Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma

IMPACT FACTOR 2018: 1.239

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

See all formats and pricing
More options …
Volume 28, Issue 7-8


Progressive osseous heteroplasia, as an isolated entity or overlapping with Albright hereditary osteodystrophy

Maria H. Lin
  • Center for Endocrinology, Diabetes, and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Nawaporn Numbenjapon
  • Division of Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Emily L. Germain-Lee
  • Albright Clinic, Kennedy Krieger Institute, Baltimore, MD, USA
  • Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Pisit Pitukcheewanont
  • Corresponding author
  • Center for Endocrinology, Diabetes, and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, USA
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-04-18 | DOI: https://doi.org/10.1515/jpem-2014-0435


Introduction: Progressive osseous heteroplasia (POH) is a condition of invasive heterotopic ossification. Reports of patients with mild POH with Albright hereditary osteodystrophy (AHO), specifically pseudohypoparathyroidism type Ia (PHP Ia) with hormonal resistance, suggest the possibility of a common molecular basis. GNAS has been implicated to account for overlapping features of POH and PHP Ia.

Case 1: A 4-year-old boy with obesity, speech delay, and expanding subcutaneous masses on buttock/forearm. Physical exam revealed round facies and brachydactyly. Blood tests showed normal Ca, P, Mg, 25-OH vitamin D levels but elevated parathyroid hormone (PTH) and thyroid-stimulating hormone (TSH). Abdominal computed tomography (CT) showed areas with calcifications in the subcutaneous tissue, fat, and muscle. Pathology of excised tissue revealed ossifications. Genomic study revealed no GNAS mutation. He had POH and PHP Ia.

Case 2: A 3-year-old boy with painful ossifications in the left lower extremity. Lab tests were notable for elevated PTH and high-normal TSH. The CT-scan showed subcutaneous/intramuscular calcifications. Genetic testing showed GNAS mutation in exon 12 [c.1024C>T (R342X)]. Patient had POH and PHP Ia.

Case 3: A 9-year-old boy with knee pain and subcutaneous ossifications in back and upper/lower extremity, causing significantly limited joint mobility. Lab tests were normal. The CT-scan showed areas corresponding to subcutaneous/intramuscular ossifications throughout torso and extremities, consistent with POH. There was no GNAS mutation.

Conclusions: Patients with heterotopic ossifications present with a wide spectrum of disease. Although GNAS-based mutations have been postulated to account for overlapping features of AHO and POH, normal DNA studies in certain patients with POH/AHO suggest that there may exist other molecular/epigenetic mechanisms explaining their overlapping features.

Keywords: Albright hereditary osteodystrophy; progressive osseous heteroplasia; pseudohypoparathyroidism


  • 1.

    Kaplan FS, Craver R, MacEwen GD, Gannon FH, Finkel G, et al. Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. Two new case reports and follow-up of three previously reported cases. J Bone Joint Surg Am 1994;76:425–36.PubMedGoogle Scholar

  • 2.

    Urtizberea JA, Testart H, Cartault F, Boccon-Gibod L, Le MM, et al. Progressive osseous heteroplasia. Report of a family. J Bone Joint Surg Br 1998;80:768–71.CrossrefPubMedGoogle Scholar

  • 3.

    Cairns DM, Pignolo RJ, Uchimura T, Brennan TA, Lindborg CM, et al. Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. J Clin Invest 2013;123:3624–33.Web of ScienceGoogle Scholar

  • 4.

    Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Miner Res 2000;15:2084–94.PubMedCrossrefGoogle Scholar

  • 5.

    Kaplan FS, Glaser DL, Hebela N, Shore EM. Heterotopic ossification. J Am Acad Orthop Surg 2004;12:116–25.PubMedGoogle Scholar

  • 6.

    Shore EM, Ahn J, Jan de BS, Li M, Xu M, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 2002;346:99–106.Google Scholar

  • 7.

    Weinstein LS, Yu S, Warner DR, Liu J. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 2001;22:675–5.PubMedGoogle Scholar

  • 8.

    Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL. Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. J Clin Endocrinol Metab 2007;92:1073–9.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 9.

    Kaplan FS. Skin and bones. Arch Dermatol 1996;132:815–8.Google Scholar

  • 10.

    Gelfand IM, Hub RS, Shore EM, Kaplan FS, Dimeglio LA. Progressive osseous heteroplasia-like heterotopic ossification in a male infant with pseudohypoparathyroidism type Ia: a case report. Bone 2007;40:1425–8.CrossrefWeb of ScienceGoogle Scholar

  • 11.

    Schimmel RJ, Pasmans SG, Xu M, Stadhouders-Keet SA, Shore EM, et al. GNAS-associated disorders of cutaneous ossification: two different clinical presentations. Bone 2010;46:868–72.Web of ScienceCrossrefPubMedGoogle Scholar

  • 12.

    Eddy MC, Jan De Beur SM, Yandow SM, McAlister WH, Shore EM, et al. Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res 2000;15:2074–83.CrossrefGoogle Scholar

  • 13.

    Faust RA, Shore EM, Stevens CE, Xu M, Shah S, et al. Progressive osseous heteroplasia in the face of a child. Am J Med Genet A 2003;118A:71–5.Google Scholar

  • 14.

    Ahmed SF, Dixon PH, Bonthron DT, Stirling HF, Barr DG, et al. GNAS1 mutational analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf) 1998;49:525–31.Google Scholar

  • 15.

    Yeh GL, Mathur S, Wivel A, Li M, Gannon FH, et al. GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis. J Bone Miner Res 2000;15:2063–73.CrossrefGoogle Scholar

  • 16.

    Jan de Beur SM, Levine LM. Pseudohypoparathyroidism: clinical, biochemical, and molecular features. In: Bilezikian JP, editor. The parathyroids: basic and clinical concepts. San Diego, CA: Academic Press, 2001:807–25.Google Scholar

  • 17.

    Patten JL, Johns DR, Valle D, Eil C, Gruppuso PA, et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med 1990;322:1412–9.Google Scholar

  • 18.

    Shields MB, Buckley E, Klintworth GK, Thresher R. Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 1985;29:387–409.PubMedCrossrefGoogle Scholar

  • 19.

    Tresserra L, Tresserra F, Grases PJ, Badosa J, Tresserra M. Congenital plate-like osteoma cutis of the forehead: an atypical presentation form. J Craniomaxillofac Surg 1998;26:102–6.CrossrefPubMedGoogle Scholar

  • 20.

    Hou JW. Progressive osseous heteroplasia controlled by intravenous administration of pamidronate. Am J Med Genet A 2006;140:910–3.Google Scholar

  • 21.

    Adegbite NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A 2008;146A:1788–96.Web of ScienceGoogle Scholar

  • 22.

    Lebrun M, Richard N, Abeguile G, David A, Coeslier DA, et al. Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans. J Clin Endocrinol Metab 2010;95:3028–38.CrossrefWeb of ScienceGoogle Scholar

  • 23.

    Hayward BE, Moran V, Strain L, Bonthron DT. Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci USA 1998;95:15475–80.CrossrefGoogle Scholar

  • 24.

    Levine MA, Downs RW, Jr., Moses AM, Breslau NA, Marx SJ, et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983;74:545–56.CrossrefPubMedGoogle Scholar

  • 25.

    Levine MA, Jap TS, Mauseth RS, Downs RW, Spiegel AM. Activity of the stimulatory guanine nucleotide-binding protein is reduced in erythrocytes from patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism: biochemical, endocrine, and genetic analysis of Albright’s hereditary osteodystrophy in six kindreds. J Clin Endocrinol Metab 1986;62:497–502.Google Scholar

  • 26.

    Brickman AS, Carlson HE, Levin SR. Responses to glucagon infusion in pseudohypoparathyroidism. J Clin Endocrinol Metab 1986;63:1354–60.PubMedCrossrefGoogle Scholar

  • 27.

    Germain-Lee EL, Groman J, Crane JL, Jan De Beur SM, Levine MA. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 2003;88:4059–69.CrossrefGoogle Scholar

  • 28.

    Germain-Lee EL. Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type 1a. Pediatr Endocrinol Rev 2006;3(Suppl 2):318–27.Google Scholar

  • 29.

    Mantovani G, Maghnie M, Weber G, De ME, Brunelli V, et al. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 2003;88:4070–4.CrossrefGoogle Scholar

  • 30.

    Germain-Lee EL, Ding CL, Deng Z, Crane JL, Saji M, et al. 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.Google Scholar

  • 31.

    Germain-Lee EL, Schwindinger W, Crane JL, Zewdu R, Zweifel LS, et al. A mouse model of Albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology 2005;146:4697–709.Google Scholar

  • 32.

    Yu S, Yu D, Lee E, Eckhaus M, Lee R, et al. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene. Proc Natl Acad Sci USA 1998;95:8715–20.CrossrefGoogle Scholar

  • 33.

    Huso DL, Edie S, Levine MA, Schwindinger W, Wang Y, et al. Heterotopic ossifications in a mouse model of Albright hereditary osteodystrophy. PLoS One 2011;6:e21755.Web of ScienceCrossrefGoogle Scholar

  • 34.

    Pignolo RJ, Xu M, Russell E, Richardson A, Kaplan J. et al. Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. J Bone Miner Res 2011;26:2647–55.Web of ScienceCrossrefPubMedGoogle Scholar

  • 35.

    Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. J Endocrinol 2008;196:193–214.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 36.

    Cortes W, Gosain AK. Recurrent ectopic calcification involving the maxillofacial skeleton: a potential harbinger of Albright’s osteodystrophy. J Craniofac Surg 2006;17:21–7.CrossrefGoogle Scholar

About the article

Corresponding author: Pisit Pitukcheewanont, Center for Endocrinology, Diabetes, and Metabolism, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, Phone: +1-323-361-2500, Fax: +1-323-361-1350, E-mail:

Received: 2014-10-17

Accepted: 2015-02-11

Published Online: 2015-04-18

Published in Print: 2015-07-01

Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 28, Issue 7-8, Pages 911–918, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2014-0435.

Export Citation

©2015 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Emily L. Germain-Lee
Current Opinion in Pediatrics, 2019, Volume 31, Number 4, Page 537
L. de Sanctis, F. Giachero, G. Mantovani, G. Weber, M. Salerno, G. I. Baroncelli, F. M. Elli, P. Matarazzo, M. Wasniewska, L. Mazzanti, G. Scirè, and D. Tessaris
Italian Journal of Pediatrics, 2016, Volume 42, Number 1
Susanne Thiele, Giovanna Mantovani, Anne Barlier, Valentina Boldrin, Paolo Bordogna, Luisa De Sanctis, Francesca M Elli, Kathleen Freson, Intza Garin, Virginie Grybek, Patrick Hanna, Benedetta Izzi, Olaf Hiort, Beatriz Lecumberri, Arrate Pereda, Vrinda Saraff, Caroline Silve, Serap Turan, Alessia Usardi, Ralf Werner, Guiomar Perez de Nanclares, and Agnès Linglart
European Journal of Endocrinology, 2016, Volume 175, Number 6, Page P1

Comments (0)

Please log in or register to comment.
Log in