{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:44:22Z","timestamp":1789447462518,"version":"build-2803163510"},"reference-count":40,"publisher":"The Endocrine Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,1]]},"abstract":"<jats:sec>\n                  <jats:title>Context:<\/jats:title>\n                  <jats:p>The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and\/or epigenetic alterations within or upstream of GNAS. Although knowledge about PHP is growing, there are few data on the prevalence of underlying molecular defects.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>The purpose of our study was to ascertain the relative prevalence of PHP-associated molecular defects.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design:<\/jats:title>\n                  <jats:p>With a specially designed questionnaire, we collected data from all patients (n = 407) clinically and molecularly characterized to date by expert referral centers in France, Italy, and Spain.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>Isolated rPTH (126\/407, 31%) was caused only by epigenetic defects, 70% of patients showing loss of imprinting affecting all four GNAS differentially methylated regions and 30% loss of methylation restricted to the GNAS A\/B:TSS-DMR. Multihormone resistance with no Albright\u2019s hereditary osteodystrophy (AHO) signs (61\/407, 15%) was essentially due to epigenetic defects, although 10% of patients had point mutations. In patients with rPTH and AHO (40\/407, 10%), the rate of point mutations was higher (28%) and methylation defects lower (about 70%). In patients with multihormone resistance and AHO (155\/407, 38%), all types of molecular defects appeared with different frequencies. Finally, isolated AHO (18\/407, 4%) and progressive osseous heteroplasia (7\/407, 2%) were exclusively caused by point mutations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion:<\/jats:title>\n                  <jats:p>With European data, we have established the prevalence of various genetic and epigenetic lesions in PHP-affected patients. Using these findings, we will develop objective criteria to guide cost-effective strategies for genetic testing and explore the implications for management and prognosis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2015-4310","type":"journal-article","created":{"date-parts":[[2016,7,18]],"date-time":"2016-07-18T17:01:30Z","timestamp":1468861290000},"page":"3657-3668","source":"Crossref","is-referenced-by-count":74,"title":["The Prevalence of GNAS Deficiency-Related Diseases in a Large Cohort of Patients Characterized by the EuroPHP Network"],"prefix":"10.1210","volume":"101","author":[{"given":"Francesca Marta","family":"Elli","sequence":"first","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico (F.M.E., E.V., P.B., G.M.), Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agn\u00e8s","family":"Linglart","sequence":"additional","affiliation":[{"name":"APHP (A.L., V.G., P.H.), Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d\u2019expertise Paris Sud Maladies Rares, Le Kremlin Bic\u00eatre, France;"},{"name":"INSERM U1169 (A.L., V.G., P.H.), H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, et Universit\u00e9 Paris-Saclay, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Intza","family":"Garin","sequence":"additional","affiliation":[{"name":"Molecular (Epi)Genetics Laboratory (I.G., A.P., G.P.d.N.), BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"de Sanctis","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatrics (L.d.S., F.G.), University of Turin, Regina Margherita Children\u2019s Hospital, Health and Science City, Turin, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Bordogna","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico (F.M.E., E.V., P.B., G.M.), Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Grybek","sequence":"additional","affiliation":[{"name":"APHP (A.L., V.G., P.H.), Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d\u2019expertise Paris Sud Maladies Rares, Le Kremlin Bic\u00eatre, France;"},{"name":"INSERM U1169 (A.L., V.G., P.H.), H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, et Universit\u00e9 Paris-Saclay, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arrate","family":"Pereda","sequence":"additional","affiliation":[{"name":"Molecular (Epi)Genetics Laboratory (I.G., A.P., G.P.d.N.), BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain;"},{"name":"Department of Biochemistry and Molecular Biology (A.P.), University of Basque Country, Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Giachero","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatrics (L.d.S., F.G.), University of Turin, Regina Margherita Children\u2019s Hospital, Health and Science City, Turin, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Verrua","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico (F.M.E., E.V., P.B., G.M.), Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Hanna","sequence":"additional","affiliation":[{"name":"APHP (A.L., V.G., P.H.), Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d\u2019expertise Paris Sud Maladies Rares, Le Kremlin Bic\u00eatre, France;"},{"name":"INSERM U1169 (A.L., V.G., P.H.), H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, et Universit\u00e9 Paris-Saclay, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico (F.M.E., E.V., P.B., G.M.), Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiomar","family":"Perez de Nanclares","sequence":"additional","affiliation":[{"name":"Molecular (Epi)Genetics Laboratory (I.G., A.P., G.P.d.N.), BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2016,7,18]]},"reference":[{"key":"2020071614205337100_B1","first-page":"922","article-title":"Pseudohypoparathyroidsm\u2014an example of \u201cSeabright syndrome.\u201d","volume":"30","author":"Albright","year":"1942","journal-title":"Endocrinology"},{"key":"2020071614205337100_B2","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1056\/NEJM197311152892003","article-title":"Pseudohypoparathyroidism type II: a possible defect in the reception of the cyclic AMP signal","volume":"289","author":"Drezner","year":"1973","journal-title":"N Engl J Med"},{"key":"2020071614205337100_B3","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1055\/s-0032-1304232","article-title":"GNAS epigenetic defects and pseudohypoparathyroidism: time for a new classification?","volume":"44","author":"Mantovani","year":"2012","journal-title":"Horm Metab Res"},{"key":"2020071614205337100_B4","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1056\/NEJM199005173222002","article-title":"Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright\u2019s hereditary osteodystrophy","volume":"322","author":"Patten","year":"1990","journal-title":"N Engl J Med"},{"key":"2020071614205337100_B5","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1515\/JPEM.2006.19.S2.641","article-title":"Different mutations within or upstream of the GNAS locus cause distinct forms of pseudohypoparathyroidism","volume":"19","author":"Juppner","year":"2006","journal-title":"J Pediatr Endocrinol Metab"},{"key":"2020071614205337100_B6","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/humu.22265","article-title":"Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations","volume":"34","author":"Elli","year":"2013","journal-title":"Hum Mutat"},{"key":"2020071614205337100_B7","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/mgg3.117","article-title":"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","volume":"3","author":"Thiele","year":"2015","journal-title":"Mole Genet Genom Med"},{"key":"2020071614205337100_B8","doi-asserted-by":"crossref","first-page":"E681","DOI":"10.1210\/jc.2014-3098","article-title":"Novel microdeletions affecting the GNAS locus in pseudohypoparathyroidism: characterization of the underlying mechanisms","volume":"100","author":"Garin","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B9","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1056\/NEJMoa011262","article-title":"Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia","volume":"346","author":"Shore","year":"2002","journal-title":"N Engl J Med"},{"key":"2020071614205337100_B10","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1002\/ajmg.a.32346","article-title":"Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification","volume":"146A","author":"Adegbite","year":"2008","journal-title":"Am J Med Genet A"},{"key":"2020071614205337100_B11","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI10431","article-title":"A GNAS1 imprinting defect in pseudohypoparathyroidism type IB","volume":"106","author":"Liu","year":"2000","journal-title":"J Clin Invest"},{"key":"2020071614205337100_B12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/hmg\/ddi009","article-title":"Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB","volume":"14","author":"Liu","year":"2005","journal-title":"Hum Mol Genet"},{"key":"2020071614205337100_B13","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/ejhg.2014.127","article-title":"European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study","volume":"23","author":"Garin","year":"2015","journal-title":"Eur J Hum Genet"},{"key":"2020071614205337100_B14","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1530\/EJE-10-0435","article-title":"New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism","volume":"163","author":"Fernandez-Rebollo","year":"2010","journal-title":"Eur J Endocrinol"},{"key":"2020071614205337100_B15","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.bone.2015.05.011","article-title":"Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B)","volume":"79","author":"Takatani","year":"2015","journal-title":"Bone"},{"key":"2020071614205337100_B16","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1172\/JCI19159","article-title":"Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS","volume":"112","author":"Bastepe","year":"2003","journal-title":"J Clin Invest"},{"key":"2020071614205337100_B17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/ng1487","article-title":"Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib","volume":"37","author":"Bastepe","year":"2005","journal-title":"Nat Genet"},{"key":"2020071614205337100_B18","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1086\/429932","article-title":"A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS","volume":"76","author":"Linglart","year":"2005","journal-title":"Am J Hum Genet"},{"key":"2020071614205337100_B19","doi-asserted-by":"crossref","first-page":"E724","DOI":"10.1210\/jc.2013-3704","article-title":"Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A\/B DMR","volume":"99","author":"Elli","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B20","doi-asserted-by":"crossref","first-page":"E863","DOI":"10.1210\/jc.2011-2804","article-title":"A new deletion ablating NESP55 causes loss of maternal imprint of A\/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib","volume":"97","author":"Richard","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B21","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1210\/jc.2009-2205","article-title":"Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis","volume":"95","author":"Chillambhi","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B22","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/ejhg.2014.133","article-title":"Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b","volume":"23","author":"Rezwan","year":"2015","journal-title":"Eur J Hum Genet"},{"key":"2020071614205337100_B23","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1210\/jc.2006-2287","article-title":"Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright\u2019s hereditary osteodystrophy","volume":"92","author":"Perez de Nanclares","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B24","doi-asserted-by":"crossref","first-page":"E508","DOI":"10.1210\/jc.2013-3086","article-title":"Quantitative analysis of methylation defects and correlation with clinical characteristics in patients with pseudohypoparathyroidism type I and GNAS epigenetic alterations","volume":"99","author":"Elli","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B25","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bone.2014.10.006","article-title":"Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS","volume":"71","author":"Turan","year":"2015","journal-title":"Bone"},{"key":"2020071614205337100_B26","doi-asserted-by":"crossref","first-page":"E996","DOI":"10.1210\/jc.2012-4164","article-title":"Endocrine profile and phenotype-(epi)genotype correlation in Spanish patients with pseudohypoparathyroidism","volume":"98","author":"Fernandez-Rebollo","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B27","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1002\/humu.22352","article-title":"Simultaneous hyper- and hypomethylation at imprinted loci in a subset of patients with GNAS epimutations underlies a complex and different mechanism of multilocus methylation defect in pseudohypoparathyroidism type 1b","volume":"34","author":"Maupetit-Mehouas","year":"2013","journal-title":"Hum Mutat"},{"key":"2020071614205337100_B28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1136\/jmg.2010.081356","article-title":"Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib","volume":"48","author":"Maupetit-Mehouas","year":"2011","journal-title":"J Med Genet"},{"key":"2020071614205337100_B29","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1210\/jcem.87.1.8133","article-title":"GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance","volume":"87","author":"Linglart","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B30","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1210\/jc.2009-0176","article-title":"Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients","volume":"95","author":"Mantovani","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614205337100_B31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/humu.22696","article-title":"GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders","volume":"36","author":"Lemos","year":"2015","journal-title":"Hum Mutat"},{"key":"2020071614205337100_B32","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1086\/374566","article-title":"Analysis of GNAS1 and overlapping transcripts identifies the parental origin of mutations in patients with sporadic Albright hereditary osteodystrophy and reveals a model system in which to observe the effects of splicing mutations on translated and untranslated messenger RNA","volume":"72","author":"Rickard","year":"2003","journal-title":"Am J Hum Genet"},{"key":"2020071614205337100_B33","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1136\/jmg.31.11.835","article-title":"Parental origin of Gs alpha gene mutations in Albright\u2019s hereditary osteodystrophy","volume":"31","author":"Wilson","year":"1994","journal-title":"J Med Genet"},{"key":"2020071614205337100_B34","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/hmg\/10.12.1231","article-title":"Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A\/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus","volume":"10","author":"Bastepe","year":"2001","journal-title":"Hum Mol Genet"},{"key":"2020071614205337100_B35","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1101\/gr.164913.113","article-title":"Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment","volume":"24","author":"Court","year":"2014","journal-title":"Genome Res"},{"key":"2020071614205337100_B36","doi-asserted-by":"crossref","first-page":"398","DOI":"10.2174\/138920207783406488","article-title":"The GNAS locus: quintessential complex gene encoding Gsalpha, XLalphas, and other imprinted transcripts","volume":"8","author":"Bastepe","year":"2007","journal-title":"Curr Genom"},{"key":"2020071614205337100_B37","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1086\/320117","article-title":"Paternal uniparental isodisomy of chromosome 20q\u2013and the resulting changes in GNAS1 methylation\u2013as a plausible cause of pseudohypoparathyroidism","volume":"68","author":"Bastepe","year":"2001","journal-title":"Am J Hum Genet"},{"key":"2020071614205337100_B38","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.bone.2010.10.168","article-title":"Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib)","volume":"48","author":"Bastepe","year":"2011","journal-title":"Bone"},{"key":"2020071614205337100_B39","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/j.1365-2265.2011.04026.x","article-title":"Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism","volume":"75","author":"Jin","year":"2011","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071614205337100_B40","doi-asserted-by":"crossref","first-page":"E103","DOI":"10.1210\/jc.2012-2639","article-title":"Pseudohypoparathyroidism type 1b due to paternal uniparental disomy of chromosome 20q","volume":"98","author":"Dixit","year":"2013","journal-title":"J Clin Endocrinol Metab"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/101\/10\/3657\/10526550\/jcem3657.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/101\/10\/3657\/10526550\/jcem3657.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T02:01:59Z","timestamp":1594951319000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/101\/10\/3657\/2764904"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,18]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2016,10,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2015-4310","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,18]]}}}