{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:01:21Z","timestamp":1791511281099,"version":"4.3.4"},"reference-count":72,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Leiden University Fund","award":["W223067-2-1"],"award-info":[{"award-number":["W223067-2-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>The growth hormone (GH) secretagogue receptor, encoded by GHSR, is expressed on somatotrophs of the pituitary gland. Stimulation with its ligand ghrelin, as well as its constitutive activity, enhances GH secretion. Studies in knockout mice suggest that heterozygous loss-of-function of GHSR is associated with decreased GH response to fasting, but patient observations in small case reports have been equivocal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This work aims to establish the phenotype of GHSR haploinsufficiency and its growth response to GH treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This case series includes 26 patients with short stature and heterozygous GHSR variants. Pathogenicity was studied in vitro using total protein levels, cell surface expression, and receptor activity in basal, stimulated, and inhibited states.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Ten different variants were identified, of which 6 were novel. Variants showed either partial or complete loss of function, primarily through loss of constitutive activity. Patients (aged 4.0-15.1 years) had proportionate short stature (height \u22122.8 \u00b1 0.5 SDS), failure to thrive with low appetite (n = 4), a mean serum insulin-like growth factor-I (IGF-I) of \u22121.6 \u00b1 0.7 SDS, and a normal stimulated GH response. Nine patients received GH treatment, showing a height gain of 0.9 \u00b1 0.4 SDS after 1 year and 1.5 \u00b1 0.4 SDS after 2 years (n = 5).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study combines phenotypical and functional data in a uniquely large group of children with short stature carrying GHSR variants, and shows their good response to GH treatment. The results strengthen the hypothesis of GHSR's role in GH secretion.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgaf010","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T07:15:04Z","timestamp":1736320504000},"page":"e1303-e1314","source":"Crossref","is-referenced-by-count":15,"title":["Loss-of-Function\n                    <i>GHSR<\/i>\n                    Variants Are Associated With Short Stature and Low IGF-I"],"prefix":"10.1210","volume":"110","author":[{"given":"Lauren D","family":"Punt","sequence":"first","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0014-5571","authenticated-orcid":false,"given":"Sander","family":"Kooijman","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noa J M","family":"Mutsters","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam , 3015 GD Rotterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiming","family":"Yue","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dani\u00eblle C M","family":"van der Kaay","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Erasmus University Medical Centre, Sophia Children's Hospital , 3015 GD Rotterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"van Tellingen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Catharina Hospital , 5623 EJ Eindhoven ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willie M","family":"Bakker-van Waarde","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, University Medical Centre Groningen, University of Groningen , 9713 GZ Groningen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemiek M","family":"Boot","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, University Medical Centre Groningen, University of Groningen , 9713 GZ Groningen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5352-9328","authenticated-orcid":false,"given":"Erica L T","family":"van den Akker","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Erasmus University Medical Centre, Sophia Children's Hospital , 3015 GD Rotterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke A","family":"van Boekholt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, VieCuri Medical Centre , 5912 BL Venlo ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"de Groote","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne R","family":"Kruijsen","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy H G","family":"van Nieuwaal-van Maren","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Gelderse Vallei Hospital , 6716 RP Ede ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Claire","family":"Woltering","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Reinier de Graaf Gasthuis , 2625 AD Delft ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malou","family":"Heijligers","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Maastricht University Medical Centre , 6229 HX Maastricht ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josine C","family":"van der Heyden","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Franciscus Gasthuis & Vlietland , 3045 PM Rotterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M N","family":"Bannink","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tergooi MC , 1212 VG Hilversum ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4350-8106","authenticated-orcid":false,"given":"Tuula","family":"Rinne","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud UMC , 6525 GA Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine E","family":"Hannema","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Amsterdam UMC, location Vrije Universiteit , 1081 HV Amsterdam ,","place":["the Netherlands"]},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism , 1081 HV Amsterdam ,","place":["the Netherlands"]},{"name":"Amsterdam Reproduction and Development , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter J","family":"de Waal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Diakonessenhuis , 3582 KE Utrecht ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia C","family":"Delemarre","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Amstelland Hospital , 1186 AM Amstelveen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-4988","authenticated-orcid":false,"given":"Patrick C N","family":"Rensen","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiaan","family":"de Bruin","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermine A","family":"van Duyvenvoorde","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Centre , 2333 ZA Leiden ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7182-3571","authenticated-orcid":false,"given":"Jenny A","family":"Visser","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam , 3015 GD Rotterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patric J D","family":"Delhanty","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical 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