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Horm Metab Res 2012; 44(10): 749-758
DOI: 10.1055/s-0032-1316330
Review
© Georg Thieme Verlag KG Stuttgart · New York

Acrodysostosis

C. Silve
1   INSERM U986, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
2   Assistance Publique-Hôpitaux de Paris, Hôpital Bichat Claude Bernard, Service de Biochimie Hormonale et Génétique, Paris, France
3   Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphore, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
4   Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d’Endocrinologie de l’Enfant, Le Kremlin Bicêtre, France
,
E. Clauser
5   Université Paris-Descartes, Faculté de Médecine Paris-Descartes-Paris-V, UMR-S970, hôpital européen Georges Pompidou (HEGP), Paris Cedex 15, France
6   INSERM U970, centre de recherche cardiovasculaire, Hôpital Européen Georges Pompidou (HEGP), Paris Cedex 15, France
,
A. Linglart
1   INSERM U986, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
3   Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphore, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
4   Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d’Endocrinologie de l’Enfant, Le Kremlin Bicêtre, France
› Author Affiliations
Further Information

Publication History

received 28 December 2011

accepted 23 May 2012

Publication Date:
19 July 2012 (online)

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Abstract

Acrodysostosis refers to a group of rare skeletal dysplasias that share in common characteristic clinical and radiological features including brachydactyly, facial dysostosis, and nasal hypoplasia. In the past, the term acrodysostosis has been used to describe patients with heterogeneous phenotypes, including, in some cases, patients that today would be given alternative diagnoses. The recent finding that mutations impairing the cAMP binding to PRKAR1A are associated with “typical” acrodysostosis and hormonal resistance initiates the era where this group of disorders can be categorized on a genetic basis. In this review, we will first discuss the clinical, radiologic, and metabolic features of acrodysostosis, emphasizing evidence that several forms of the disease are likely to exist. Second, we will describe recent results explaining the pathogenesis of acrodysostosis with hormonal resistance (ADOHR). Finally, we will discuss the similarities and differences observed comparing patients with ADOHR and other diseases resulting from defects in the PTHR1 signaling pathway, in particular, pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism.

Key words

PRKAR1A - proteine kinase A - parathyroid hormone (PTH)/PTHrP - hormonal resistance - GNAS/Gsα - pseudohypoparathyroidism (PHP) - PDE
 

  • References

  • 1 Giedion A. Zapfenepiphysen. Naturgeschichte und diagnostische Bedeutung einer Störung des enchondralen Wachstums. ErgebnRadiol 1968; 1: 59-124
    PubMedGoogle Scholar
  • 2 Maroteaux P, Malamut G. Acrodysostosis. Presse Med 1968; 76: 2189-2192
    PubMedGoogle Scholar
  • 3 Robinow M, Pfeiffer RA, Gorlin RJ, McKusick VA, Renuart AW, Johnson GF, Summitt RL. Acrodysostosis. A syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am J Dis Child 1971; 121: 195-203
    PubMedGoogle Scholar
  • 4 Giedion A. Acrodysplasias. In: Kaufmann HJ. (ed.). Progress in Pediatric Radiology. Vol 4. Intrinsic Diseases of Bones. New York: S. Karger; 1973: 325-345
    Google Scholar
  • 5 Maroteaux P, Le Merrer M, Faure C, Fessard C. Les Maladies Osseuses de l’Enfant. 4 ed. Paris: Médecine-Sciences Flammarion; 2002
    Google Scholar
  • 6 Poznanski AK, Werder EA, Giedion A, Allan Martin RT, Helen Shaw BA. 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
    PubMedGoogle Scholar
  • 7 Jüppner H, Schipani E, Silve C. Jansen’s metaphyseal chondrodysplasia and Blomstrand’s lethal chondrodysplasia: two genetic disorders caused by PTH/PTHrP receptor mutations. In: Bilezikian J, Raisz LG, Rodan GA. (ed.). Principles of bone biology. San Diego: Academic Press; 2002: 1117-1136
    Google Scholar
  • 8 Linglart A, Menguy C, Couvineau A, Auzan C, Gunes Y, Cancel M, Motte E, Pinto G, Chanson P, Bougnères P, Clauser E, Silve C. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N Engl J Med 2011; 364: 2218-2226
    Google Scholar
  • 9 Ablow RC, Hsia YE, Brandt IK. Acrodysostosis coinciding with pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism. AJR Am J Roentgenol 1977; 128: 95-99
    CrossrefPubMedGoogle Scholar
  • 10 Butler MG, Rames LJ, Wadlington WB. Acrodysostosis: report of a 13-year-old boy with review of literature and metacarpophalangeal pattern profile analysis. Am J Med Genet 1988; 30: 971-980
    CrossrefPubMedGoogle Scholar
  • 11 Graham Jr JM, Krakow D, Tolo VT, Smith AK, Lachmann RS. Radiographic findings and Gs-alpha bioactivity studies and mutation screening in acrodysostosis indicate a different etiology from pseudohypoparathyroidism. Pediatr Radiol 2001; 31: 2-9
    CrossrefPubMedGoogle Scholar
  • 12 Hernandez RM, Miranda A, Kofman-Alfaro S. Acrodysostosis in two generations: an autosomal dominant syndrome. Clin Genet 1991; 39: 376-382
    PubMedGoogle Scholar
  • 13 Reiter S. Acrodysostosis. A case of peripheral dysostosis, nasal hypoplasia, mental retardation and impaired hearing. Pediatr Radiol 1978; 7: 53-55
    CrossrefPubMedGoogle Scholar
  • 14 Sheela SR, Perti A, Thomas G. Acrodysostosis: autosomal dominant transmission. Indian Pediatr 2005; 42: 822-826
    PubMedGoogle Scholar
  • 15 Steiner RD, Pagon RA. Autosomal dominant transmission of acrodysostosis. Clin Dysmorphol 1992; 1: 201-206
    PubMedGoogle Scholar
  • 16 Taillet-Bellemere C, Maroteaux P. Acrodysostosis in a sister and brother born to normal parents. Ann Pediatr (Paris) 1991; 38: 31-36
    PubMedGoogle Scholar
  • 17 Wilson LC, Oude Luttikhuis ME, Baraitser M, Kingston HM, Trembath RC. Normal erythrocyte membrane Gs alpha bioactivity in two unrelated patients with acrodysostosis. J Med Genet 1997; 34: 133-136
    CrossrefPubMedGoogle Scholar
  • 18 Davies SJ, Hughes HE. Familial acrodysostosis: can it be distinguished from Albright’s hereditary osteodystrophy?. Clin Dysmorphol 1992; 1: 207-215
    CrossrefPubMedGoogle Scholar
  • 19 Niikawa N, Matsuda I, Ohsawa T, Kajii T. Acrodysostosis and blue eyes. Hum Genet 1980; 53: 285
    PubMedGoogle Scholar
  • 20 Frey G, Martin J, Dietel K. Acrodysostosis – an autosomal dominant peripheral dysplasia. Kinderarztl Prax 1982; 50: 149-153
    PubMedGoogle Scholar
  • 21 Kim C, Cheng CY, Saldanha SA, Taylor SS. PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation. Cell 2007; 130: 1032-1043
    Google Scholar
  • 22 Spaulding SW. The ways in which hormones change cyclic adenosine 3′,5′-monophosphate-dependent protein kinase subunits, and how such changes affect cell behavior. Endocr Rev 1993; 14: 632-650
    PubMedGoogle Scholar
  • 23 Tasken K, Skalhegg BS, Tasken KA, Solberg R, Knutsen HK, Levy FO, Sandberg M, Orstavik S, Larsen T, Johansen AK, Vang T, Schrader HP, Reinton NT, Torgersen KM, Hansson V, Jahnsen T. Structure, function, and regulation of human cAMP-dependent protein kinases. Adv Second Messenger Phosphoprotein Res 1997; 31: 191-204
    PubMedGoogle Scholar
  • 24 Taylor SS, Buechler JA, Yonemoto W. cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annu Rev Biochem 1990; 59: 971-1005
    Google Scholar
  • 25 Taylor SS, Kim C, Cheng CY, Brown SH, Wu J, Kannan N. Signaling through cAMP and cAMP-dependent protein kinase: diverse strategies for drug design. Biochim Biophys Acta 2008; 1784: 16-26
    CrossrefPubMedGoogle Scholar
  • 26 Correll LA, Woodford TA, Corbin JD, Mellon PL, McKnight GS. Functional characterization of cAMP-binding mutations in type I protein kinase. J Biol Chem 1989; 264: 16672-16678
    PubMedGoogle Scholar
  • 27 Clegg CH, Correll LA, Cadd GG, McKnight GS. Inhibition of intracellular cAMP-dependent protein kinase using mutant genes of the regulatory type I subunit. J Biol Chem 1987; 262: 13111-13119
    PubMedGoogle Scholar
  • 28 Steinberg RA, Gorman KB, Øgreid D, Døskeland SO, Weber IT. Mutations that alter the charge of type I regulatory subunit and modify activation properties of cyclic AMP-dependent protein kinase from S49 mouse lymphoma cells. J Biol Chem 1991; 266: 3547-3553
    PubMedGoogle Scholar
  • 29 Willis BS, Niswender CM, Su T, Amieux PS, McKnight GS. Cell-type specific expression of a dominant negative PKA mutation in mice. PLoS One 2011; 6: e18772
    CrossrefPubMedGoogle Scholar
  • 30 Shuntoh H, Steinberg RA. Analysis of the dominance of mutations in cAMP-binding sites of murine type I cAMP-dependent protein kinase in activation of kinase from heterozygous mutant lymphoma cells. J Cell Physiol 1991; 146: 86-93
    CrossrefPubMedGoogle Scholar
  • 31 Gorman KB, Steinberg RA. Spectrum of spontaneous missense mutations causing cyclic AMP-resistance phenotypes in cultured S49 mouse lymphoma cells differs markedly from those of mutations induced by alkylating mutagens. Somat Cell Mol Genet 1994; 20: 301-311
    CrossrefPubMedGoogle Scholar
  • 32 Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, Cazabat L, Libe R, René-Corail F, Stergiopoulos S, Bourdeau I, Bei T, Clauser E, Calender A, Kirschner LS, Bertagna X, Carney JA, Stratakis CA. Mutations in regulatory subunit type 1A of cyclic adenosine 5′-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab 2009; 94: 2085-2091
    CrossrefPubMedGoogle Scholar
  • 33 Bossis I, Voutetakis A, Bei T, Sandrini F, Griffin KJ, Stratakis CA. Protein kinase A and its role in human neoplasia: the Carney complex paradigm. Endocr Relat Cancer 2004; 11: 265-280
    CrossrefPubMedGoogle Scholar
  • 34 Tsang KM, Starost MF, Nesterova M, Boikos SA, Watkins T, Almeida MQ, Harran M, Li A, Collins MT, Cheadle C, Mertz EL, Leikin S, Kirschner LS, Robey P, Stratakis CA. Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone. Proc Natl Acad Sci USA 2010; 107: 8683-8688
    CrossrefPubMedGoogle Scholar
  • 35 Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 2007; 76: 51-74
    CrossrefPubMedGoogle Scholar
  • 36 Greene EL, Horvath AD, Nesterova M, Giatzakis C, Bossis I, Stratakis C. In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay. Hum Mutat 2008; 29: 633-639
    Google Scholar
  • 37 Meoli E, Bossis I, Cazabat L, Mavrakis M, Horvath A, Sterrgiopoulos S, Shiferaw ML, Fumey G, Perlemoine K, Muchow M, Robinson-White A, Weinberg F, Nesterova M, Patromas Y, Grousin L, Bertherat J, Stratakis C. Protein kinase A effects of an expressed PRKAR1A mutation associated with aggressive tumors. Cancer Res 2008; 68: 3133-3141
    Google Scholar
  • 38 Karaplis AC, Goltzman D. PTH and PTHrP effects on the skeleton. Rev Endocr Metab Disord 2000; 1: 331-341
    CrossrefPubMedGoogle Scholar
  • 39 Kronenberg HM. Developmental regulation of the growth plate. Nature 2003; 423: 332-336
    CrossrefPubMedGoogle Scholar
  • 40 Silve CA. Cup Half-Full or Half-Empty? When PTHrP Levels Matter. IBMS BoneKEy 2010; 7: 325-332
    CrossrefPubMedGoogle Scholar
  • 41 Wysolmerski JJ, Stewart AF. The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor. Annu Rev Physiol 1998; 60: 431-460
    CrossrefPubMedGoogle Scholar
  • 42 Gensure RC, Gardella TJ, Juppner H. Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem Biophys Res Commun 2005; 328: 666-678
    CrossrefPubMedGoogle Scholar
  • 43 Parnot C, Miserey-Lenkei S, Bardin S, Corvol P, Clauser E. Lessons from constitutively active mutants of G protein-coupled receptors. Trends Endocrinol Metab 2002; 13: 336-343
    PubMedGoogle Scholar
  • 44 Klopocki E, Hennig BP, Dathe K, Koll R, de Ravel T, Baten E, Blom E, Gillerot Y, Weigel JFW, Krüger G, Hiort O, Seemann P, Mundlos S. Deletion and point mutations of PTHLH cause brachydactyly type E. Am J Hum Genet 2010; 86: 434-439
    CrossrefPubMedGoogle Scholar
  • 45 Maass PG, Wirth J, Aydin A, Rump A, Stricker S, Tinschert S, Otero M, Tsuchimochi K, Goldring MB, Luft FC, Bähring S. A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E. Hum Mol Genet 2010; 19: 848-860
    CrossrefPubMedGoogle Scholar
  • 46 Decker E, Stellzig-Eisenhauer A, Fiebig BS, Rau C, Kress W, Saar K, Rüschendorf F, Hubner N, Grimm T, Weber BHF. PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption. Am J Hum Genet 2008; 83: 781-786
    CrossrefPubMedGoogle Scholar
  • 47 Bastepe M, Juppner H. GNAS locus and pseudohypoparathyroidism. Horm Res 2005; 63: 65-74
    CrossrefPubMedGoogle Scholar
  • 48 Levine MA. Pseudohypoparathyroidism. In: Bilezikian LR JP, Rodan GA. (eds.). Principles of Bone biology. New York: Academic Press; 2002: 1137-1159
    CrossrefGoogle Scholar
  • 49 Linglart A, Carel JC, Garabedian M, Lé T, Mallet E, Kottler ML. 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
    CrossrefPubMedGoogle Scholar
  • 50 Thiele S, de Sanctis L, Werner R, Grötzinger J, Aydin C, Jüppner H, Bastepe M, Hiort O. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsalpha-receptor interaction. Hum Mutat 2011; 32: 653-660
    CrossrefPubMedGoogle Scholar
  • 51 Drezner M, Neelon FA, Lebovitz HE. Pseudohypoparathyroidism type II: a possible defect in the reception of the cyclic AMP signal. N Engl J Med 1973; 289: 1056-1060
    CrossrefPubMedGoogle Scholar
  • 52 Rao DS, Parfitt AM, Kleerekoper M, Pumo BS, Frame B. Dissociation between the effects of endogenous parathyroid hormone on adenosine 3′,5′-monophosphate generation and phosphate reabsorption in hypocalcemia due to vitamin D depletion: an acquired disorder resembling pseudohypoparathyroidism type II. J Clin Endocrinol Metab 1985; 61: 285-290
    CrossrefPubMedGoogle Scholar
  • 53 Kruse K, Kracht U, Gopfert G. Response of kidney and bone to parathyroid hormone in children receiving anticonvulsant drugs. Neuropediatrics 1982; 13: 3-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Lee H, Graham Jr JM, Rimoin DL, Lachman RS, Krejci P, Tompson SW, Nelson SF, Krakow D, Cohn DH. Exome Sequencing Identifies PDE4D Mutations in Acrodysostosis. Am J Hum Genet 2012; 90: 746-751
    CrossrefPubMedGoogle Scholar
  • 55 Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C, Kinning E, Guerrot A-M, Flahaut P, Duncombe A, Baujat G, Lyonnet S, Thalassinos C, Nitschke P, Casanova J-L, Le Merrer M, Munnich A, Cormier-Daire V. Exome Sequencing Identifies PDE4D Mutations as Another Cause of Acrodysostosis. Am J Hum Genet 2012; 90: 740-745
    CrossrefPubMedGoogle Scholar
  • 56 Weinstein LS, Xie T, Qasem A, Wang J, Chen M. The role of GNAS and other imprinted genes in the development of obesity. Int J Obes (Lond) 2010; 34: 6-17
    CrossrefPubMedGoogle Scholar
  • 57 Temtamy SA, Aglan MS. Brachydactyly. Orphanet J Rare Dis 2008; 3: 15
    CrossrefPubMedGoogle Scholar
  • 58 Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 2010; 6: 518-527
    Google Scholar