Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pseudohypoparathyroidism and Gsα–cAMP-linked disorders: current view and open issues

Nature Reviews Endocrinology volume 12, pages 347–356 (2016)Cite this article

Subjects

Key Points

  • Pseuohypoparathyroidism, together with Albright hereditary osteodystrophy (AHO), are rare, disabling disorders

  • These disorders encompass heterogeneous features such as brachydactyly, ectopic ossifications, short stature, mental retardation and endocrine deficiencies due to resistance to the action of different hormones, primarily parathyroid hormone

  • The main subtypes of pseuohypoparathyroidism are caused by mutations and/or methylation defects within the imprinted GNAS cluster, whose main transcript encodes the α subunit of the stimulatory G protein

  • The clinical and molecular overlap between these different but related disorders represents a challenge for endocrinologists for making a differential diagnosis and providing genetic counseling

  • Moreover, this challenge highlights the need for different classification models and alters our understanding of the mechanisms through which defects in the cAMP signalling cascade cause AHO-related disorders

Abstract

Pseudohypoparathyroidism exemplifies an unusual form of hormone resistance as the underlying molecular defect is a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key regulator of the cAMP signalling pathway, rather than of the parathyroid hormone (PTH) receptor itself. Despite the first description of this disorder dating back to 1942, later findings have unveiled complex epigenetic alterations in addition to classic mutations in GNAS underpining the molecular basis of the main subtypes of pseudohypoparathyroidism. Moreover, mutations in PRKAR1A and PDE4D, which encode proteins crucial for Gsα–cAMP-mediated signalling, have been found in patients with acrodysostosis. As acrodysostosis, a disease characterized by skeletal malformations and endocrine disturbances, shares clinical and molecular characteristics with pseudohypoparathyroidism, making a differential diagnosis and providing genetic counselling to patients and families is a challenge for endocrinologists. Accumulating data on the genetic and clinical aspects of this group of diseases highlight the limitation of the current classification system and prompt the need for a new definition as well as for new diagnostic and/or therapeutic algorithms. This Review discusses both the current understanding and future challenges for the clinical and molecular diagnosis, classification and treatment of pseudohypoparathyroidism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The cAMP-mediated signalling pathway.
Figure 2: GNAS locus and transcripts.
Figure 3: Proposed molecular diagnostic algorithm for patients suspected of having a disorder linked to defective Gsα–cAMP signalling.

Similar content being viewed by others

References

  1. Bastepe, M. The GNAS locus and pseudohypoparathyroidism. Adv. Exp. Med. Biol. 626, 27–40 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Levine, M. A. An update on the clinical and molecular characteristics of pseudohypoparathyroidism. Curr. Opin. Endocrinol. Diabetes Obes. 19, 443–451 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bastepe, M. Genetics and epigenetics of parathyroid hormone resistance. Endocr. Dev. 24, 11–24 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Silve, C., Clauser, E. & Linglart, A. Acrodysostosis. Horm. Metab. Res. 44, 749–758 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Falk, R. E. & Casas, K. A. Chromosome 2q37 deletion: clinical and molecular aspects. Am. J. Med. Genet. C Semin. Med. Genet. 145C, 357–371 (2007).

    Article  PubMed  Google Scholar 

  6. Shore, E. M. et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N. Engl. J. Med. 346, 99–106 (2002); erratum N. Engl. J. Med. 346, 1678 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Elli, F. M. et al. Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series. Bone 56, 276–280 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Mantovani, G. Clinical review: pseudohypoparathyroidism: diagnosis and treatment. J. Clin. Endocrinol. Metab. 96, 3020–3030 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Mantovani, G., Elli, F. M. & Spada, A. GNAS epigenetic defects and pseudohypoparathyroidism: time for a new classification? Horm. Metab. Res. 44, 716–723 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Albright, F. et al. Pseudohypoparathyroidism: an example of 'Seabright-Bantam syndrome'. Endocrinology 30, 922–932 (1942).

    CAS  Google Scholar 

  11. Albright, F., Forbes, A. P. & Henneman, P. H. Pseudopseudohypoparathyroidism. Trans. Assoc. Am. Physicians 65, 337–350 (1952).

    CAS  PubMed  Google Scholar 

  12. Mann, J. B., Alterman, S. & Hills, A. G. Albright's hereditary osteodystrophy comprising pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism: with a report of two cases representing the complete syndrome occurring in successive generations. Ann. Intern. Med. 56, 315–342 (1962).

    Article  CAS  PubMed  Google Scholar 

  13. Eyre, W. G. & Reed, W. B. Albright's hereditary osteodystrophy with cutaneous bone formation. Arch. Dermatol. 104, 634–642 (1971).

    Article  CAS  PubMed  Google Scholar 

  14. Farfel, Z. & Friedman, E. Mental deficiency in pseudohypoparathyroidism type I is associated with Ns-protein deficiency. Ann. Intern. Med. 105, 197–199 (1986).

    Article  CAS  PubMed  Google Scholar 

  15. Farfel, Z. et al. Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proc. Natl Acad. Sci. USA 78, 3098–3102 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fitch, N. Albright's hereditary osteodystrophy: a review. Am. J. Med. Genet. 11, 11–29 (1982).

    Article  CAS  PubMed  Google Scholar 

  17. Weinberg, A. G. & Stone, R. T. Autosomal dominant inheritance in Albright's hereditary osteodystrophy. J. Pediatr. 79, 996–999 (1971).

    Article  CAS  PubMed  Google Scholar 

  18. Tashjian, A. H. Jr, Frantz, A. G. & Lee, J. B. Pseudohypoparathyroidism: assays of parathyroid hormone and thyrocalcitonin. Proc. Natl Acad. Sci. USA 56, 1138–1142 (1966).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chase, L. R., Melson, G. L. & Aurbach, G. D. Pseudohypoparathyroidism: defective excretion of 3′,5′-AMP in response to parathyroid hormone. J. Clin. Invest. 48, 1832–1844 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Spiegel, A. M., Shenker, A. & Weinstein, L. S. Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction. Endocr. Rev. 13, 536–565 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Taskén, K. et al. Structure, function, and regulation of human cAMP-dependent protein kinases. Adv. Second Messenger Phosphoprotein Res. 31, 191–204 (1997).

    Article  PubMed  Google Scholar 

  22. Taylor, S. S., Buechler, J. A. & Yonemoto, W. cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annu. Rev. Biochem. 59, 971–1005 (1990).

    Article  CAS  PubMed  Google Scholar 

  23. Lania, A. G., Mantovani, G. & Spada, A. Mechanisms of disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases. Nat. Clin. Pract. Endocrinol. Metab. 2, 681–693 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Levine, M. A. et al. Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism. Biochem. Biophys. Res. Commun. 94, 1319–1324 (1980).

    Article  CAS  PubMed  Google Scholar 

  25. Patten, J. L. et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy. N. Engl. J. Med. 322, 1412–1419 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Weinstein, L. S. et al. Mutations of the Gs α-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc. Natl Acad. Sci. USA 87, 8287–8290 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Levine, M. A., Modi, W. S., O'Brien, S. J. Mapping of the gene encoding the α subunit of the stimulatory G protein of adenylyl cyclase (GNAS1) to 20q13.2→q13.3 in human by in situ hybridization. Genomics 11, 478–479 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Davies, S. J. & Hughes, H. E. Imprinting in Albright's hereditary osteodystrophy. J. Med. Genet. 30, 101–103 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Campbell, R., Gosden, C. M. & Bonthron, D. T. Parental origin of transcription from the human GNAS1 gene. J. Med. Genet. 31, 607–614 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wilson, L. C., Oude Luttikhuis, M. E., Clayton, P. T., Fraser, W. D. & Trembath, R. C. Parental origin of Gsα gene mutations in Albright's hereditary osteodystrophy. J. Med. Genet. 31, 835–839 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nakamoto, J. M., Sandstrom, A. T., Brickman, A. S., Christenson, R. A. & Van Dop, C. Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsα gene mutation. Am. J. Med. Genet. 77, 261–267 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Yu, S. et al. 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. USA 95, 8715–8720 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hayward, B. E. et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc. Natl Acad. Sci. USA 95, 10038–10043 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hayward, B. E., Moran, V., Strain, L. & Bonthron, D. T. Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc. Natl Acad. Sci. USA 95, 15475–15480 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu, J. et al. GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J. Clin. Invest. 106, 1167–1174 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Weinstein, L. S., Yu, S. & Ecelbarger, C. A. Variable imprinting of the heterotrimeric G protein Gsα-subunit within different segments of the nephron. Am. J. Physiol. Renal Physiol. 278, F507–F514 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Zheng, H., Radeva, G., McCann, J. A., Hendy, G. N. & Goodyer, C. G. Gαs transcripts are biallelically expressed in the human kidney cortex: implications for pseudohypoparathyroidism type 1b. J. Clin. Endocrinol. Metab. 86, 4627–4629 (2001).

    CAS  PubMed  Google Scholar 

  38. Mantovani, G., Ballare, E., Giammona, E., Beck-Peccoz, P. & Spada, A. The Gsα gene: predominant maternal origin of transcription in human thyroid gland and gonads. J. Clin. Endocrinol. Metab. 87, 4736–4740 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Mantovani, G. et al. Biallelic expression of the Gsα gene in human bone and adipose tissue. J. Clin. Endocrinol. Metab. 89, 6316–6319 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Klenke, S., Siffert, W. & Frey, U. H. A novel aspect of GNAS imprinting: higher maternal expression of Gαs in human lymphoblasts, peripheral blood mononuclear cells, mammary adipose tissue, and heart. Mol. Cell. Endocrinol. 341, 63–70 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Liu, J., Erlichman, B. & Weinstein, L. S. The stimulatory G protein α-subunit Gsα is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J. Clin. Endocrinol. Metab. 88, 4336–4341 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Bastepe, M. 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. 112, 1255–1263 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bastepe, M. et al. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat. Genet. 37, 25–27 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Linglart, A., Gensure, R. C., Olney, R. C., Juppner, H. & Bastepe, M. A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am. J. Hum. Genet. 76, 804–814 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chillambhi, S. et al. Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis. J. Clin. Endocrinol. Metab. 95, 3993–4002 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Richard, N. et al. A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib. J. Clin. Endocrinol. Metab. 97, E863–E867 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Elli, F. M. et al. Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR. J. Clin. Endocrinol. Metab. 99, E724–E728 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Bastepe, M., Lane, A. H. & Jüppner, H. Paternal uniparental isodisomy of chromosome 20q — and the resulting changes in GNAS1 methylation — as a plausible cause of pseudohypoparathyroidism. Am. J. Hum. Genet. 68, 1283–1289 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lecumberri, B. et al. Coexistence of two different pseudohypoparathyroidism subtypes (Ia and Ib) in the same kindred with independent Gsα coding mutations and GNAS imprinting defects. J. Med. Genet. 47, 276–280 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Fernández-Rebollo, E. et al. New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism. Eur. J. Endocrinol. 163, 953–962 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Dixit, A. et al. Pseudohypoparathyroidism type 1b due to paternal uniparental disomy of chromosome 20q. J. Clin. Endocrinol. Metab. 98, E103–E108 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Takatani, R. et al. Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B). Bone 79, 15–20 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. de Nanclares, G. P. et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright hereditary osteodystrophy. J. Clin. Endocrinol. Metab. 92, 2370–2373 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Mariot, V., Maupetit-Méhouas, S., Sinding, C., Kottler, M. L. & Linglart, A. A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J. Clin. Endocrinol. Metab. 93, 661–665 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Unluturk, U. et al. Molecular diagnosis and clinical characterization of pseudohypoparathyroidism type-Ib in a patient with mild Albright hereditary osteodystrophy-like features, epileptic seizures, and defective renal handling of uric acid. Am. J. Med. Sci. 336, 84–90 (2008).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Brix, B. et al. Different pattern of epigenetic changes of the GNAS gene locus in patients with pseudohypoparathyroidism type Ic confirm the heterogeneity of underlying pathomechanisms in this subgroup of pseudohypoparathyroidism and the demand for a new classification of GNAS-related disorders. J. Clin. Endocrinol. Metab. 99, E1564–E1570 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Elli, F. M. et al. Quantitative analysis of methylation defects and correlation with clinical characteristics in patients with pseudohypoparathyroidism type I and GNAS epigenetic alterations. J. Clin. Endocrinol. Metab. 99, E508–E517 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Turan, S. et al. Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS. Bone 71, 53–57 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Genevieve, D. et al. Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Eur. J. Hum. Genet. 13, 1033–1039 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Fernandez-Rebollo, E. et al. Deletion involving exon A/B in pseudohypoparathyroidism type 1a resulting in an apparent loss of exon A/B methylation: potential for misdiagnosis of pseudohypoparathyroidism type 1B. J. Clin. Endocrinol. Metab. 95, 765–771 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Fernandez-Rebollo, E. et al. New mutation type in pseudohypoparathyroidism type Ia. Clin. Endocrinol. (Oxf.) 69, 705–712 (2008).

    Article  CAS  Google Scholar 

  63. Mitsui, T. et al. A family of pseudohypoparathyroidism type Ia with an 850-kb submicroscopic deletion encompassing the whole GNAS locus. Am. J. Med. Genet. A 158A, 261–264 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Garin, I. et al. Novel microdeletions affecting the GNAS locus in pseudohypoparathyroidism: characterization of the underlying mechanisms. J. Clin. Endocrinol. Metab. 100, E681–E687 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Michot, C. et al. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am. J. Hum. Genet. 90, 740–745 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee, H. et al. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am. J. Hum. Genet. 90, 746–751 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nagasaki, K. et al. PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance. Clin. Endocrinol. Metab. 97, E1808–E1813 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  70. Lynch, D. C. et al. Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis. Hum. Mutat. 34, 97–102 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Muhn, F. et al. Novel mutations of the PRKAR1A gene in patients with acrodysostosis. Clin. Genet. 84, 531–538 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Lindstrand, A. et al. Different mutations in PDE4D associated with developmental disorders with mirror phenotypes. J. Med. Genet. 51, 45–54 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Kaname, T. et al. Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis. Cell. Signal. 26, 2446–2459 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Li, N. et al. The first mutation identified in a Chinese acrodysostosis patient confirms a p.G289E variation of PRKAR1A causes acrodysostosis. Int. J. Mol. Sci. 15, 13267–13274 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mitsui, T. et al. Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2. Am. J. Med. Genet. A 164A, 2529–2534 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Potts, J. T. Parathyroid hormone: past and present. J. Endocrinol. 187, 311–325 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Gensure, R. C., Gardella, T. J. & Jüppner, H. Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem. Biophys. Res. Commun. 328, 666–678 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Stone, M. D. et al. The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone 14, 727–735 (1993).

    Article  CAS  PubMed  Google Scholar 

  79. Gardner, D. & Shoback, D. Greenspan's Basic & Clinical Endocrinology 9th edn (McGraw Hill, 2011).

    Google Scholar 

  80. Poole, K. & Reeve, J. Parathyroid hormone — a bone anabolic and catabolic agent. Curr. Opin. Pharmacol. 5, 612–617 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Murray, T. M. et al. Pseudohypoparathyroidism with osteitis fibrosa cystica: direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone. J. Bone Miner. Res. 8, 83–91 (1993).

    Article  CAS  PubMed  Google Scholar 

  82. Ish-Shalom, S. et al. Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudohypoparathyroidism. J. Bone Miner. Res. 11, 8–14 (1996).

    Article  CAS  PubMed  Google Scholar 

  83. Kidd, G. S. et al. Skeletal responsiveness in pseudohypoparathyroidism: a spectrum of clinical disease. Am. J. Med. 68, 772–781 (1980).

    Article  CAS  PubMed  Google Scholar 

  84. Eubanks, P. J. & Stabile, B. E. Osteitis fi brosa cystica with renal parathyroid hormone resistance: a review of pseudohypoparathyroidism with insight into calcium homeostasis. Arch. Surg. 133, 673–676 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Cohen, R. D. & Vince, F. P. Pseudohypoparathyroidism with raised plasma alkaline phosphatase. Arch. Dis. Child. 44, 96–101 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kolb, F. O. & Steinbach, H. L. Pseudohypoparathyroidism with secondary hyperparathyroidism and osteitis fibrosa. J. Clin. Endocrinol. Metab. 22, 59–70 (1962).

    Article  CAS  PubMed  Google Scholar 

  87. Tollin, S. R., Perlmutter, S. & Aloia, J. F. Serial changes in bone mineral density and bone turnover after correction of secondary hyperparathyroidism in a patient with pseudohypoparathyroidism type Ib. J. Bone Miner. Res. 15, 1412–1416 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. de Sanctis, L. et al. Brachydactyly in 14 genetically characterized pseudohypoparathyroidism type Ia patients. J. Clin. Endocrinol. Metab. 89, 1650–1655 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Roberts, T. T. et al. Spinal cord compression in pseudohypoparathyroidism. Spine J. 13, e15–e19 (2013).

    Article  PubMed  Google Scholar 

  90. Joseph, A. W., Shoemaker, A. H. & Germain-Lee, E. L. Increased prevalence of carpal tunnel syndrome in Albright hereditary osteodystrophy. J. Clin. Endocrinol. Metab. 96, 2065–2073 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Eddy, M. C. et al. Deficiency of the α-subunit of the stimulatory G protein and severe extraskeletal ossification. J. Bone Miner. Res. 15, 2074–2083 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Adegbite, N. S., Xu, M., Kaplan, F. S., Shore, E. M. & Pignolo, R. J. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am. J. Med. Genet. A 146A, 1788–1796 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Barret, D. et al. New form of pseudohypoparathyroidism with abnormal catalytic adenylate cyclase. Am. J. Physiol. 257, E277–E283 (1989).

    Article  Google Scholar 

  94. Weinstein, L. S. et al. Endocrine manifestations of stimulatory G protein α-subunit mutations and the role of genomic imprinting. Endocr. Rev. 22, 675–705 (2001).

    CAS  PubMed  Google Scholar 

  95. Turan, S. et al. 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 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Levine, M. A. et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am. J. Med. 74, 545–556 (1983).

    Article  CAS  PubMed  Google Scholar 

  97. Wemeau, J. L. et al. Multihormonal resistance to parathyroid hormone, thyroid stimulating hormone, and other hormonal and neurosensory stimuli in patients with pseudohypoparathyroidism. J. Pediatr. Endocrinol. Metab. 19 (Suppl. 2), 653–661 (2006).

    CAS  PubMed  Google Scholar 

  98. Germain-Lee, E. L. Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type Ia. Pediatr. Endocrinol. Rev. 3, 318–327 (2006).

    PubMed  Google Scholar 

  99. Levine, M. A., Jap, T. S. & Hung, W. Infantile hypothyroidism in two sibs: an unusual presentation of pseudohypoparathyroidism type Ia. J. Pediatr. 107, 919–922 (1985).

    Article  CAS  PubMed  Google Scholar 

  100. Pohlenz, J., Ahrens, W. & Hiort, O. A new heterozygous mutation (L338N) in the human Gsα (GNAS1) gene as a cause for congenital hypothyroidism in Albright's hereditary osteodystrophy. Eur. J. Endocrinol. 148, 463–468 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Pinsker, J. E. et al. Pseudohypoparathyroidism type 1a with congenital hypothyroidism. J. Pediatr. Endocrinol. Metab. 19, 1049–1052 (2006).

    Article  PubMed  Google Scholar 

  102. Mantovani, G. & Spada, A. Resistance to growth hormone releasing hormone and gonadotropins in Albright's hereditary osteodystrophy. J. Pediatr. Endocrinol. Metab. 19, 663–670 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Mantovani, G. et al. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gsα gene. J. Clin. Endocrinol. Metab. 88, 4070–4074 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  105. de Sanctis, L. et al. GH secretion in a cohort of children with pseudohypoparathyroidism type Ia. J. Endocrinol. Invest. 30, 97–103 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Vlaeminck-Guillem, V. et al. Pseudohypoparathyroidism Ia and hypercalcitoninemia. J. Clin. Endocrinol. Metab. 86, 3091–3096 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Moses, A. M. et al. Evidence for normal antidiuretic responses to endogenous and exogenous arginine vasopressin in patients with guanine nucleotide-binding stimulatory protein-deficient pseudohypoparathyroidism. J. Clin. Endocrinol. Metab. 62, 221–224 (1986).

    Article  CAS  PubMed  Google Scholar 

  108. Faull, C. M. et al. Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family. Q. J. Med. 78, 251–264 (1991).

    CAS  PubMed  Google Scholar 

  109. Tsai, K. S. et al. Deficient erythrocyte membrane Gsα activity and resistance to trophic hormones of multiple endocrine organs in two cases of pseudohypoparathyroidism. Taiwan Yi Xue Hui Za Zhi 88, 450–455 (1989).

    CAS  PubMed  Google Scholar 

  110. Muniyappa, R. et al. Reduced insulin sensitivity in adults with pseudohypoparathyroidism type 1a. J. Clin. Endocrinol. Metab. 98, E1796–E1801 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Long, D. N., McGuire, S., Levine, M. A., Weinstein, L. S. & Germain-Lee, E. L. 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 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Bréhin, A. C. et al. Loss of methylation at GNAS exon A/B is associated with increased intrauterine growth. J. Clin. Endocrinol. Metab. 100, E623–E631 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Richard, N. et al. Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLas in fetal development. J. Clin. Endocrinol. Metab. 98, E1549–E1556 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kaplan, F. S. et al. Progressive osseous heteroplasia: a distinct developmmental disorder of heterotopic ossification two new case reports and follow-up of three previously reported cases. J. Bone Joint Surg. 76, 425–436 (1994).

    Article  CAS  PubMed  Google Scholar 

  115. Cairns, D. M. et al. Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. J. Clin. Invest. 123, 3624–3633 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tresserra, L., Tresserra, F., Grases, P. J., Badosa, J. & Tresserra, M. Congenital plate-like osteoma cutis of the forehead: an atypical presentation form. J. Craniomaxillofac. Surg. 26, 102–106 (1998).

    Article  CAS  PubMed  Google Scholar 

  117. Lebrun, M. et al. Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans. J. Clin. Endocrinol. Metab. 95, 3028–3038 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Winter, J. S. & Hughes, I. A. Familial pseudohypoparathyroidism without somatic anomalies. Can. Med. Assoc. J. 123, 26–31 (1986).

    Google Scholar 

  119. Nusynowitz, M. L., Frame, B. & Kolb, F. O. The spectrum of the hypoparathyroid states: a classification based on physiologic principles. Medicine (Baltimore) 55, 105–119 (1976).

    Article  CAS  Google Scholar 

  120. Mantovani, G. et al. Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib. J. Clin. Endocrinol. Metab. 92, 3738–3742 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Sano, S. et al. Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib. Endocr. J. 62, 523–529 (2015).

    Article  CAS  PubMed  Google Scholar 

  122. Kidd, G. S., Schaaf, M., Adler, R. A., Lassman, M. N. & Wray, H. L. Skeletal responsiveness in pseudohypoparathyroidism: a spectrum of clinical disease. Am. J. Med. 68, 772–781 (1980).

    Article  CAS  PubMed  Google Scholar 

  123. Burnstein, M. I. et al. Metabolic bone disease in pseudohypoparathyroidism: radiologic features. Radiology 155, 351–356 (1985).

    Article  CAS  PubMed  Google Scholar 

  124. Jacobson, H. G. Dense bone — too much bone: radiological considerations and differential diagnosis. Skeletal Radiol. 13, 1–20 (1985).

    Article  CAS  PubMed  Google Scholar 

  125. Balkissoon, A. R. & Hayes, C. W. Case 14: intramedullary osteosclerosis. Radiology 212, 708–710 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Sbrocchi, A. M. et al. Osteosclerosis in two brothers with autosomal dominant pseudohypoparathyroidism type 1b: bone histomorphometric analysis. Eur. J. Endocrinol. 164, 295–301 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Brailsford, J. F. Radiology of Bones and Joints 4th edn (Williams & Wilkins, 1948).

    Google Scholar 

  128. Maroteaux, P. & Malamut, G. Acrodysostosis. Presse Med. 76, 2189–2192 (1968).

    CAS  PubMed  Google Scholar 

  129. Robinow, M. et al. Acrodysostosis. A syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am. J. Dis. Child. 121, 195–203 (1971).

    Article  CAS  PubMed  Google Scholar 

  130. Reiter, S. Acrodysostosis. A case of peripheral dysostosis, nasal hypoplasia, mental retardation and impaired hearing. Pediatr. Radiol. 7, 53–55 (1978).

    Article  CAS  PubMed  Google Scholar 

  131. Davies, S. J. & Hughes, H. E. Familial acrodysostosis: can it be distinguished from Albright's hereditary osteodystrophy? Clin. Dysmorphol. 1, 207–215 (1992).

    Article  CAS  PubMed  Google Scholar 

  132. Silve, C. et al. Acrodysostosis syndromes. BoneKEy Rep. 225, 1–7 (2012).

    Google Scholar 

  133. Ablow, R. C., Hsia, Y. E. & Brandt, I. K. Acrodysostosis coinciding with pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism. AJR Am. J. Roentgenol. 128, 95–99 (1977).

    Article  CAS  PubMed  Google Scholar 

  134. Elli, F. M. et al. Screening of PRKAR1A and PDE4D in a large Italian series of patients clinically diagnosed with Albright hereditary osteodystrophy and/or pseudohypoparathyroidism. J. Bone Miner. Res. http://dx.doi.org/10.1002/jbmr.2785 (2016).

  135. Phelan, M. C. et al. Albright's hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals. Am. J. Med. Genet. 58, 1–7 (1995).

    Article  CAS  PubMed  Google Scholar 

  136. Wilson, L. C. et al. Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localized to 2q37. Am. J. Hum. Genet. 56, 400–407 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Chassaing, N. et al. Molecular characterization of a cryptic 2q37 deletion in a patient with Albright hereditary osteodystrophy-like phenotype. Am. J. Med. Genet. A 128A, 410–413 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Aldred, M. A. et al. Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes. J. Med. Genet. 41, 433–439 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Williams, S. R. et al. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am. J. Hum. Genet. 87, 219–228 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Leroy, C. et al. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients. Eur. J. Hum. Genet. 21, 602–612 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. Villavicencio-Lorini, P. et al. Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4. Eur. J. Hum. Genet. 21, 743–748 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Williamson, C. M. et al. A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nat. Genet. 36, 894–899 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Elli, F. M. et al. Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations. Hum. Mutat. 34, 411–416 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Thiele, S. et al. A positive genotype–phenotype correlation in a large cohort of patients with pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism and 33 newly identified mutations in the GNAS gene. Mol. Genet. Genomic Med. 3, 111–120 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Lemos, M. C. & Thakker, R. V. GNAS mutations in pseudohypoparathyroidism type 1a and related disorders. Hum. Mutat. 36, 11–19 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. Todorova-Koteva, K., Wood, K., Imam, S. & Jaume, J. C. Screening for parathyroid hormone resistance in patients with non-phenotypically evident pseudohypoparathyroidism. Endocr. Pract. 18, 864–869 (2012).

    Article  PubMed  Google Scholar 

  147. Neary, N. M. et al. Development and treatment of tertiary hyperparathyroidism in patients with pseudohypoparathyroidism type 1B. J. Clin. Endocrinol. Metab. 97, 3025–3030 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Mantovani, G. et al. 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 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Underbjerg, L., Sikjaer, T., Mosekilde, L. & Rejnmark, L. Pseudohypoparathyroidism — epidemiology, mortality and risk of complications. Clin. Endocrinol. (Oxf.) http://dx.doi.org/10.1111/cen.12948 (2015).

Download references

Acknowledgements

The authors acknowledge funding support from the Italian Ministry of Health (GR-2009-1608394 to G.M.) and the Ricerca Corrente Funds of Fondazione IRCCS Ca Granda Policlinico, Milan. The authors are Members of the EuroPHP and of the EUCID.net (COST action BM1208 on imprinting disorders; www.imprinting-disorders.eu).

Author information

Authors and Affiliations

  1. Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, University of Milan, Via Francesco Sforza 35, Milan, 20122, Italy

    Giovanna Mantovani, Anna Spada & Francesca Marta Elli

Authors
  1. Giovanna Mantovani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Spada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca Marta Elli
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.M. and F.M.E. researched data for the article. G.M. and A.S. made substantial contributions to discussions of the content. G.M. and F.M.E. wrote the article. G.M. and A.S. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Giovanna Mantovani.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mantovani, G., Spada, A. & Elli, F. Pseudohypoparathyroidism and Gsα–cAMP-linked disorders: current view and open issues. Nat Rev Endocrinol 12, 347–356 (2016). https://doi.org/10.1038/nrendo.2016.52

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2016.52

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing