZF, Kim J, et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 2000; 406:199.
  6. Ding C, Buckingham B, Levine MA. Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest 2001; 108:1215.
  7. Bilous RW, Murty G, Parkinson DB, et al. Brief report: autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia. N Engl J Med 1992; 327:1069.
  8. Hasegawa T, Hasegawa Y, Aso T, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet 1997; 73:416.
  9. Van Esch H, Groenen P, Nesbit MA, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 2000; 406:419.
  10. Muroya K, Hasegawa T, Ito Y, et al. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 2001; 38:374.
  11. Yumita S, Furukawa Y, Sohn HE, et al. Familial idiopathic hypoparathyroidism and progressive sensorineural deafness. Tohoku J Exp Med 1986; 148:135.
  12. Barakat AY, D'Albora JB, Martin MM, Jose PA. Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 1977; 91:61.
  13. Sanjad SA, Sakati NA, Abu-Osba YK, et al. A new syndrome of congenital hypoparathyroidism, severe growth failure, and dysmorphic features. Arch Dis Child 1991; 66:193.
  14. Tahseen K, Khan S, Uma R, et al. Kenny-Caffey syndrome in six Bedouin sibships: autosomal recessive inheritance is confirmed. Am J Med Genet 1997; 69:126.
  15. Bergada I, Schiffrin A, Abu Srair H, et al. Kenny syndrome: description of additional abnormalities and molecular studies. Hum Genet 1988; 80:39.
  16. Kelly TE, Blanton S, Saif R, et al. Confirmation of the assignment of the Sanjad-Sakati (congenital hypoparathyroidism) syndrome (OMIM 241410) locus to chromosome lq42-43. J Med Genet 2000; 37:63.
  17. Parvari R, Hershkovitz E, Grossman N, et al. Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nat Genet 2002; 32:448.
  18. Thakker RV, Davies KE, Whyte MP, et al. Mapping the gene causing X-linked recessive idiopathic hypoparathyroidism to Xq26-Xq27 by linkage studies. J Clin Invest 1990; 86:40.
  19. Bowl MR, Nesbit MA, Harding B, et al. An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism. J Clin Invest 2005; 115:2822.
  20. Arnold A, Horst SA, Gardella TJ, et al. Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest 1990; 86:1084.
  21. Zupanc ML, Moraes CT, Shanske S, et al. Deletion of mitochondrial DNA in patients with combined features of Kearns-Sayre and MELAS syndromes. Ann Neurol 1991; 29:680.
  22. Dionisi-Vici C, Garavaglia B, Burlina AB, et al. Hypoparathyroidism in mitochondrial trifunctional protein deficiency. J Pediatr 1996; 129:159.
  23. Kifor O, McElduff A, LeBoff MS, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2004; 89:548.
  24. De Sanctis V, Vullo C, Bagni B, Chiccoli L. Hypoparathyroidism in beta-thalassemia major. Clinical and laboratory observations in 24 patients. Acta Haematol 1992; 88:105.
  25. Carpenter TO, Carnes DL Jr, Anast CS. Hypoparathyroidism in Wilson's disease. N Engl J Med 1983; 309:873.
  26. Thacher TD, Fischer PR, Pettifor JM, et al. A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med 1999; 341:563.
  27. Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature 1987; 325:62.
  28. Ziegler EE, Hollis BW, Nelson SE, Jeter JM. Vitamin D deficiency in breastfed infants in Iowa. Pediatrics 2006; 118:603.
  29. Scriver CR, Reade TM, DeLuca HF, Hamstra AJ. Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease. N Engl J Med 1978; 299:976.
  30. Kitanaka S, Takeyama K, Murayama A, et al. Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 1998; 338:653.
  31. Yoshida T, Monkawa T, Tenenhouse HS, et al. Two novel 1alpha-hydroxylase mutations in French-Canadians with vitamin D dependency rickets type I1. Kidney Int 1998; 54:1437.
  32. Wang JT, Lin CJ, Burridge SM, et al. Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. Am J Hum Genet 1998; 63:1694.
  33. Brooks MH, Bell NH, Love L, et al. Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D. N Engl J Med 1978; 298:996.
  34. Labuda M, Fujiwara TM, Ross MV, et al. Two hereditary defects related to vitamin D metabolism map to the same region of human chromosome 12q13-14. J Bone Miner Res 1992; 7:1447.
  35. Baker AR, McDonnell DP, Hughes M, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U S A 1988; 85:3294.
  36. Hughes MR, Malloy PJ, Kieback DG, et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 1988; 242:1702.
  37. Marx SJ, Spiegel AM, Brown EM, et al. A familial syndrome of decrease in sensitivity to 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab 1978; 47:1303.
  38. Balsan S, Garabédian M, Larchet M, et al. Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D. J Clin Invest 1986; 77:1661.
  39. Hochberg Z, Tiosano D, Even L. Calcium therapy for calcitriol-resistant rickets. J Pediatr 1992; 121:803.
  40. Albright, F, Burnett, CH, Smith, PH, Parson, W. Pseudo-hypoparathyroidism--an example of 'Seabright-Bantam syndrome': report of three cases. Endocrinology 1942; 30:922.
  41. Chase LR, Fedak SA, Aurbach GD. Activation of skeletal adenyl cyclase by parathyroid hormone in vitro. Endocrinology 1969; 84:761.
  42. Chase LR, Melson GL, Aurbach GD. Pseudohypoparathyroidism: defective excretion of 3',5'-AMP in response to parathyroid hormone. J Clin Invest 1969; 48:1832.
  43. Bastepe M, Jüppner H. GNAS locus and pseudohypoparathyroidism. Horm Res 2005; 63:65.
  44. Spiegel AM, Weinstein LS, Shenker A. Abnormalities in G protein-coupled signal transduction pathways in human disease. J Clin Invest 1993; 92:1119.
  45. Shapira H, Mouallem M, Shapiro MS, et al. Pseudohypoparathyroidism type Ia: two new heterozygous frameshift mutations in exons 5 and 10 of the Gs alpha gene. Hum Genet 1996; 97:73.
  46. Ahmed SF, Dixon PH, Bonthron DT, et al. GNAS1 mutational analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf) 1998; 49:525.
  47. Hayward BE, Kamiya M, Strain L, et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci U S A 1998; 95:10038.
  48. Farfel Z, Brickman AS, Kaslow HR, et al. Defect of receptor-cyclase coupling protein in psudohypoparathyroidism. N Engl J Med 1980; 303:237.
  49. Nakamoto JM, Sandstrom AT, Brickman AS, et al. Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsalpha gene mutation. Am J Med Genet 1998; 77:261.
  50. Farfel Z, Friedman E. Mental deficiency in pseudohypoparathyroidism type I is associated with Ns-protein deficiency. Ann Intern Med 1986; 105:197.
  51. Levine MA, Downs RW Jr, Moses AM, et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983; 74:545.
  52. Carlson HE, Brickman AS. Blunted plasma cyclic adenosine monophosphate response to isoproterenol in pseudohypoparathyroidism. J Clin Endocrinol Metab 1983; 56:1323.
  53. ALBRIGHT F, FORBES AP, HENNEMAN PH. Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians 1952; 65:337.
  54. Fitch N. Albright's hereditary osteodystrophy: a review. Am J Med Genet 1982; 11:11.
  55. Germain-Lee EL, Groman J, Crane JL, et al. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 2003; 88:4059.
  56. Mantovani G, Maghnie M, Weber G, et al. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 2003; 88:4070.
  57. Shore EM, Ahn J, Jan de Beur S, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 2002; 346:99.
  58. Murray TM, Rao LG, Wong MM, et al. Pseudohypoparathyroidism with osteitis fibrosa cystica: direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone. J Bone Miner Res 1993; 8:83.
  59. Ishikawa Y, Bianchi C, Nadal-Ginard B, Homcy CJ. Alternative promoter and 5' exon generate a novel Gs alpha mRNA. J Biol Chem 1990; 265:8458.
  60. Swaroop A, Agarwal N, Gruen JR, et al. Differential expression of novel Gs alpha signal transduction protein cDNA species. Nucleic Acids Res 1991; 19:4725.
  61. Bastepe M, Fröhlich LF, Hendy GN, et al. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest 2003; 112:1255.
  62. Bastepe M, Fröhlich LF, Linglart A, et al. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet 2005; 37:25.
  63. Farfel Z, Brothers VM, Brickman AS, et al. Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proc Natl Acad Sci U S A 1981; 78:3098.
  64. Rodriguez HJ, Villarreal H Jr, Klahr S, Slatopolsky E. Pseudohypoparathyroidism type II: restoration of normal renal responsiveness to parathyroid hormone by calcium administration. J Clin Endocrinol Metab 1974; 39:693.
  65. Drezner M, Neelon FA, Lebovitz HE. Pseudohypoparathyroidism type II: a possible defect in the reception of the cyclic AMP signal. N Engl J Med 1973; 289:1056.
  66. Linglart A, Menguy C, Couvineau A, et al. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N Engl J Med 2011; 364:2218.
  67. Marraffa JM, Hui A, Stork CM. Severe hyperphosphatemia and hypocalcemia following the rectal administration of a phosphate-containing Fleet pediatric enema. Pediatr Emerg Care 2004; 20:453.
  68. Wason S, Tiller T, Cunha C. Severe hyperphosphatemia, hypocalcemia, acidosis, and shock in a 5-month-old child following the administration of an adult Fleet enema. Ann Emerg Med 1989; 18:696.
  69. Gessner BD, Beller M, Middaugh JP, Whitford GM. Acute fluoride poisoning from a public water system. N Engl J Med 1994; 330:95.
  70. Walder RY, Shalev H, Brennan TM, et al. Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint. Hum Mol Genet 1997; 6:1491.
  71. Walder RY, Landau D, Meyer P, et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 2002; 31:171.