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Hypoparathyroidism in Children

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Abstract

Hypoparathyroidism is a very uncommon endocrine disorder in children. In contrast to adults, in whom most cases of hypoparathyroidism are due to neck surgery, in children and adolescents, hypoparathyroidism is typically due to a genetic etiology. Identifying the genetic basis for hypoparathyroidism has important implications for both the patient and their family and can guide treatment as well as facilitate screening for anticipated comorbidities. Treatment and management can be challenging, especially in infancy. It is important to monitor treatment of hypoparathyroidism regularly in order to reduce the risk of developing nephrocalcinosis and nephrolithiasis. For at least some children with hypoparathyroidism who do not optimally respond to conventional therapy, PTH and PTH analogs represent an alternative treatment option.

Keywords

Hypoparathyroidism Pediatrics Parathyroid hormone Etiologies Treatment 

Notes

Conflict of Interest

Dr. Michael A. Levine has served as an advisory board member, research investigator, and consultant for Shire/Takeda.

References

  1. 1.
    Sargent JD, Stukel TA, Kresel J, Klein RZ. Normal values for random urinary calcium to creatinine ratios in infancy. J Pediatr. 1993;123(3):393–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Tsang RC, Light IJ, Sutherland JM, Kleinman LI. Possible pathogenetic factors in neonatal hypocalcemia of prematurity. The role of gestation, hyperphosphatemia, hypomagnesemia, urinary calcium loss, and parathormone responsiveness. J Pediatr. 1973;82(3):423–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Hsu SC, Levine MA. Perinatal calcium metabolism: physiology and pathophysiology. Sem Neonatol. 2004;9(1):23–36.CrossRefGoogle Scholar
  4. 4.
    Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet. 2002;31(2):166–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Fujimura J, Nozu K, Yamamura T, Minamikawa S, Nakanishi K, Horinouchi T, et al. Clinical and genetic characteristics in patients with Gitelman syndrome. Kidney Int Rep. 2019;4(1):119–25.PubMedCrossRefGoogle Scholar
  6. 6.
    Goldberg R, Motzkin B, Marion R, Scambler PJ, Shprintzen RJ. Velo-cardio-facial syndrome: a review of 120 patients. Am J Med Genet. 1993;45(3):313–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Greenberg F, Elder FF, Haffner P, Northrup H, Ledbetter DH. Cytogenetic findings in a prospective series of patients with DiGeorge anomaly. Am J Hum Genet. 1988;43(5):605–11.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Li D, Gordon CT, Oufadem M, Amiel J, Kanwar HS, Bakay M, et al. Heterozygous mutations in TBX1 as a cause of isolated hypoparathyroidism. J Clin Endocrinol Metab. 2018;103(11):4023–32.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kapadia CR, Kim YE, McDonald-McGinn DM, Zackai EH, Katz LE. Parathyroid hormone reserve in 22q11.2 deletion syndrome. Genet Med. 2008;10(3):224–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Jyonouchi S, McDonald-McGinn DM, Bale S, Zackai EH, Sullivan KE. CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome and chromosome 22q11.2 deletion syndrome: a comparison of immunologic and nonimmunologic phenotypic features. Pediatrics. 2009;123(5):e871–7.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature. 2000;406(6794):419–22.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, et al. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet. 2001;38(6):374–80.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Chien WW, Leiding JW, Hsu AP, Zalewski C, King K, Holland SM, et al. Auditory and vestibular phenotypes associated with GATA3 mutation. Otol Neurotol. 2014;35(4):577–81.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Pearce SH, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med. 1996;335(15):1115–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Gordon RJ, Levine MA. Genetic disorders of parathyroid development and function. Endocrinol Metab Clin N Am. 2018;47(4):809–23.CrossRefGoogle Scholar
  16. 16.
    Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, et al. Mutations affecting G-protein subunit alpha11 in hypercalcemia and hypocalcemia. N Engl J Med. 2013;368(26):2476–86.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Li D, Opas EE, Tuluc F, Metzger DL, Hou C, Hakonarson H, et al. Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization. J Clin Endocrinol Metab. 2014;99(9):E1774–83.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Brown EM, Pollak M, Chou YH, Seidman CE, Seidman JG, Hebert SC. The cloning of extracellular Ca(2+)-sensing receptors from parathyroid and kidney: molecular mechanisms of extracellular Ca(2+)-sensing. J Nutr. 1995;125(7 Suppl):1965s–70s.PubMedCrossRefGoogle Scholar
  19. 19.
    Parkinson DB, Thakker RV. A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet. 1992;1(2):149–52.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM. Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest. 1990;86(4):1084–7.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Lee S, Mannstadt M, Guo J, Kim SM, Yi HS, Khatri A, et al. A homozygous [Cys25]PTH(1-84) mutation that impairs PTH/PTHrP receptor activation defines a novel form of hypoparathyroidism. J Bone Miner Res Off J Am Soc Bone Miner Res. 2015;30(10):1803–13.CrossRefGoogle Scholar
  22. 22.
    Canaff L, Zhou X, Mosesova I, Cole DE, Hendy GN. Glial cells missing-2 (GCM2) transactivates the calcium-sensing receptor gene: effect of a dominant-negative GCM2 mutant associated with autosomal dominant hypoparathyroidism. Hum Mutat. 2009;30(1):85–92.PubMedCrossRefGoogle Scholar
  23. 23.
    Mirczuk SM, Bowl MR, Nesbit MA, Cranston T, Fratter C, Allgrove J, et al. A missense glial cells missing homolog B (GCMB) mutation, Asn502His, causes autosomal dominant hypoparathyroidism. J Clin Endocrinol Metab. 2010;95(7):3512–6.PubMedCrossRefGoogle Scholar
  24. 24.
    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(8):1215–20.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Bowl MR, Mirczuk SM, Grigorieva IV, Piret SE, Cranston T, Southam L, et al. Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism. Hum Mol Genet. 2010;19(10):2028–38.PubMedCrossRefGoogle Scholar
  26. 26.
    Guan B, Welch JM, Sapp JC, Ling H, Li Y, Johnston JJ, et al. GCM2-activating mutations in familial isolated hyperparathyroidism. Am J Hum Genet. 2016;99(5):1034–44.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Shoback DM, Silva BC, Thakker RV, Vokes T, Bouillon R, Bilezikian JP, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metabol. 2016;101(6):2300–12.CrossRefGoogle Scholar
  28. 28.
    Li D, Streeten EA, Chan A, Lwin W, Tian L, Pellegrino da Silva R, et al. Exome sequencing reveals mutations in AIRE as a cause of isolated hypoparathyroidism. J Clin Endocrinol Metab. 2017;102(5):1726–33.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Rubin MR, Cusano NE, Bilezikian JP, Brandi ML, Potts JT Jr, Mannstadt M, et al. Management of hypoparathyroidism: present and future. J Clin Endocrinol Metabol. 2016;101(6):2313–24.CrossRefGoogle Scholar
  30. 30.
    Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke BL, Thakker RV, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab. 2016;101(6):2273–83.CrossRefGoogle Scholar
  31. 31.
    Mannstadt M, Bilezikian JP, Thakker RV, Hannan FM, Clarke BL, Rejnmark L, et al. Hypoparathyroidism. Nat Rev Dis Primers. 2017;3:17055.CrossRefGoogle Scholar
  32. 32.
    So NP, Osorio AV, Simon SD, Alon US. Normal urinary calcium/creatinine ratios in African-American and Caucasian children. Pediatr Nephrol (Berlin, Germany). 2001;16(2):133–9.CrossRefGoogle Scholar
  33. 33.
    Burritt MF, Slockbower JM, Forsman RW, Offord KP, Bergstralh EJ, Smithson WA. Pediatric reference intervals for 19 biologic variables in healthy children. Mayo Clin Proc. 1990;65(3):329–36.PubMedCrossRefGoogle Scholar
  34. 34.
    Matos V, van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr. 1997;131(2):252–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Hebert SC, Brown EM, Harris HW. Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis. J Exp Biol. 1997;200.(Pt 2:295–302.PubMedGoogle Scholar
  36. 36.
    Rubin MR, Bilezikian JP. Parathyroid hormone as an anabolic skeletal therapy. Drugs. 2005;65(17):2481–98.PubMedCrossRefGoogle Scholar
  37. 37.
    Winer KK, Sinaii N, Peterson D, Sainz B Jr, Cutler GB Jr. Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with hypoparathyroidism. J Clin Endocrinol Metab. 2008;93(9):3389–95.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Winer KK, Sinaii N, Reynolds J, Peterson D, Dowdy K, Cutler GB Jr. Long-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium. J Clin Endocrinol Metab. 2010;95(6):2680–8.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Winer KK. Advances in the treatment of hypoparathyroidism with PTH 1-34. Bone. 2019;120:535–41.PubMedCrossRefGoogle Scholar
  40. 40.
    Peterson D, Cutler GB Jr, Reynolds J, Dowdy K, Sinaii N, Winer KK. Long-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium. J Clin Endocrinol Metabol. 2010;95(6):2680–8.CrossRefGoogle Scholar
  41. 41.
    Winer KK, Zhang B, Shrader JA, Peterson D, Smith M, Albert PS, et al. Synthetic human parathyroid hormone 1-34 replacement therapy: a randomized crossover trial comparing pump versus injections in the treatment of chronic hypoparathyroidism. J Clin Endocrinol Metab. 2012;97(2):391–9.CrossRefGoogle Scholar
  42. 42.
    Winer KK, Fulton KA, Albert PS, Cutler GB. Effects of pump versus twice-daily injection delivery of synthetic parathyroid hormone 1-34 in children with severe congenital hypoparathyroidism. J Pediatr. 2014;165(3):556–63. e1PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Winer KK, Kelly A, Johns A, Zhang B, Dowdy K, Kim L, et al. Long-term parathyroid hormone 1-34 replacement therapy in children with hypoparathyroidism. J Pediatr. 2018;203:391–9 e1.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Burkett L, Mittelman SD, Geffner ME, Hendy GN, Mosesova I, Canaff L, et al. A hypocalcemic child with a novel activating mutation of the calcium-sensing receptor gene: successful treatment with recombinant human parathyroid hormone. J Clin Endocrinol Metabol. 2006;91(7):2474–9.CrossRefGoogle Scholar
  45. 45.
    Theman TA, Collins MT, Dempster DW, Zhou H, Reynolds JC, Brahim JS, et al. Clinical vignette: PTH(1–34) replacement therapy in a child with hypoparathyroidism caused by a sporadic calcium receptor mutation. J Bone Miner Res. 2009;24(5):964–73.PubMedCrossRefGoogle Scholar
  46. 46.
    Ramakrishnan Y, Cocks HC. Impact of recombinant PTH on management of hypoparathyroidism: a systematic review. Eur Arch Otorhinolaryngol. 2016;273(4):827–35.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Division of Endocrinology and Diabetes and the Center for Bone HealthThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Department of PediatricsUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  3. 3.Division of EndocrinologyBoston Children’s Hospital, Harvard Medical SchoolBostonUSA

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