{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T18:05:06Z","timestamp":1792260306635,"version":"4.4.0"},"reference-count":17,"publisher":"The Endocrine Society","issue":"9","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008484","name":"BioMarin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008484","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Genetic defects in many biological pathways, including activation of the Ras-MAPK pathway, cause short stature. Vosoritide, a C-type natriuretic peptide analog that inhibits this pathway, has been approved for use in achondroplasia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To determine whether vosoritide improves growth in children with disorders of the Ras-MAPK pathway, including RASopathies, ACAN, and NPR2 deficiency.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Prospective Phase 2 basket trial<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>Academic medical center<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>Thirty prepubertal children aged 3 to 11 years with a RASopathy, ACAN or NPR2 deficiency and height \u2264 \u22122.25 SD<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Intervention<\/jats:title>\n                    <jats:p>Six-month observation period followed by 12-month treatment with vosoritide subcutaneously 15 \u00b5g\/kg\/day.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Outcome Measures<\/jats:title>\n                    <jats:p>Co-primary outcomes included incidence of adverse events, change in annualized growth velocity (AGV), and height standard deviation scores.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The AGV increased from 4.53 \u00b1 1.61 cm\/year to 8.09 \u00b1 1.58 cm\/year with treatment (P &amp;lt; .0001). This corresponded to a 4.0 SD (95%CI 3.08-4.91) increase in age and sex-adjusted AGV Z-score (P &amp;lt; .0001). The increase in AGV was seen in all genetic subgroups. There was a height increase of 0.65 SD (95%CI 0.53-0.77) in the treatment vs observation period (P &amp;lt; .0001).<\/jats:p>\n                    <jats:p>Short-term safety was reassuring, with mild injection site reactions being the most common adverse events. However, with longer use, 5 subjects discontinued medication due to adverse events, including 3 slipped capital femoral epiphyses and 4 cases of genu valgum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Vosoritide led to marked increases in growth velocity in children with RASopathies, ACAN, and NPR2 deficiency, raising the possibility that vosoritide could be an effective precision medicine for all growth disorders affecting the MAPK pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag157","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T11:43:41Z","timestamp":1775735021000},"page":"2416-2425","source":"Crossref","is-referenced-by-count":5,"title":["A phase II basket trial of vosoritide in children with RASopathies, ACAN, and NPR2 deficiency"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4890-0262","authenticated-orcid":false,"given":"Andrew","family":"Dauber","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Children's National Hospital , Washington, DC 20010 ,","place":["USA"]},{"name":"Department of Pediatrics, The George Washington University School of Medicine and Health Sciences , Washington, DC 20052 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Children's National Hospital , Washington, DC 20010 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niusha","family":"Shafaei","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Children's National Hospital , Washington, DC 20010 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raheem","family":"Seaforth","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Children's National Hospital , Washington, DC 20010 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Pitner","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Children's National Hospital , Washington, DC 20010 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niti","family":"Dham","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The George Washington University School of Medicine and Health Sciences , Washington, DC 20052 ,","place":["USA"]},{"name":"Division of Cardiology, Children's National Hospital , Washington, DC 20010 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9653-8865","authenticated-orcid":false,"given":"Roopa","family":"Kanakatti Shankar","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Children's National Hospital , Washington, DC 20010 ,","place":["USA"]},{"name":"Department of Pediatrics, The George Washington University School of Medicine and Health Sciences , Washington, DC 20052 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Merchant","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, University of Texas Southwestern Medical Center , Dallas, TX 75390 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"2026081219562669700_dgag157-B1","doi-asserted-by":"crossref","DOI":"10.1016\/j.eclinm.2024.102591","article-title":"Vosoritide treatment for children with hypochondroplasia: a phase 2 trial","volume":"71","author":"Dauber","year":"2024","journal-title":"EClinicalMedicine"},{"issue":"6","key":"2026081219562669700_dgag157-B2","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.jpeds.2011.05.024","article-title":"Spectrum of mutations in noonan syndrome and their correlation with phenotypes","volume":"159","author":"Lee","year":"2011","journal-title":"J Pediatr"},{"issue":"9863","key":"2026081219562669700_dgag157-B3","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","author":"Roberts","year":"2013","journal-title":"The Lancet"},{"issue":"6","key":"2026081219562669700_dgag157-B4","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/gim.2017.159","article-title":"Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature","volume":"20","author":"Hauer","year":"2018","journal-title":"Genet Med"},{"issue":"2","key":"2026081219562669700_dgag157-B5","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1210\/jc.2016-3313","article-title":"Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations","volume":"102","author":"Gkourogianni","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2026081219562669700_dgag157-B6","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.ydbio.2009.02.024","article-title":"Aggrecan modulation of growth plate morphogenesis","volume":"329","author":"Domowicz","year":"2009","journal-title":"Dev Biol"},{"key":"2026081219562669700_dgag157-B7","doi-asserted-by":"crossref","unstructured":"Dauber A, Zhang A, Shafaei N, et al \u00a02026. Data from: a phase II basket trial of vosoritide in children with RASopathies, ACAN and NPR2 deficiency. Figshare. 10.6084\/m9.figshare.31662460. Date of deposit 11 March 2026.","DOI":"10.1210\/clinem\/dgag157"},{"key":"2026081219562669700_dgag157-B8","volume-title":"Quality of Life in Short Stature Youth\u2014the QoLISSY Questionnaire User's Manual","author":"The European QoLISSY Group","year":"2013"},{"issue":"10252","key":"2026081219562669700_dgag157-B9","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/S0140-6736(20)31541-5","article-title":"Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial","volume":"396","author":"Savarirayan","year":"2020","journal-title":"Lancet"},{"issue":"1","key":"2026081219562669700_dgag157-B10","doi-asserted-by":"crossref","first-page":"e255","DOI":"10.1210\/clinem\/dgaa721","article-title":"Norms for clinical use of CXM, a real-time marker of height velocity","volume":"106","author":"Coghlan","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026081219562669700_dgag157-B11","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1159\/000512429","article-title":"Long-term effectiveness and safety of childhood growth hormone treatment in noonan syndrome","volume":"93","author":"Rohrer","year":"2020","journal-title":"Horm Res Paediatr"},{"issue":"12","key":"2026081219562669700_dgag157-B12","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvae177","article-title":"Treatment of short stature in aggrecan-deficient patients with recombinant human GH: 3-year response","volume":"8","author":"Muthuvel","year":"2024","journal-title":"J Endocr Soc"},{"issue":"1","key":"2026081219562669700_dgag157-B13","doi-asserted-by":"crossref","first-page":"e166","DOI":"10.1210\/clinem\/dgaf309","article-title":"Clinical characteristics and response to growth hormone treatment in 27 children with heterozygous NPR2 variants: real-world data","volume":"111","author":"Renes","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2026081219562669700_dgag157-B14","first-page":"100566","article-title":"Sustained growth-promoting effects of vosoritide in children with achondroplasia from an ongoing phase 3 extension study","volume":"6","author":"Savarirayan","year":"2025","journal-title":"Med (N. Y)"},{"issue":"8","key":"2026081219562669700_dgag157-B15","doi-asserted-by":"crossref","first-page":"E1510","DOI":"10.1210\/jc.2014-1332","article-title":"Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations","volume":"99","author":"Nilsson","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2026081219562669700_dgag157-B16","doi-asserted-by":"crossref","first-page":"481","DOI":"10.4274\/jcrpe.galenos.2021.2021.0081","article-title":"A novel heterozygous ACAN variant in a short patient born small for gestational age with recurrent patellar dislocation: a case report","volume":"14","author":"Kim","year":"2022","journal-title":"J Clin Res Pediatr Endocrinol"},{"issue":"1","key":"2026081219562669700_dgag157-B17","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1002\/ajmg.a.36218","article-title":"Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene","volume":"164","author":"Miura","year":"2014","journal-title":"Am J Med Genet A"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgag157\/68023240\/dgag157.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/9\/2416\/68023240\/dgag157.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/9\/2416\/68023240\/dgag157.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T23:56:34Z","timestamp":1786578994000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/111\/9\/2416\/8650949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":17,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,4,10]]},"published-print":{"date-parts":[[2026,8,13]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgag157","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,4,10]]}}}