{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:07:51Z","timestamp":1740136071805,"version":"3.37.3"},"reference-count":7,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD093622"],"award-info":[{"award-number":["R01HD093622"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To determine whether high-dose GH can overcome GH resistance in this specific patient resulting in normal insulin-like growth factor (IGF)-1 levels and improved growth rates.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Single patient trial of ascending doses of GH followed by a dose stable phase: total 12 months of treatment. The patient has a heterozygous variant in the GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. Daily subcutaneous GH was administered, starting at 50\u2005\u00b5g\/kg\/day and escalating to 250\u2005\u00b5g\/kg\/day until goal IGF-1 achieved. The subject continued on 250\u2005\u00b5g\/kg\/day for a total treatment duration of 12 months. The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the midpoint of the normal range. Secondary endpoints included height velocity and the change in height SDS during the first year of treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A dose of GH of 250\u2005\u00b5g\/kg\/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7\u2005cm\/year, an increase of 3.4\u2005cm\/year from baseline, resulting in a 0.81 SD gain in height.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgae244","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T09:39:39Z","timestamp":1712741979000},"page":"2937-2942","source":"Crossref","is-referenced-by-count":0,"title":["A Clinical Trial of High-Dose Growth Hormone in a Patient With a Dominant-Negative Growth Hormone Receptor Mutation"],"prefix":"10.1210","volume":"109","author":[{"given":"Nadia","family":"Merchant","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Children\u2019s National Hospital , Washington, DC 20010 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Houchin","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Levine Children's Hospital, Atrium Health , Charlotte, NC 28203 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly","family":"Boucher","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Children\u2019s National Hospital , Washington, DC 20010 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4890-0262","authenticated-orcid":false,"given":"Andrew","family":"Dauber","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Children\u2019s 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":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"issue":"2","key":"2024101600050862700_dgae244-B1","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1210\/er.2018-00146","article-title":"Nonclassical GH insensitivity: characterization of mild abnormalities of GH action","volume":"40","author":"Storr","year":"2019","journal-title":"Endocr Rev"},{"issue":"4","key":"2024101600050862700_dgae244-B2","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1210\/js.2016-1119","article-title":"Novel dominant-negative GH receptor mutations expands the Spectrum of GHI and IGF-I deficiency","volume":"1","author":"Vairamani","year":"2017","journal-title":"J Endocr Soc"},{"issue":"4","key":"2024101600050862700_dgae244-B3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/cen.14148","article-title":"Severe growth failure associated with a novel heterozygous nonsense mutation in the GHR transmembrane domain leading to elevated growth hormone binding protein","volume":"92","author":"Rughani","year":"2020","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"2","key":"2024101600050862700_dgae244-B4","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1210\/jc.2007-1581","article-title":"Height velocity targets from the national cooperative growth study for first-year growth hormone responses in short children","volume":"93","author":"Bakker","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2024101600050862700_dgae244-B5","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1159\/000371798","article-title":"Effectiveness and safety of rhIGF-1 therapy in children: the European increlex\u00ae growth forum database experience","volume":"83","author":"Bang","year":"2015","journal-title":"Horm Res Paediatr"},{"issue":"7","key":"2024101600050862700_dgae244-B6","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/ng1379","article-title":"A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone","volume":"36","author":"Dos Santos","year":"2004","journal-title":"Nat Genet"},{"issue":"10","key":"2024101600050862700_dgae244-B7","doi-asserted-by":"crossref","first-page":"3721","DOI":"10.1210\/jc.2009-0425","article-title":"Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: a systematic review and meta-analysis","volume":"94","author":"Wassenaar","year":"2009","journal-title":"J Clin Endocrinol Metab"}],"container-title":["The Journal of Clinical Endocrinology &amp; 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