{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T02:19:49Z","timestamp":1786760389556,"version":"build-2736575974"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"5","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,5]]},"abstract":"\nBackground<\/jats:title>\nPatients with homozygous intronic pseudoexon GH receptor (GHR<\/jats:italic>) mutations (6\u03a8) have growth hormone insensitivity (GHI) (growth failure, IGF1 deficiency and normal\/elevated serum GH). We report 9 patients in addition to previously described 11 GHR<\/jats:italic> 6\u03a8 patients and their responses to rhIGF1 therapy.<\/jats:p>\n<\/jats:sec>\n\nMethods<\/jats:title>\n20 patients (12 males, 11 families, mean age 4.0\u2009\u00b1\u20092.2 years) were diagnosed genetically in our centre. Phenotypic data and responses to rhIGF1 treatment were provided by referring clinicians. Continuous parametric variables were compared using Student t<\/jats:italic>-test or ANOVA.<\/jats:p>\n<\/jats:sec>\n\nResults<\/jats:title>\n10\/20 (50%) had typical facial features of GHI, 19\/20 (95%) from consanguineous families and 18\/20 (90%) of Pakistani origin. At diagnosis, mean height SDS: \u22124.1\u2009\u00b1\u20090.95, IGF1 SDS: \u22122.8\u2009\u00b1\u20091.4; IGFBP3 SDS: \u22123.0\u2009\u00b1\u20092.1 and mean basal and peak GH levels: 11.9\u2009\u00b5g\/L and 32.9\u2009\u00b5g\/L, respectively. 1\/12 who had IGF1 generation test, responded (IGF1: 132\u2013255\u2009ng\/mL). 15\/20 (75%; 11M) received rhIGF1 (mean dose: 114\u2009\u00b5g\/kg twice daily, mean duration: 5.3\u2009\u00b1\u20092.5 years). Mean baseline height velocity of 4.7\u2009\u00b1\u20091.1\u2009cm\/year increased to 7.4\u2009\u00b1\u20091.8\u2009cm\/year (P<\/jats:italic>\u2009=\u20090.001) during year 1 of therapy. Year 3 mean height SDS (\u22123.2\u2009\u00b1\u20091.0) was higher than pre-treatment height SDS (\u22124.3\u2009\u00b1\u20090.8) (P<\/jats:italic>\u2009=\u20090.03). Mean cumulative increase in height SDS after year 5 was 1.4\u2009\u00b1\u20090.9. Difference between target height (TH) SDS and adult or latest height SDS was less than that of TH SDS and pre-treatment height SDS (2.1\u2009\u00b1\u20091.2 vs 3.0\u2009\u00b1\u20090.8; P<\/jats:italic>\u2009=\u20090.02).<\/jats:p>\n<\/jats:sec>\n\nConclusion<\/jats:title>\nIn addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6\u03a8 GHR<\/jats:italic> mutations. rhIGF1 treatment improved height outcomes.<\/jats:p>\n<\/jats:sec>","DOI":"10.1530\/eje-18-0042","type":"journal-article","created":{"date-parts":[[2018,3,3]],"date-time":"2018-03-03T01:25:34Z","timestamp":1520040334000},"page":"481-489","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":16,"title":["Phenotypic spectrum and responses to recombinant human IGF1 (rhIGF1) therapy in patients with homozygous intronic pseudoexon growth hormone receptor mutation"],"prefix":"10.1093","volume":"178","author":[{"given":"Sumana","family":"Chatterjee","sequence":"first","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Shapiro","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J","family":"Rose","sequence":"additional","affiliation":[{"name":"2Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talat","family":"Mushtaq","sequence":"additional","affiliation":[{"name":"3The Leeds Teaching Hospital NHS Trust, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter E","family":"Clayton","sequence":"additional","affiliation":[{"name":"4Royal Manchester Children\u2019s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana B","family":"Ten","sequence":"additional","affiliation":[{"name":"5Maimonides Pediatric Specialty Center, Brooklyn, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrit","family":"Bhangoo","sequence":"additional","affiliation":[{"name":"6CHOC Children\u2019s Clinic, Orange, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Kumbattae","sequence":"additional","affiliation":[{"name":"7Royal Stoke University Hospital, Stoke-on-Trent, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renuka","family":"Dias","sequence":"additional","affiliation":[{"name":"8Birmingham Children\u2019s Hospital, Birmingham, UK"},{"name":"9Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin O","family":"Savage","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise A","family":"Metherell","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen L","family":"Storr","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"key":"ref741","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1159\/000184637","article-title":"Insulin-like growth factor I improves height in growth hormone insensitivity: two years\u2019 results","volume":"44","year":"1995","journal-title":"Hormone Research"},{"key":"ref191","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1136\/adc.44.235.291","article-title":"Variations in pattern of pubertal changes in girls","volume":"44","year":"1969","journal-title":"Archives of Disease in Childhood"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1136\/adc.73.1.17","article-title":"Cross sectional stature and weight reference curves for the 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trafficking rather than impaired signalling","volume":"188","year":"2006","journal-title":"Journal of Endocrinology"},{"key":"ref81","first-page":"1","article-title":"Genetic defects in the growth hormone-IGF1 axis causing growth hormone insensitivity and impaired linear growth","volume":"2","year":"2011","journal-title":"Frontiers in Endocrinology"},{"key":"ref171","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1210\/jc.2006-1527","article-title":"An intronic growth hormone receptor mutation causing activation of a pseudoexon is associated with a broad spectrum of growth hormone insensitivity phenotypes","volume":"92","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref431","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1056\/NEJMoa013100","article-title":"Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene","volume":"350","year":"2004","journal-title":"New England Journal of Medicine"},{"key":"ref541","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1677\/joe.1.06252","article-title":"A 36 residues insertion in the dimerization domain of the growth hormone receptor results in defective trafficking rather than impaired signalling","volume":"188","year":"2006","journal-title":"Journal of Endocrinology"},{"key":"ref181","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1136\/adc.45.239.13","article-title":"Variations in the pattern of pubertal changes in boys","volume":"45","year":"1970","journal-title":"Archives of Disease in Childhood"},{"key":"ref691","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1159\/000049983","article-title":"Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome","volume":"55","year":"2001","journal-title":"Hormone Research"},{"key":"ref291","first-page":"4436","article-title":"Growth hormone receptor deficiency in Ecuador","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref231","first-page":"117","article-title":"Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls. Pharmacia Study Group on Insulin-like Growth Factor I Treatment in Growth Hormone Insensitivity Syndromes","volume":"399","year":"1994","journal-title":"Acta Paediatrica Supplement"},{"key":"ref631","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1210\/jc.2003-031033","article-title":"Laron syndrome (primary growth hormone resistance or insensitivity): the Personal Experience 1958\u20132003","volume":"89","year":"2004","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref621","first-page":"128","article-title":"The insulin-like growth factor I generation test in the investigation of short stature","volume":"399","year":"1994","journal-title":"Acta Paediatrica Supplement"},{"key":"ref481","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1210\/edrv-15-3-369","article-title":"Growth hormone (GH) insensitivity due to primary GH receptor deficiency","volume":"15","year":"1994","journal-title":"Endocrine Reviews"},{"key":"ref351","first-page":"1504","article-title":"Therapy for 6.5\u20137.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: a clinical research center study","volume":"86","year":"2001","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref531","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1086\/323266","article-title":"Pseudoexon activation as a novel mechanism for disease resulting in a typical growth hormone insensitivity","volume":"69","year":"2001","journal-title":"American Journal of Human Genetics"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"363","DOI":"10.15252\/emmm.201506106","article-title":"Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability","volume":"8","year":"2016","journal-title":"EMBO Molecular Medicine"},{"key":"ref311","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1159\/000049983","article-title":"Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome","volume":"55","year":"2001","journal-title":"Hormone Research"},{"key":"ref681","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s40618-015-0327-2","article-title":"Growth Hormone Insensitivity: diagnostic and therapeutic approaches","volume":"39","year":"2016","journal-title":"Journal of Endocrinological Investigation"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1056\/NEJMoa013100","article-title":"Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene","volume":"350","year":"2004","journal-title":"New England Journal of Medicine"},{"key":"ref391","doi-asserted-by":"crossref","first-page":"8083","DOI":"10.1073\/pnas.86.20.8083","article-title":"Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism","volume":"86","year":"1989","journal-title":"PNAS"},{"key":"ref321","first-page":"149","article-title":"Three year IGF-I treatment of children with Laron syndrome","volume":"8","year":"1995","journal-title":"Journal of Pediatric Endocrinology and Metabolism"},{"key":"ref491","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/ncpendmet0195","article-title":"Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders","volume":"2","year":"2006","journal-title":"Nature Clinical Practice. 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growth hormone insensitivity syndrome","volume":"91","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/ng0597-13","article-title":"A dominant-negative mutation of the growth hormone receptor causes familial short stature","volume":"16","year":"1997","journal-title":"Nature Genetics"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJM198910123211501","article-title":"Laron dwarfism and mutations of the growth hormone-receptor gene","volume":"321","year":"1989","journal-title":"New England Journal of Medicine"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1056\/NEJMoa022926","article-title":"Growth hormone insensitivity associated with a STAT5b mutation","volume":"349","year":"2003","journal-title":"New England Journal of 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