Skip to main content
SpringerLink
Log in
Book cover

Hypoparathyroidism pp 355–362Cite as

Pseudohypoparathyroidism Type 1a, Pseudopseudohypoparathyroidism, and Albright Hereditary Osteodystrophy

  • Chapter
  • First Online:

  • 1238 Accesses

Abstract

Albright hereditary osteodystrophy (AHO) is a congenital disorder caused by heterozygous loss-of-function mutations of the GNAS gene encoding Gsα, the ubiquitously expressed G protein α-subunit that is required for intracellular cAMP generation in response to hormones and other extracellular signals. AHO patients develop short stature, brachydactyly, subcutaneous ossifications, and, in some cases, neurocognitive impairment. Due to genomic imprinting of GNAS, mutations on the maternal allele also lead to multihormone resistance and early-onset obesity, a condition known as pseudohypoparathyroidism type 1a. In contrast paternal mutations only lead to AHO, also known as pseudopseudohypoparathyroidism. In some instances, the same Gsα mutations are associated with a more severe form of ectopic ossification known as progressive osseous heteroplasia.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   199.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Weinstein LS (2008) Guanine nucleotide-binding protein Gsα (GNAS1): fibrous dysplasia, McCune-Albright syndrome, Albright hereditary osteodystrophy, and pseudohypoparathyroidism. In: Epstein CJ, Erickson RP, Wynshaw-Boris A (eds) Inborn errors of development: the molecular basis of clinical disorders of morphogenesis, 2nd edn. Oxford University Press, New York, pp 1277–1288

    Google Scholar 

  2. de Sanctis L, Vai S, Andreo MR et al (2004) Brachydactyly in 14 genetically characterized pseudohypoparathyroidism type Ia patients. J Clin Endocrinol Metab 89:1650–1655

    Article  PubMed  Google Scholar 

  3. Roberts TT, Khasnavis S, Papaliodis DN et al (2013) Spinal cord compression in pseudohypoparathyroidism. Spine J 13:e15–e19

    Article  PubMed  Google Scholar 

  4. Joseph AW, Shoemaker AH, Germain-Lee EL (2011) Increased prevalence of carpal tunnel syndrome in Albright hereditary osteodystrophy. J Clin Endocrinol Metab 96:2065–2073

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Mouallem M, Shaharabany M, Weintrob N et al (2008) Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsα. Clin Endocrinol (Oxf) 68:233–239

    CAS  Google Scholar 

  6. Kaplan FS, Shore EI (2000) Progressive osseous heteroplasia. J Bone Miner Res 15:2084–2094

    Article  CAS  PubMed  Google Scholar 

  7. Long DN, Levine MA, Germain-Lee EL (2010) Bone mineral density in pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab 95:4465–4475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Namnoum AB, Merriam GR, Moses AM et al (1998) Reproductive dysfunction in women with Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab 83:824–829

    CAS  PubMed  Google Scholar 

  9. Germain-Lee EL, Groman J, Crane JL et al (2003) Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 88:4059–4069

    Article  CAS  PubMed  Google Scholar 

  10. Long DN, McGuire S, Levine MA et al (2007) Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Gαs in the development of human obesity. J Clin Endocrinol Metab 92:1073–1079

    Article  CAS  PubMed  Google Scholar 

  11. Muniyappa R, Warren MA, Zhao X et al (2013) Reduced insulin sensitivity in adults with pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab 98:E1796–E1801

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Chen M, Wang J, Dickerson KE et al (2009) Central nervous system imprinting of the G protein Gsα and its role in metabolic regulation. Cell Metab 9:548–555

    Article  PubMed Central  PubMed  Google Scholar 

  13. Weinstein LS, Xie T, Zhang QH et al (2007) Studies of the regulation and function of the Gsα gene Gnas using gene targeting technology. Pharmacol Ther 115:271–291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Mariot V, Maupetit-Mehouas S, Sinding C et al (2008) A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J Clin Endocrinol Metab 93:661–665

    Article  CAS  PubMed  Google Scholar 

  15. Mantovani G, de Sanctis L, Barbieri AM et al (2010) Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab 95:651–658

    Article  CAS  PubMed  Google Scholar 

  16. Zazo C, Thiele S, Martin C et al (2011) Gsα activity is reduced in erythrocyte membranes of patients with pseudohypoparathyroidism due to epigenetic alterations at the GNAS locus. J Bone Miner Res 26:1864–1870

    Article  CAS  PubMed  Google Scholar 

  17. Yu S, Yu D, Hainline BE et al (1995) A deletion hot-spot in exon 7 of the Gsα gene (GNAS1) in patients with Albright hereditary osteodystrophy. Hum Mol Genet 4:2001–2002

    Article  CAS  PubMed  Google Scholar 

  18. Thiele S, Werner R, Ahrens W et al (2007) A disruptive mutation in exon 3 of the GNAS gene with Albright hereditary osteodystrophy, normocalcemic pseudohypoparathyroidism, and selective long transcript variant Gsα-L deficiency. J Clin Endocrinol Metab 92:1764–1768

    Article  CAS  PubMed  Google Scholar 

  19. Shore EM, Ahn J, Jan de Beur S et al (2002) Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 346:99–106

    Article  CAS  PubMed  Google Scholar 

  20. Yu S, Yu D, Lee E et al (1998) Variable and tissue-specific hormone resistance in heterotrimeric Gs protein α-subunit Gsα knockout mice is due to tissue-specific imprinting of the Gsα gene. Proc Natl Acad Sci U S A 95:8715–8720

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Turan S, Fernandez-Rebollo E, Aydin C et al (2014) Postnatal establishment of allelic Gαs silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous Gαs disruption. J Bone Miner Res 29:749–760

    Article  CAS  PubMed  Google Scholar 

  22. Weinstein LS (2001) The stimulatory G protein α-subunit gene: mutations and imprinting lead to complex phenotypes. J Clin Endocrinol Metab 86:4622–4626

    CAS  PubMed  Google Scholar 

  23. Stone MD, Hosking DJ, Garcia-Himmelstine C et al (1993) The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone 14:727–735

    Article  CAS  PubMed  Google Scholar 

  24. Xie T, Chen M, Gavrilova O et al (2008) Severe obesity and insulin resistance due to deletion of the maternal Gsα allele is reversed by paternal deletion of the Gsα imprint control region. Endocrinology 149:2443–2450

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Chen M, Berger A, Kablan A et al (2012) Gsα deficiency in the paraventricular nucleus of the hypothalamus partially contributes to obesity associated with Gsα mutations. Endocrinology 153:4256–4265

    Google Scholar 

  26. Carel JC, Le Stunff C, Condamine L et al (1999) Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency. J Clin Endocrinol Metab 84:4127–4131

    Article  CAS  PubMed  Google Scholar 

  27. Dekelbab BH, Aughton DJ, Levine MA (2009) Pseudohypoparathyroidism type 1A and morbid obesity in infancy. Endocr Pract 15:249–253

    Article  PubMed  Google Scholar 

  28. Shoemaker AH, Lomenick JP, Saville BR et al (2013) Energy expenditure in obese children with pseudohypoparathyroidism type 1a. Int J Obes (Lond) 37:1147–1153

    Article  CAS  Google Scholar 

  29. Sakamoto A, Chen M, Kobayashi T et al (2005) Chondrocyte-specific knockout of the G protein Gsα leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation. J Bone Miner Res 20:663–671

    Article  CAS  PubMed  Google Scholar 

  30. Bastepe M, Weinstein LS, Ogata N et al (2004) Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc Natl Acad Sci U S A 101:14794–14799

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Huso DL, Edie S, Levine MA et al (2011) Heterotopic ossifications in a mouse model of Albright hereditary osteodystrophy. PLoS One 6:e21755

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Regard JB, Malhotra D, Gvozdenovic-Jeremic J et al (2013) Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med 19:1505–1512

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Linglart A, Fryssira H, Hiort O et al (2012) PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance. J Clin Endocrinol Metab 97:E2328–E2338

    Article  CAS  PubMed  Google Scholar 

  34. Linglart A, Menguy C, Couvineau A et al (2011) Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N Engl J Med 364:2218–2226

    Article  CAS  PubMed  Google Scholar 

  35. Thiele S, de Sanctis L, Werner R et al (2011) Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsα-receptor interaction. Hum Mutat 32:653–660

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Neary NM, El-Maouche D, Hopkins R et al (2012) Development and treatment of tertiary hyperparathyroidism in patients with pseudohypoparathyroidism type 1B. J Clin Endocrinol Metab 97:3025–3030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Mantovani G, Ferrante E, Giavoli C et al (2010) Recombinant human GH replacement therapy in children with pseudohypoparathyroidism type Ia: first study on the effect on growth. J Clin Endocrinol Metab 95:5011–5017

    Article  CAS  PubMed  Google Scholar 

  38. Lietman SA, Goldfarb J, Desai N et al (2008) Preimplantation genetic diagnosis for severe Albright hereditary osteodystrophy. J Clin Endocrinol Metab 93:901–904

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Weinstein LS, Collins MT, Spiegel AM (2013) Gsα, pseudohypoparathyroidism, fibrous dysplasia, and McCune-Albright syndrome. In: Thakkar RV, Whyte MP, Eisman JA, Igarashi T (eds) (2013) Genetics of bone biology and skeletal disease. Academic, London, pp 425–440

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 10 Rm 8C101, Bethesda, MD, 20892-1752, USA

    Lee S. Weinstein

Authors
  1. Lee S. Weinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lee S. Weinstein .

Editor information

Editors and Affiliations

  1. Unit of Metabolic and Bone Diseases, University of Florence, Florence, Italy

    Maria Luisa Brandi

  2. Division of Endocrinology, Diabetes and Hypertension, Harvard Medical School and Brigham & Women's Hospital, Boston, Massachusetts, USA

    Edward Meigs Brown

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Italia

About this chapter

Cite this chapter

Weinstein, L.S. (2015). Pseudohypoparathyroidism Type 1a, Pseudopseudohypoparathyroidism, and Albright Hereditary Osteodystrophy. In: Brandi, M., Brown, E. (eds) Hypoparathyroidism. Springer, Milano. https://doi.org/10.1007/978-88-470-5376-2_33

Download citation

  • DOI: https://doi.org/10.1007/978-88-470-5376-2_33

  • Published:

  • Publisher Name: Springer, Milano

  • Print ISBN: 978-88-470-5375-5

  • Online ISBN: 978-88-470-5376-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation