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Semin Musculoskelet Radiol 2002; 06(4): 273-284
DOI: 10.1055/s-2002-36726
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Albright's Hereditary Osteodystrophy and Pseudohypoparathyroidism

Louise C. Wilson1 , Christine M. Hall2
  • 1Clinical and Molecular Genetics Unit, Institute of Child Health and Great Ormond Street Hospital, London
  • 2Department of Paediatric Radiology, Great Ormond Street Hospital, London, England, United Kingdom
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Publication History

Publication Date:
22 January 2003 (online)

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ABSTRACT

Pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO) are not interchangeable terms. AHO describes a constellation of physical features, including short adult stature, obesity, brachydactyly, and ectopic ossifications. PHP means end-organ resistance to PTH and is subclassified into types Ia, Ib, and Ic and type II. Pseudopseudohypoparathyroidism (PPHP) is a term used for individuals with AHO who have normal end-organ responses to PTH. Both the PHPIa and PPHP forms of AHO result from heterozygous deactivating mutations in the GNAS1 gene associated with a 50% reduction in bioactivity of the Gsα protein that it encodes. The GNAS1 gene is subject to tissue-specific genomic imprinting. Patients with mutations on their maternally derived allele are likely to have associated PHPIa, whereas mutations on the paternal allele usually cause PPHP. Isolated PTH resistance (PHPIb) can result from mutations within the GNAS1 gene but is more commonly caused by epigenetic imprinting abnormalities affecting the upstream exon 1A. The causes of PHP type Ic and PHP type II are not yet clear, and the latter is likely to be heterogeneous.

KEYWORD

Albright's hereditary osteodystrophy - pseudohypoparathyroidism - Gs alpha - GNAS1 - imprinting

REFERENCES

  • 1 Albright F, Burnett C H, Smith P H, Parson W. Pseudo-hypoparathyroidism-an example of "Seabright-Bantam syndrome."  Endocrinology . 1942;  30 922-932
    PubMedSearch in Google Scholar
  • 2 Albright F, Forbes A P, Henneman P H. Pseudo-pseudohypoparathyroidism.  Trans Assoc Am Phys . 1952;  65 337-350
    PubMedSearch in Google Scholar
  • 3 Lewin I G, Papapoulos S E, Tomlinson S, Hendy G N, O'Riordan J LH. Studies of hypoparathyroidism and pseudohypoparathyroidism.  QJM . 1978;  47 533-548
    PubMedSearch in Google Scholar
  • 4 Tomlinson S, Barling P M, Albano J DM, Brown B L, O'Riordan J LH. The effects of exogenous parathyroid hormone on plasma and urinary adenosine 3',5'-cyclic monophosphate in man.  Clin Sci Molec Med . 1974;  47 481-492
    PubMedSearch in Google Scholar
  • 5 Bourne H R, Stryer L. G proteins. The target sets the tempo [news].  Nature . 1992;  358 541-543
    CrossrefPubMedSearch in Google Scholar
  • 6 Levine M A, Downs Jr W R, Moses A M. Resistance to multiple hormones in patients with pseudohypoparathyroidism: association with deficient activity of guanine nucleotide regulatory protein.  Am J Med . 1983;  74 545-556
    Search in Google Scholar
  • 7 Spiegel A M, Weinstein L S. Pseudohypoparathyroidism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th ed New York: McGraw-Hill 1995: 3073-3089
    Search in Google Scholar
  • 8 Patten J L, Levine M A. Immunochemical analysis of the alpha-subunit of the stimulatory G-protein of adenylyl cyclase in patients with Albright's hereditary osteodystrophy.  J Clin Endocrinol Metab . 1990;  71 1208-1214
    CrossrefPubMedSearch in Google Scholar
  • 9 Levine M A, Ahn T G, Klupt S F. Genetic deficiency of the α subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy.  Proc Natl Acad Sci USA . 1988;  85 617-621
    CrossrefPubMedSearch in Google Scholar
  • 10 Kozasa T, Itoh H, Tsukamoto T, Kaziro Y. Isolation and characterization of the human Gsα gene.  Proc Natl Acad Sci USA . 1988;  85 2081-2085
    CrossrefPubMedSearch in Google Scholar
  • 11 Aldred M A, Trembath R C. Activating and inactivating mutations in the human GNAS1 gene.  Hum Mutat . 2000;  16 183-189
    CrossrefPubMedSearch in Google Scholar
  • 12 Yu S, Yu D, Hainline B E. A deletion hotspot in exon 7 of the Gsα gene (GNAS1) in patients with Albright's hereditary osteodystrophy.  Hum Mol Genet . 1995;  4 2001-2002
    CrossrefPubMedSearch in Google Scholar
  • 13 Wilson L C, Oude Luttikhuis E M M, Clayton P T, Fraser W D, Trembath R C. Parental origin of Gsα mutations-evidence for imprinting in Albright hereditary osteodystrophy.  J Med Genet . 1994;  31 835-839
    CrossrefPubMedSearch in Google Scholar
  • 14 Davies S J, Hughes H E. Imprinting in Albright's hereditary osteodystrophy [review].  J Med Genet . 1993;  30 101-103
    CrossrefPubMedSearch in Google Scholar
  • 15 Schuster V, Kress W, Kruse K. Paternal and maternal transmission of pseudohypoparathyroidism type Ia in a family with Albright hereditary osteodystrophy: no evidence of genomic imprinting.  J Med Genet . 1994;  31 84
    PubMedSearch in Google Scholar
  • 16 Hayward B E, Barlier A, Korbonits M. Imprinting of the Gsα gene GNAS1 in the pathogenesis of acromegaly.  J Clin Invest . 2001;  107 R31-R36
    Search in Google Scholar
  • 17 Germain-Lee E L, Ding C L, Deng Z. Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a.  Biochem Biophys Res Commun . 2002;  296 67-72
    Search in Google Scholar
  • 18 Yu S, Yu D, Lee E. 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 . 1998;  95 8715-8720
    Search in Google Scholar
  • 19 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 . 1998;  95 15475-15480
    CrossrefPubMedSearch in Google Scholar
  • 20 Liu J, Litman D, Rosenberg M J. A GNAS1 imprinting defect in pseudohypoparathyroidism type IB.  J Clin Invest . 2000;  106 1167-1174
    Search in Google Scholar
  • 21 Wu W I, Schwindinger W F, Aparicio L F, Levine M A. Selective resistance to parathyroid hormone caused by a novel uncoupling mutation in the carboxyl terminus of Gsα.  J Biol Chem . 2001;  276 165-171
    PubMedSearch in Google Scholar
  • 22 Linglart A, Carel J C, Garabedian M. GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance.  J Clin Endocrinol Metab . 2002;  87 189-197
    CrossrefPubMedSearch in Google Scholar
  • 23 de Wijn M E, Steendijk R. Growth and maturation in pseudo-hypoparathyroidism; a longitudinal study in 5 patients.  Acta Endocrinol . 1982;  101 223-226
    PubMedSearch in Google Scholar
  • 24 Fitch N. Albright's hereditary osteodystrophy: a review.  Am J Med Genet . 1982;  11 11-29
    CrossrefPubMedSearch in Google Scholar
  • 25 Steinbach H L, Young D A. The roentgen appearance of pseudohypoparathyroidism (PH) and pseudo-pseudohypoparathyroidism (PPH). Differentiation from other syndromes associated with short metacarpals, metatarsals, and phalanges.  AJR Am J Roentgenol . 1966;  97 49-66
    PubMedSearch in Google Scholar
  • 26 Poznanski A K, Werder E A, Giedion A. The pattern of shortening of the bones of the hand in PHP and PPHP-a comparison with brachydactyly E, Turner syndrome, and acrodysostosis.  Radiology . 1977;  123 707-718
    PubMedSearch in Google Scholar
  • 27 Illum F, Dupont E. Prevalences of CT-detected calcification in the basal ganglia in idiopathic hypoparathyroidism and pseudohypoparathyroidism.  Neuroradiology . 1985;  27 32-37
    CrossrefPubMedSearch in Google Scholar
  • 28 Prendiville J S, Lucky A W, Mallory S B. Osteoma cutis as a presenting sign of pseudohypoparathyroidism.  Pediatr Dermatol . 1992;  9 11-18
    PubMedSearch in Google Scholar
  • 29 Steinbach H L, Rudhe U, Jonsson M, Young D A. Evolution of skeletal lesions in pseudohypoparathyroidism.  Radiology . 1965;  85 670-676
    PubMedSearch in Google Scholar
  • 30 Wong S, Zakov Z N, Albert D M. Scleral and choroidal calcifications in a patient with pseudohypoparathyroidism.  Br J Ophthalmol . 1979;  63 177-180
    PubMedSearch in Google Scholar
  • 31 Schuster V, Sandhage K. Intracardiac calcifications in a case of pseudohypoparathyroidism type Ia (PHP-Ia).  Pediatr Cardiol . 1992;  13 237-239
    CrossrefPubMedSearch in Google Scholar
  • 32 Farfel Z, Friedman E. Mental deficiency in pseudohypoparathyroidism type I is associated with Ns-protein deficiency.  Ann Intern Med . 1986;  105 197-199
    CrossrefPubMedSearch in Google Scholar
  • 33 Spranger J W. Skeletal dysplasias and the eye: Albright's hereditary osteodystrophy.  Birth Defects Original Article Series . 1969;  5 122-128
    PubMedSearch in Google Scholar
  • 34 Koch T, Lehnhardt E, Bottinger H. Sensorineural hearing loss owing to deficient G proteins in patients with pseudohypoparathyroidism: results of a multicentre study.  Eur J Clin Invest . 1990;  20 416-421
    PubMedSearch in Google Scholar
  • 35 Ritchie G M. Dental manifestations of pseudohypoparathyroidism.  Arch Dis Child . 1965;  40 565-572
    PubMedSearch in Google Scholar
  • 36 Faull C M, Welbury R R, Paul B, Kendall-Taylor P. Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family.  QJM . 1991;  78 251-264
    PubMedSearch in Google Scholar
  • 37 Okada K, Iida K, Sakusabe N. Pseudohypoparathyroidism-associated spinal stenosis.  Spine . 1994;  19 1186-1189
    PubMedSearch in Google Scholar
  • 38 Burnstein M I, Kottamasu S R, Pettifor J M. Metabolic bone disease in pseudohypoparathyroidism: radiologic features.  Radiology . 1985;  155 351-356
    PubMedSearch in Google Scholar
  • 39 Kerr D, Hosking D J. Pseudohypoparathyroidism: clinical expression of PTH resistance.  QJM . 1987;  65 889-894
    PubMedSearch in Google Scholar
  • 40 Shore E M, Ahn J, Jan de Beur S. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.  N Engl J Med . 2002;  346 99-106
    Search in Google Scholar
  • 41 Weinstein L S, Shenker A, Gejman P V. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome.  N Engl J Med . 1991;  325 1688-1695
    Search in Google Scholar
  • 42 Lyons J, Landis C A, Harsh G. Two G protein oncogenes in human endocrine tumors.  Science . 1990;  249 655-659
    Search in Google Scholar
  • 43 Lania A, Mantovani G, Spada A. G protein mutations in endocrine diseases.  Eur J Endocrinol . 2001;  145 543-559
    CrossrefPubMedSearch in Google Scholar
  • 44 Oude Luttikhuis E M, Williams D K, Trembath R C. Isolated autosomal dominant type E brachydactyly: exclusion of linkage to candidate regions 2q37 and 20q13.  J Med Genet . 1996;  33 873-876
    PubMedSearch in Google Scholar
  • 45 Wilson L C, Oude Luttikhuis E M M, Baraitser M, Kingston H M, Trembath R C. Normal erythrocyte membrane Gsα bioactivity in two unrelated patients with acrodysostosis.  J Med Genet . 1997;  34 133-136
    CrossrefPubMedSearch in Google Scholar
  • 46 Wilson L C, Leverton K, Oude Luttikhuis E M M. Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localised to 2q37.  Am J Hum Genet . 1995;  56 400-407
    Search in Google Scholar