{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T21:22:46Z","timestamp":1787692966420,"version":"build-2784847793"},"reference-count":25,"publisher":"The Endocrine Society","issue":"3","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100004726","name":"Ministry of Health","doi-asserted-by":"publisher","award":["16-31211A"],"award-info":[{"award-number":["16-31211A"]}],"id":[{"id":"10.13039\/501100004726","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design, Settings and Patients<\/jats:title>\n                  <jats:p>Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height \u2264 \u20132 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In 5\/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm\/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgaa037","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T20:33:25Z","timestamp":1580243605000},"page":"e746-e752","source":"Crossref","is-referenced-by-count":37,"title":["<i>NPR2<\/i> Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy"],"prefix":"10.1210","volume":"105","author":[{"given":"Lukas","family":"Plachy","sequence":"first","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Dusatkova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Maratova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenka","family":"Petruzelkova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Zemkova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenka","family":"Elblova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Kucerova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ledjona","family":"Toni","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislava","family":"Kolouskova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Snajderova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zdenek","family":"Sumnik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Lebl","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-115X","authenticated-orcid":false,"given":"Stepanka","family":"Pruhova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, 150 06, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2020,1,28]]},"reference":[{"key":"2021122102320006800_CIT0001","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.biocel.2018.07.004","article-title":"Molecular and in silico analyses validates pathogenicity of homozygous mutations in the NPR2 gene underlying variable phenotypes of scromesomelic dysplasia, type Maroteaux","volume":"102","author":"Irfanullah","year":"2018","journal-title":"Int J Biochem Cell Biol."},{"issue":"21","key":"2021122102320006800_CIT0002","doi-asserted-by":"crossref","first-page":"11385","DOI":"10.1074\/jbc.M115.704015","article-title":"Catalytically active guanylyl cyclase B requires endoplasmic reticulum-mediated glycosylation, and mutations that inhibit this process cause Dwarfism","volume":"291","author":"Dickey","year":"2016","journal-title":"J Biol Chem."},{"issue":"12","key":"2021122102320006800_CIT0003","doi-asserted-by":"crossref","first-page":"E1988","DOI":"10.1210\/jc.2013-2358","article-title":"An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities","volume":"98","author":"Hannema","year":"2013","journal-title":"J Clin Endocrinol Metab."},{"issue":"8","key":"2021122102320006800_CIT0004","doi-asserted-by":"crossref","first-page":"E1133","DOI":"10.1210\/jc.2015-1612","article-title":"Heterozygous NPR2 mutations cause disproportionate short stature, similar to L\u00e9ri-Weill dyschondrosteosis","volume":"100","author":"Hisado-Oliva","year":"2015","journal-title":"J Clin Endocrinol Metab."},{"issue":"10","key":"2021122102320006800_CIT0005","doi-asserted-by":"crossref","first-page":"E1636","DOI":"10.1210\/jc.2013-2142","article-title":"Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature","volume":"98","author":"Vasques","year":"2013","journal-title":"J Clin Endocrinol Metab."},{"issue":"4","key":"2021122102320006800_CIT0006","doi-asserted-by":"crossref","first-page":"E713","DOI":"10.1210\/jc.2013-3525","article-title":"Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature","volume":"99","author":"Amano","year":"2014","journal-title":"J Clin Endocrinol Metab."},{"issue":"4","key":"2021122102320006800_CIT0007","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/humu.22773","article-title":"Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature","volume":"36","author":"Wang","year":"2015","journal-title":"Hum Mutat."},{"issue":"6","key":"2021122102320006800_CIT0008","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1210\/jc.2018-01971","article-title":"Multigene sequencing analysis of children born small for gestational age with isolated short stature","volume":"104","author":"Freire","year":"2019","journal-title":"J Clin Endocrinol Metab."},{"issue":"1","key":"2021122102320006800_CIT0009","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1515\/jpem-2016-0280","article-title":"Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2","volume":"30","author":"Vasques","year":"2017","journal-title":"J Pediatr Endocrinol Metab."},{"key":"2021122102320006800_CIT0010","first-page":"7658496","article-title":"Heterozygous NPR2 mutation in two family members with short stature and skeletal dysplasia","volume":"2018","author":"Jacob","year":"2018","journal-title":"Case Rep Endocrinol."},{"issue":"10","key":"2021122102320006800_CIT0011","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1055\/s-2006-924458","article-title":"Analyse des Neugeborenenkollektivs der Bundesrepublik Deutschland","volume":"66","author":"Voigt","year":"2006","journal-title":"Geburtshilfe Frauenheilkd."},{"issue":"3","key":"2021122102320006800_CIT0012","first-page":"126","article-title":"The 6th nationwide anthropological survey of children and adolescents in the Czech Republic in 2001","volume":"12","author":"Kobzov\u00e1","year":"2004","journal-title":"Cent Eur J Public Health."},{"issue":"8","key":"2021122102320006800_CIT0013","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1136\/adc.2004.050799","article-title":"Nationwide age references for sitting height, leg length, and sitting height\/height ratio, and their diagnostic value for disproportionate growth disorders","volume":"90","author":"Fredriks","year":"2005","journal-title":"Arch Dis Child."},{"issue":"11","key":"2021122102320006800_CIT0014","first-page":"3990","article-title":"Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society","volume":"85","author":"Kommunehospital","year":"2000","journal-title":"J Clin Endocrinol Metab."},{"issue":"3","key":"2021122102320006800_CIT0015","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1210\/jc.2006-2017","article-title":"Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society","volume":"92","author":"Clayton","year":"2007","journal-title":"J Clin Endocrinol Metab."},{"issue":"10","key":"2021122102320006800_CIT0016","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1210\/jc.2018-02288","article-title":"High prevalence of growth plate gene variants in children with familial short stature treated with GH","volume":"104","author":"Plachy","year":"2019","journal-title":"J Clin Endocrinol Metab."},{"key":"2021122102320006800_CIT0017","volume-title":"NPR2 variants are frequent among children with familiar short stature and respond well to growth hormone therapy. Open Science Framework 2019","author":"Plachy","year":"2019"},{"issue":"W1","key":"2021122102320006800_CIT0018","doi-asserted-by":"crossref","first-page":"W545","DOI":"10.1093\/nar\/gky471","article-title":"VarAFT: a variant annotation and filtration system for human next generation sequencing data","volume":"46","author":"Desvignes","year":"2018","journal-title":"Nucleic Acids Res."},{"issue":"8","key":"2021122102320006800_CIT0019","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1111\/j.1399-5448.2010.00646.x","article-title":"Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations","volume":"11","author":"Pruhova","year":"2010","journal-title":"Pediatr Diabetes."},{"issue":"5","key":"2021122102320006800_CIT0020","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med."},{"issue":"8","key":"2021122102320006800_CIT0021","doi-asserted-by":"crossref","first-page":"E1383","DOI":"10.1210\/jc.2013-1222","article-title":"GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial","volume":"98","author":"Blum","year":"2013","journal-title":"J Clin Endocrinol Metab."},{"issue":"1","key":"2021122102320006800_CIT0022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.6065\/apem.2014.19.1.1","article-title":"Growth hormone treatment in non-growth hormone-deficient children","volume":"19","author":"Loche","year":"2014","journal-title":"Ann Pediatr Endocrinol Metab."},{"issue":"1","key":"2021122102320006800_CIT0023","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1159\/000452973","article-title":"Safety outcomes and near-adult height gain of growth hormone-treated children with SHOX deficiency: data from an observational study and a clinical trial","volume":"87","author":"Benabbad","year":"2017","journal-title":"Horm Res Paediatr."},{"issue":"1","key":"2021122102320006800_CIT0024","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1210\/jc.2006-1409","article-title":"Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: two-year results of a randomized, controlled, multicenter trial","volume":"92","author":"Blum","year":"2007","journal-title":"J Clin Endocrinol Metab."},{"issue":"9","key":"2021122102320006800_CIT0025","first-page":"3323","article-title":"Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children","volume":"81","author":"Ghigo","year":"1996","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\/advance-article-pdf\/doi\/10.1210\/clinem\/dgaa037\/32120955\/dgaa037.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/105\/3\/e746\/41823977\/jcem_105_3_e746.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/105\/3\/e746\/41823977\/jcem_105_3_e746.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T02:34:49Z","timestamp":1640054089000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/105\/3\/e746\/5716766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,28]]},"references-count":25,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,1,28]]},"published-print":{"date-parts":[[2020,3,1]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgaa037","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,3]]},"published":{"date-parts":[[2020,1,28]]}}}