Hypoparathyroidism and Pseudohypoparathyroidism

  • Rajesh V. ThakkerEmail author


This chapter focuses on problems with hypoparathyroidism and pseudohypoparathyroidism, in contrast to previous chapters in which these problems were discussed in children. It provides clinical information on medical history, clinical symptoms and medical management. Up-to-date information is summarized about the genetic abnormalities associated with hypoparathyroid disorders as well as disorders such as pluriglandular autoimmune hypoparathyroidism. Blomstand’s disease, mitochondrial disorders associated with hypoparathyroidism, and recessive hypoparathyroid.


Hypoparathyroidism Hypocalcemia Hyperphosphataemia DiGeorge syndrome Autoimmune Hypomagnesaemia Pluriglandular disorder Endocrinopathy Normal serum calcium Subcapsular cataract Papilloedema 25 Hydroxy vitamin D 1,25 Dihydroxy vitamin D Pseudohypoparathyroidism Tetany Calcium gluconate Celiac disease Persistent hypocalcemia Cholecalciferol Ergocalciferol Alfacalcidiol Calcitriol Hypercalciuria Hypercalcemia Autosomal disorder X-linked disorder Infiltrating metastases Seizures PTH gene mutation Chromosome 11p15 Autosomal dominant isolated hyperparathyroidism Autosomal recessive hypoparathyroidism Calcium receptor GCMB gene X-linked recessive hypoparathyroidism Sox 3 gene SRY gene Acquired hypoparathyroidism Hemochromatosis Amyloidosis Sarcoidosis Thalassemia Wilson’s disease Neonatal hypoparathyroidism Kenney Caffey syndrome Barakat syndrome Dysmorphic features Lymphoedema Deafness Renal dysplasia Haploinsufficiency Mitochondrial disorders Kearns-Sayre syndrome MELAS syndrome Opthalmoplegia Pigmentary retinopathy Cardiomyopathy Lactic ­acidosis Diabetes mellitus Sensorineural deafness Trifunctional ­protein deficiency Osteosclerosis Nanophthalmos Hyperopia Kirk-Richardson syndrome Sanjad–Sakati syndrome Tubulin-specific chaperone Brachytelephalangy Blomstrand disease Chondrodysplasia Pluriglandular autoimmune hypoparathyroidism Candidiasis Hypogonadism Steatorrhea Alopecia Vitiligo Autoimmune polyglandular candidiasis ectodermal dystrophy Polyglandular autoimmune type 1 syndrome Autoantibodies Addison’s disease Diabetes mellitus type 1 Inflammasome Innate immune system Familial benign hypocalciuric hypercalcemia Barter syndrome type 5 Hypokalemic alkalosis Hyperrenninemia Hyperaldosteronism Gain-of-function mutation Inactivating mutation Carpopedal spasm Nephrocalcinosis Autoimmune acquired hypoparathyroidism Pseudohypoparathyroidism type 1a and 1b Pseudopseudohypoparathyroidism Albright’s hereditary osteodystrophy Dental hypoplasia Brachydactyly Adenyl cyclase Parathyroid hormone-related protein GNAS gene 



I am grateful: to the Medical Research Council (UK) for support and to Mrs Tracey Walker for typing the manuscript and for expert secretarial assistance.


  1. 1.
    Rubin MR, Levine MA. Hypoparathyroidism and pseudohypoparathyroidism. In: Rosen CJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 7th ed. Washington, DC: American Society of Bone and Mineral Research; 2008. p. 354–61.CrossRefGoogle Scholar
  2. 2.
    Shoback D. Hypocalcaemia: definition, etiology, pathogenesis, diagnosis and management. In: Rosen CJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 7th ed. Washington, DC: American Society of Bone and Mineral Research; 2008. p. 313–7.CrossRefGoogle Scholar
  3. 3.
    Thakker RV. Hypocalcaemic disorders. In: Thakker RV, Wass JAH, editors. Endocrine disorders, medicine. Abingdon, Oxon: The Medicine Group [Journals] Ltd, 25(6):68–70.Google Scholar
  4. 4.
    Thakker RV, Juppner H. Genetic disorders of calcium homeostasis caused by abnormal regulation of parathyroid hormone secretion or responsiveness. In: DeGroot LJ, Jameson JL, editors. Endocrinology. 5th ed. Philadelphia: Elsevier Saunders; 2006. p. 1511–31.Google Scholar
  5. 5.
    Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM. Mutations of the signal peptide encoding region of preproparathyroid hormone gene in isolated hypoparathyroidism. J Clin Invest. 1990;86:1084–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Parkinson DB, Thakker RV. A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet. 1992;1:149–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Ding C, Buckingham B, Levine M. Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest. 2001;108:1215–20.PubMedGoogle Scholar
  8. 8.
    Baumber L, Tufarelli C, Patel S, King P, Johnson CA, Maher ER, Trembath RC. Identification of a novel mutation disrupting the DNA binding activity of GCM2 in autosomal recessive familial isolated hypoparathyroidism. J Med Genet. 2005;2005(42):443–8.CrossRefGoogle Scholar
  9. 9.
    Mannstadt M, Bertrand G, Grandechamp B, Jueppner H, Silve C. Dominant-negative GCMB mutations cause hypoparathyroidism. J Bone Miner Res. 2007;22:S9.Google Scholar
  10. 10.
    Bowl MR, Mirczuk SM, Grigorieva IV, Piret SE, Cranston T, Southam L, Allgrove J, Bahl S, Brain C, Loughlin J, Mughal Z, Ryan F, Shaw N, Thakker YV, Tiosano D, Nesbit MA, Thakker RV. Identification and characterization of novel parathyroid-specific transcription factor glial cells missing homolog B (GCBM) mutations in 8 families with autosomal recessive hypoparathyroidism. Hum Mol Genet. 2010;19(10):2028–38.PubMedCrossRefGoogle Scholar
  11. 11.
    Mirczuk SM, Bowl MR, Nesbit MA, Cranston T, Fratter C, Allgrove J, Brain C, Thakker RV. A missense glial cells missing homologue B (GCMB) ­mutation, Asn502His causes autosomal dominant hypoparathyroidism. J Clin Endocrinol Metab. 2010;95(7):3512–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Pearce SH, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, Brown EM, Thakker RV. A familial syndrome of hypocalcaemia with hypocalciuria due to mutations in the calcium-sensing receptor gene. N Engl J Med. 1996;335:1115–22.PubMedCrossRefGoogle Scholar
  13. 13.
    Whyte MP, Weldon VV. Idiopathic hypoparathyroidism presenting with seizures during infancy: X-linked recessive inheritance in a large Missouri kindred. J Pediatr. 1981;99:608–11.PubMedCrossRefGoogle Scholar
  14. 14.
    Whyte MP, Kim GS, Kosanovich M. Absence of parathyroid tissue in sex-linked recessive hypoparathyroidism (Letter). J Pediatr. 1986;109:915.PubMedGoogle Scholar
  15. 15.
    Thakker RV, Davies KE, Whyte MP, Wooding C, O’Riordan JLH. Mapping the gene causing X-linked recessive idiopathic hypoparathyroidism to Xq26–Xq27 by linkage studies. J Clin Invest. 1990;6:40–5.CrossRefGoogle Scholar
  16. 16.
    Bowl MR, Nesbit MA, Harding B, Levy E, Jefferson A, Volpi E, Rozzoti K, Lovell-Badge R, Schlessinger D, Whyte M, Thakker RV. An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism. J Clin Invest. 2005;115:2822–31.PubMedCrossRefGoogle Scholar
  17. 17.
    Kleinjan DA, van Heyningen V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet. 2005;76:8–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Scambler PJ, Carey AH, Wyse RK, Roach S, Dumanski JP, Nordenskjold M, Williamson R. Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome. Genomics. 1991;10:201–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Monaco G, Pignata C, Rossi E, et al. DiGeorge anomaly associated with 10p deletion. Am J Med Genet. 1991;39:215–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Scambler PJ. The 22q11 deletion syndromes. Hum Mol Genet. 2000;9:2421–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, Kamatani N, Momma K, Takao A, Nakazawa M, Shimizu N, Matsuoka R. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362:1366–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Baldini A. DiGeorge’s syndrome: a gene at last. Lancet. 2003;362:1342–3.PubMedCrossRefGoogle Scholar
  23. 23.
    Sykes KS, Bachrach LK, Siegel-Bartelt J, Ipp M, Kooh SW, Cytrynbaum C. Velocardio-facial syndrome presenting as hypocalcemia in early adolescence. Arch Pediatr Adolesc Med. 1997;151:745–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Bilous RW, Murty G, Parkinson DB, Thakker RV, Coulthard MG, Burn J, Mathias D, Kendall-Taylor P. Autosomal dominant familial hypoparathyroidism, sensorineural deafness and renal dysplasia. N Engl J Med. 1992;327:1069–84.PubMedCrossRefGoogle Scholar
  25. 25.
    Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K. GATA3 haploinsufficiency causes human HDR syndrome. Nature. 2000;406:419–22.PubMedCrossRefGoogle Scholar
  26. 26.
    Ali A, Christie PT, Grigorieva IV, Harding B, Van Esch H, Ahmed SF, Bitner-Glindzicz M, Blind E, Bloch C, Christin P, Clayton P, Gecz J, Gilbert-Dussardier B, Guillen-Navarro E, Hackett A, Halac I, Hendy GN, Lalloo F, Mache CJ, Mughal Z, Ong ACM, Rinat C, Shaw N, Smithson SF, Tolmie J, Weill J, Nesbit MA, Thakker RV. Functional characterisation of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum Mol Genet. 2007;16:265–75.PubMedCrossRefGoogle Scholar
  27. 27.
    Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S. Mitochondrial deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N Engl J Med. 1989;320:1293–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Morten KJ, Cooper JM, Brown GK, Lake BD, Pike D, Poulton J. A new point mutation associated with mitochondrial encephalomyopathy. Hum Mol Genet. 1993;2:2081–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Isotani H, Fukumoto Y, Kawamura H, Furukawa K, Ohsawa N, Goto Y, Nishino I, Nonaka I. Hypoparathyroidism and insulin-dependent diabetes mellitus in a patient with Kearns–Sayre syndrome harbouring a mitochondrial DNA deletion. Clin Endocrinol. 1996;45:637–41.CrossRefGoogle Scholar
  30. 30.
    Dionisi-Vici C, Garavaglia B, Burlina AB, Bertini E, Saponara I, Sabetta G, Taroni F. Hypoparathyroidism in mitochondrial trifunctional protein deficiency. J Pediatr. 1996;129:159–62.PubMedCrossRefGoogle Scholar
  31. 31.
    Franceschini P, Testa A, Bogetti G, Girardo E, Guala A, Lopez-Bell G, Buzio G, Ferrario E, Piccato E. Kenny-Caffey syndrome in two sibs born to consanguineous parents: evidence for an autosomal recessive variant. Am J Med Genet. 1992;42:112–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Boynton JR, Pheasant TR, Johnson BL, Levin DB, Streeten BW. Ocular findings in Kenny’s syndrome. Arch Ophthalmol (Chicago). 1979;97:896–900.Google Scholar
  33. 33.
    Richardson RJ, Kirk JM. Short stature, mental retardation, and hypoparathyroidism: a new syndrome. Arch Dis Child. 1990;65:1113–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Sanjad SA, Sakati NA, Abu-Osba YK, Kaddoura R, Milner RD. A new syndrome of congenital hypoparathyroidism, severe growth failure, and dysmorphic features. Arch Dis Child. 1991;66:193–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loeys B, Zecic A, Mortier G, Gregory S, Sharony R, Kambouris M, Sakati N, Meyer BF, Al Aqeel AI, Al Humaidan AK, Al Zanhrani F, Al Swaid A, Al Othman J, Diaz GA, Weiner R, Khan KT, Gordon R, Gelb BD, HRD/Autosomal Recessive Kenny-Caffey Syndrome Consortium. Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nat Genet. 2002;32:448–52.CrossRefGoogle Scholar
  36. 36.
    Jobert AS, Zhang P, Couvineau A, Bonaventure J, Roume J, Le Merrer M, Silve C. Absence of functional receptors parathyroid hormones and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest. 1998;102:34–40.PubMedCrossRefGoogle Scholar
  37. 37.
    Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322:1829–36.PubMedCrossRefGoogle Scholar
  38. 38.
    Aaltonen J, Björses P, Sandkuijl L, Perheentupa J, Peltonen L. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type 1 assigned to chromosome 21. Nat Genet. 1994;8:83–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N. Positional cloning of the APECED gene. Nat Genet. 1997;17:393–8.PubMedCrossRefGoogle Scholar
  40. 40.
    The Finnish-German APECED consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc finger domains. Nat Genet. 1997;17:399–403.CrossRefGoogle Scholar
  41. 41.
    Pearce SH, Cheetham T, Imrie H, Vaidya B, Barnes ND, Bilous RW, Carr D, Meeran K, Shaw NJ, Smith CS, Toft AD, Williams G, Kendall-Taylor P. A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. Am J Hum Genet. 1998;63:1675–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. Aire regulates negative selection of organ-specific T cells. Nat Immunol. 2003;4:350–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Meaager A, Visvalingam K, Peterson P, Moll K, Murumagi A, Krohn K, Eskelin P, Perheentupa J, Husebye E, Kadota Y, Willcox N. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 2006;3:e289.CrossRefGoogle Scholar
  44. 44.
    Alimohammadi M, Bjorklund P, Hallgren A, Pontynen N, Szinnai G, Shikama N, Keller MP, Ekwall O, Kinkel SA, Husebye ES, Gustafsson J, Rorsman F, Peltonen L, Betterle C, Perheentupa J, Akerstrom G, Westin G, Scott HS, Hollander GA, Kampe O. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med. 2008;358:1018–28.PubMedCrossRefGoogle Scholar
  45. 45.
    Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453:1122–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcaemia and ­neonatal severe hyperparathyroidism. Cell. 1993;75:1297–303.PubMedCrossRefGoogle Scholar
  47. 47.
    Thakker RV. Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium. 2004;35:275–82.PubMedCrossRefGoogle Scholar
  48. 48.
    Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T. Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet. 2002;360:692–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Vargas-Poussou R, Huang C, Hulin P, Houillier P, Jeunemaitre X, Paillard M, Planelles G, Dechaux M, Miller RT, Antignac C. Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. J Am Soc Nephrol. 2002;13:2259–66.PubMedCrossRefGoogle Scholar
  50. 50.
    Li Y, Song YH, Rais N, Connor E, Schatz D, Muir A, Maclaren N. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest. 1996;97:910–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Kifor O, Moore Jr FD, Delaney M, Garber J, Hendy GN, Butters R, Gao P, Cantor TL, Kifor I, Brown EM, Wysolmerski J. A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J Clin Endocrinol Metab. 2003;88:60–72.PubMedCrossRefGoogle Scholar
  52. 52.
    Weinstein LS, Gejman PV, Friedman E, et al. Mutations of the Gsα-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA. 1990;87:8287–90.PubMedCrossRefGoogle Scholar
  53. 53.
    Yu S, Yu D, Hainline BE, Brener JL, Wilson KA, Wilson LC, Oude-Luttikhuis ME, Trembath RC, Weinstein LS. A deletion hot-spot in exon 7 of the Gsα gene (GNAS1) in patients with Albright ­hereditary osteodystrphy. Hum Mol Genet. 1995;4:2001–2.PubMedCrossRefGoogle Scholar
  54. 54.
    Wilson LC, Oude-Luttikhuis MEM, Clayton PT, et al. Parental origin of Gsα gene mutations in Albright’s hereditary osteodystrophy. J Med Genet. 1994;31:835–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Schipani E, Weinstein LS, Bergwitz C, et al. Pseudohypoparathyroidism type Ib is not caused by mutations in the coding exons of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene. J Clin Endocrinol Metab. 1995;80:1611–21.PubMedCrossRefGoogle Scholar
  56. 56.
    Jüppner H, Schipani E, Bastepe M, Cole DE, Lawson ML, Mannstadt M, Hendy GN, Plotkin H, Koshiyama H, Koh T, Crawford JD, Olsen BR, Vikkula M. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci USA. 1998;95:11798–803.PubMedCrossRefGoogle Scholar
  57. 57.
    Thakker RV. Parathyroid disorders: molecular genetics and physiology. In: Morris PJ, Wood WC, editors. Oxford Textbook of Surgery. Oxford: Oxford University Press; 2000. p. 1121–9.Google Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Nuffield Department of MedicineUniversity of Oxford, OCDEM, Churchill HospitalOxfordUK

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