{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:26:58Z","timestamp":1790864818623,"version":"4.1.0"},"reference-count":164,"publisher":"Oxford University Press (OUP)","issue":"2","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:p>Twenty years ago, we described kindred of 105 individuals with isolated GH deficiency (IGHD) in Itabaianinha County, in northeast Brazil, carrying a homozygous mutation in the GH-releasing hormone receptor gene. These subjects exhibit markedly reduced GH responsiveness to stimulatory tests, and anterior pituitary hypoplasia. Serum concentrations of IGF-I, IGF binding protein type 3 and the acid-labile subunit are markedly reduced, with a lesser reduction of IGF-II. The most striking physical findings of these IGHD individuals are the proportionate short stature, doll facies, high-pitched voice and visceral obesity with reduced fat-free mass. There is neither microphallus, nor neonatal hypoglycemia. Puberty is delayed, menopause anticipated, but fertility is preserved in both genders. The reduction in bone sizes is not even, with mean standard deviation scores for height of \u22127.2, total maxillary length of \u22126.5, total facial height of \u22124.3 and cephalic perimeter of \u22122.7. In addition, the non-osseous growth is not uniform, preserving some organs, like pancreas, liver, kidney, brain and eyes, and compromising others such as thyroid, heart, uterus and spleen. These subjects present higher prevalence of dizziness, mild high-tones sensorineural hearing loss, reduction of vascular retinal branching points, increase of optic disk, genu valgum and increased systolic blood pressure. Biochemically, they have high low density lipoprotein cholesterol and C-reactive protein levels, but maintain increased insulin sensitivity, and do not show premature atherosclerosis. Finally, they have normal immune function, and normal longevity. This review details the findings and summarizes 20 years of clinical research carried out in this unique population.<\/jats:p>","DOI":"10.1530\/eje-16-1047","type":"journal-article","created":{"date-parts":[[2017,4,21]],"date-time":"2017-04-21T00:25:37Z","timestamp":1492734337000},"page":"R85-R97","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":51,"title":["MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH\/GH\/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation"],"prefix":"10.1093","volume":"177","author":[{"given":"Manuel H","family":"Aguiar-Oliveira","sequence":"first","affiliation":[{"name":"1Division of Endocrinology, Federal University of Sergipe, Aracaju, Sergipe, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita H O","family":"Souza","sequence":"additional","affiliation":[{"name":"1Division of Endocrinology, Federal University of Sergipe, Aracaju, Sergipe, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla R P","family":"Oliveira","sequence":"additional","affiliation":[{"name":"1Division of Endocrinology, Federal University of Sergipe, Aracaju, Sergipe, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviane C","family":"Campos","sequence":"additional","affiliation":[{"name":"1Division of Endocrinology, Federal University of Sergipe, Aracaju, Sergipe, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u00edz A","family":"Oliveira-Neto","sequence":"additional","affiliation":[{"name":"1Division of Endocrinology, Federal University of Sergipe, Aracaju, Sergipe, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Salvatori","sequence":"additional","affiliation":[{"name":"2Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"key":"ref1251","first-page":"70ra13","article-title":"Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans","volume":"3","year":"2011","journal-title":"Science Translational Medicine"},{"key":"ref1431","first-page":"341","article-title":"Growth hormone (GH) insensitivity due to primary GH receptor deficiency","volume":"15","year":"1994","journal-title":"Endocrine Reviews"},{"key":"ref161","first-page":"4671","article-title":"Molecular and clinical aspects of GHRH receptor mutations","volume":"24","year":"2013","journal-title":"Endocrine Development"},{"key":"ref211","first-page":"4065","article-title":"Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins, and terna complex formation throughout life","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1111","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.1210\/jc.2014-2132","article-title":"Increased visceral adiposity and cortisol to cortisone ratio in adults with congenital lifetime isolated GH deficiency","volume":"99","year":"2014","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref941","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1210\/edrv-8-4-426","article-title":"Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth","volume":"8","year":"1987","journal-title":"Endocrine Reviews"},{"key":"ref1541","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1210\/jc.2012-4059","article-title":"Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality","volume":"98","year":"2013","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref911","first-page":"1734","article-title":"Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone","volume":"6","year":"1992","journal-title":"Molecular Endocrinology"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1073\/pnas.82.1.63","article-title":"Gene encoding human growth hormone-releasing factor precursor: structure, sequence, and chromosomal assignment","volume":"82","year":"1985","journal-title":"PNAS"},{"key":"ref381","first-page":"2699","article-title":"Hearing status in adult individuals with lifetime, untreated isolated growth hormone deficiency","volume":"150","year":"2014","journal-title":"Otolaryngology Head and Neck Surgery"},{"key":"ref971","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/ng0793-227","article-title":"GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function","volume":"4","year":"1993","journal-title":"Nature Genetics"},{"key":"ref1181","first-page":"451","article-title":"Sexual development in patients with laron syndrome","volume-title":"Laron Syndrome from Man to Mouse: Lessons from Clinical Experience","year":"2011"},{"key":"ref1371","first-page":"1013","article-title":"Liver status in congenital, untreated, isolated GH deficiency","volume":"3","year":"2014","journal-title":"Endocrine Connections"},{"key":"ref1511","first-page":"35","article-title":"Sizes of abdominal organs in adults with severe short stature due to severe, untreated, congenital GH deficiency caused by a homozygous mutation in the GHRH receptor gene","volume":"69","year":"2008","journal-title":"Clinical Endocrinology"},{"key":"ref671","first-page":"35","article-title":"Sizes of abdominal organs in adults with severe short stature due to severe, untreated, congenital GH deficiency caused by a homozygous mutation in the GHRH receptor gene","volume":"69","year":"2008","journal-title":"Clinical Endocrinology"},{"key":"ref1331","first-page":"41","article-title":"Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification","volume":"47","year":"2014","journal-title":"Endocrine"},{"key":"ref1401","first-page":"182","article-title":"Periodontal disease in adults with untreated congenital growth hormone deficiency: a case-control study","volume":"38","year":"2011","journal-title":"Journal of Clinical Periodontology"},{"key":"ref1071","first-page":"1958","article-title":"Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 4118\u20134126","volume":"89","year":"2004","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1591","first-page":"4664","article-title":"Arrest of atherosclerosis progression after interruption of GH replacement in adults with congenital isolated GH deficiency","volume":"166","year":"2012","journal-title":"European Journal of Endocrinology"},{"key":"ref1491","first-page":"657","article-title":"Pereira F de A, Oliveira CR, Pereira RM, Farias CT, Vicente TA & Salvatori R. Consequences of lifetime isolated growth hormone (GH) deficiency and effects of short-term GH treatment on bone in adults with a mutation in the GHRH-receptor gene","volume":"70","year":"2009","journal-title":"Clinical Endocrinology"},{"key":"ref151","first-page":"4671","article-title":"The discovery of growth hormone releasing hormone","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref591","first-page":"341","article-title":"Growth hormone (GH) insensitivity due to primary GH receptor deficiency","volume":"15","year":"1994","journal-title":"Endocrine Reviews"},{"key":"ref1201","first-page":"101","article-title":"Quality of life in congenital, untreated, lifetime isolated growth hormone deficiency","volume":"34","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"ref1281","first-page":"559","article-title":"Familial isolated growth hormone deficiency is associated with increased systolic blood pressure, central obesity, and dyslipidemia","volume":"87","year":"2002","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref661","doi-asserted-by":"publisher","first-page":"201398","DOI":"10.1210\/jc.2013-2349","article-title":"GH deficiency due to a GHRH receptor mutation causes hip joint problems and genu valgum reduces size but not density of trabecular and mixed bone of and","author":"Epit\u00e1cio","journal-title":"Journal Clinical Endocrinology Metabolism"},{"key":"ref901","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1073\/pnas.82.1.63","article-title":"Gene encoding human growth hormone-releasing factor precursor: structure, sequence, and chromosomal assignment","volume":"82","year":"1985","journal-title":"PNAS"},{"key":"ref321","first-page":"427","article-title":"Magnetic resonance imaging study of pituitary morphology in subjects homozygous and heterozygous for a null mutation of the GHRH receptor gene","volume":"148","year":"2003","journal-title":"European Journal of Endocrinology"},{"key":"ref1061","first-page":"1465","article-title":"Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome)","volume":"77","year":"1993","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref301","first-page":"558","article-title":"Prolactin and sex steroids levels in congenital lifetime isolated GH deficiency","volume":"44","year":"2013","journal-title":"Endocrine"},{"key":"ref511","first-page":"714","article-title":"Adipokine profile and urinary albumin excretion in isolated growth hormone deficiency","volume":"95","year":"2010","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref761","first-page":"977","article-title":"Effects of depot growth hormone replacement on thyroid function and volume in adults with congenital isolated growth hormone deficiency","volume":"35","year":"2012","journal-title":"Journal of Endocrinological Investigation"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/300276a0","article-title":"Vale W Characterization of a growth hormone-releasing factor from a human pancreatic islet tumor","volume":"300","year":"1982","journal-title":"Nature"},{"key":"ref451","first-page":"2018","article-title":"Subjects with isolated GH deficiency due to a null GH RHR mutation eat proportionally more, but healthier than controls","volume":"51","year":"2016","journal-title":"Endocrine"},{"key":"ref1651","first-page":"956","article-title":"Selective lack of growth hormone (GH) response to the gh-releasing peptide hexarelin in patients with GH-releasing hormone receptor deficiency","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1101","first-page":"3279","article-title":"Molecular basis of familial growth hormone deficiency","volume":"42","year":"1994","journal-title":"Hormone Research"},{"key":"ref1241","first-page":"11","article-title":"Lifetime congenital isolated GH deficiency does not protect from the development of diabetes","volume":"15","year":"2013","journal-title":"Endocrine Connections"},{"key":"ref1611","first-page":"265","article-title":"Heterozygosity for a mutation in the growth hormone-releasing hormone receptor gene does not influence adult stature, but affects body composition","volume":"92","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1031","first-page":"286","article-title":"The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene","volume":"423","year":"1997","journal-title":"Acta Paediatric Supplement"},{"key":"ref181","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1159\/000342760","article-title":"GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects","volume":"78","year":"2012","journal-title":"Hormone Research in Paediatrics"},{"key":"ref131","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/ng0793-227","article-title":"GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function","volume":"4","year":"1993","journal-title":"Nature Genetics"},{"key":"ref461","first-page":"317","article-title":"Lipid profiles in untreated severe congenital isolated growth hormone deficiency through the lifespan","volume":"57","year":"2002","journal-title":"Clinical Endocrinology"},{"key":"ref991","first-page":"4671","article-title":"The discovery of growth hormone releasing hormone","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref261","first-page":"3279","article-title":"Molecular basis of familial growth hormone deficiency","volume":"42","year":"1994","journal-title":"Hormone Research"},{"key":"ref1601","first-page":"977","article-title":"Effects of depot growth hormone replacement on thyroid function and volume in adults with congenital isolated growth hormone deficiency","volume":"35","year":"2012","journal-title":"Journal of Endocrinological Investigation"},{"key":"ref1141","first-page":"558","article-title":"Prolactin and sex steroids levels in congenital lifetime isolated GH deficiency","volume":"44","year":"2013","journal-title":"Endocrine"},{"key":"ref1641","doi-asserted-by":"publisher","first-page":"2002282","DOI":"10.1152\/ajpendo.00537.2001","article-title":"Pulsatile growth hormone secretion persists in genetic growth hormone - releasing hormone resistance of and","journal-title":"American Journal Physiology Endocrinology Metabolism"},{"key":"ref741","first-page":"466","article-title":"Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults","volume":"92","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref191","first-page":"286","article-title":"The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene","volume":"423","year":"1997","journal-title":"Acta Paediatric Supplement"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1172\/JCI109658","article-title":"Partial purification and characterization of a peptide with growth hormone-releasing activity from extra pituitary tumors in patients with acromegaly","volume":"65","year":"1980","journal-title":"Journal of Clinical Investigation"},{"key":"ref281","first-page":"189","article-title":"Type IA isolated growth hormone deficiency (IGHD) consistent with compound heterozygous deletions of6.7 and 7.6 Kb at the GH1 gene locus","volume":"56","year":"2012","journal-title":"Archives of Endocrinology and Metabolism"},{"key":"ref1301","first-page":"317","article-title":"Lipid profiles in untreated severe congenital isolated growth hormone deficiency through the lifespan","volume":"57","year":"2002","journal-title":"Clinical Endocrinology"},{"key":"ref1271","first-page":"112","article-title":"Serum leptin and body composition in children with familial GH deficiency (GHD) due to a mutation in the growth hormone-releasing hormone (GHRH) receptor","volume":"51","year":"1999","journal-title":"Clinical Endocrinology"},{"key":"ref371","first-page":"894","article-title":"Lifetime growth hormone deficiency: impact on growth, metabolism, body composition, and survival capacity","year":"2012","journal-title":"Handbook of Growth and Growth Monitoring in Health and Disease"},{"key":"ref571","first-page":"175","article-title":"Low serum levels of IGF-1, BP3 and ALS are associated to severe short stature, obesity premature aging, increased cardiovascular mortality and absence of cancer in the Ecuadorian cohort of Laron syndrome subjects","volume":"68","year":"2007","journal-title":"Hormone Research"},{"key":"ref771","first-page":"265","article-title":"Heterozygosity for a mutation in the growth hormone-releasing hormone receptor gene does not influence adult stature, but affects body composition","volume":"92","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1121","first-page":"189","article-title":"Type IA isolated growth hormone deficiency (IGHD) consistent with compound heterozygous deletions of6.7 and 7.6 Kb at the GH1 gene locus","volume":"56","year":"2012","journal-title":"Archives of Endocrinology and Metabolism"},{"key":"ref731","first-page":"153","article-title":"Metabolic effects of growth hormone (GH) replacement in children and adolescents with severe isolated GH deficiency due to a GHRH receptor mutation","volume":"66","year":"2007","journal-title":"Clinical Endocrinology"},{"key":"ref1581","first-page":"466","article-title":"Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults","volume":"92","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref271","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.1210\/jc.2014-2132","article-title":"Increased visceral adiposity and cortisol to cortisone ratio in adults with congenital lifetime isolated GH deficiency","volume":"99","year":"2014","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref221","first-page":"1465","article-title":"Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome)","volume":"77","year":"1993","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref801","doi-asserted-by":"publisher","first-page":"2002282","DOI":"10.1152\/ajpendo.00537.2001","article-title":"Pulsatile growth hormone secretion persists in genetic growth hormone - releasing hormone resistance of and","journal-title":"American Journal Physiology Endocrinology Metabolism"},{"key":"ref1501","doi-asserted-by":"publisher","first-page":"201398","DOI":"10.1210\/jc.2013-2349","article-title":"GH deficiency due to a GHRH receptor mutation causes hip joint problems and genu valgum reduces size but not density of trabecular and mixed bone of and","author":"Epit\u00e1cio","journal-title":"Journal Clinical Endocrinology Metabolism"},{"key":"ref1001","first-page":"4671","article-title":"Molecular and clinical aspects of GHRH receptor mutations","volume":"24","year":"2013","journal-title":"Endocrine Development"},{"key":"ref701","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1210\/jc.2012-4059","article-title":"Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality","volume":"98","year":"2013","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref891","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/300276a0","article-title":"Vale W Characterization of a growth hormone-releasing factor from a human pancreatic islet tumor","volume":"300","year":"1982","journal-title":"Nature"},{"key":"ref781","first-page":"2353","article-title":"The consequences of growth hormone-releasing hormone receptor haploinsufficiency for bone quality and insulin resistance","volume":"77","year":"2012","journal-title":"Clinical Endocrinology"},{"key":"ref1471","first-page":"13","article-title":"Voice formants in individuals with congenital, isolated, lifetime growth hormone deficiency","volume":"30","year":"2016","journal-title":"Journal of Voice"},{"key":"ref561","first-page":"182","article-title":"Periodontal disease in adults with untreated congenital growth hormone deficiency: a case-control study","volume":"38","year":"2011","journal-title":"Journal of Clinical Periodontology"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1530\/EJE-16-0357","volume":"175","year":"2016","journal-title":"European Journal of Endocrinology"},{"key":"ref1131","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1210\/jc.2005-2555","article-title":"Thyroid morphology and function in adults with untreated isolated growth hormone deficiency","volume":"91","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref501","first-page":"191","article-title":"Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene","volume":"95","year":"2010","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref01","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1210\/jc.2008-2783","article-title":"Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency","volume":"94","year":"2009","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref931","first-page":"435","article-title":"Ghrelin \u2013 a new endogenous growth hormone secretagogue","volume":"51","year":"2002","journal-title":"Physiological Research"},{"key":"ref1231","first-page":"464","article-title":"Abnormal vascular and neural retinal morphology in congenital lifetime isolated growth hormone deficiency","volume":"27","year":"2016","journal-title":"Growth Hormone and IGF Research"},{"key":"ref841","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1210\/jc.2008-2783","article-title":"Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency","volume":"94","year":"2009","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref331","first-page":"743","article-title":"Histopathology of the pituitary gland in neonatal little (lit) mutant mice","volume":"7","year":"1992","journal-title":"Histology and Histopathology"},{"key":"ref711","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1210\/jc.2002-021938","article-title":"Reduced longevity in untreated patients with isolated growth hormone deficiency","volume":"88","year":"2003","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1126\/science.6812220","article-title":"Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly","volume":"218","year":"1982","journal-title":"Science"},{"key":"ref11","first-page":"917","article-title":"Familial isolated growth hormone deficiency due to a novel mutation in the growth hormone releasing hormone receptor","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref91","first-page":"435","article-title":"Ghrelin \u2013 a new endogenous growth hormone secretagogue","volume":"51","year":"2002","journal-title":"Physiological Research"},{"key":"ref1361","first-page":"693","article-title":"Insulin sensitivity and \u03b2-cell function in adults with lifetime, untreated isolated growth hormone deficiency","volume":"97","year":"2012","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1441","doi-asserted-by":"crossref","first-page":"578","DOI":"10.2319\/102210-618.1","article-title":"Cephalometric features in isolated growth hormone deficiency","volume":"81","year":"2011","journal-title":"Angle Orthodontist"},{"key":"ref1671","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1210\/jc.2002-021120","article-title":"The impact of congenital, severe, untreated growth hormone (GH) deficiency on bone size and density in young adults: insights from genetic gh-releasing hormone receptor deficiency","volume":"88","year":"2003","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/45230","article-title":"Ghrelin is a growth-hormone-releasing acylated peptide from stomach","volume":"402","year":"1999","journal-title":"Nature"},{"key":"ref491","first-page":"41","article-title":"Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification","volume":"47","year":"2014","journal-title":"Endocrine"},{"key":"ref1291","first-page":"2018","article-title":"Subjects with isolated GH deficiency due to a null GH RHR mutation eat proportionally more, but healthier than controls","volume":"51","year":"2016","journal-title":"Endocrine"},{"key":"ref1481","first-page":"281","article-title":"Pathophysiological and clinical importance of insulin-like growth factor-I with respect to bone metabolism","volume":"52","year":"2003","journal-title":"Physiological Research"},{"key":"ref1261","first-page":"103","article-title":"Diabetic retinopathy in two patients with congenital IGFI deficiency (Laron syndrome)","volume":"151","year":"2004","journal-title":"European Journal of Endocrinology"},{"key":"ref71","first-page":"1734","article-title":"Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone","volume":"6","year":"1992","journal-title":"Molecular Endocrinology"},{"key":"ref1561","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1210\/jc.2016-2118","article-title":"Hormonal replacement in hypopituitarism in adults: an Endocrine Society Clinical Practice Guideline","volume":"101","year":"2016","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref471","first-page":"89","article-title":"Lack of evidence of premature atherosclerosis in untreated severe isolated growth hormone (GH) deficiency due to a GH-releasing hormone receptor mutation","volume":"91","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref341","first-page":"451","article-title":"Sexual development in patients with laron syndrome","volume-title":"Laron Syndrome from Man to Mouse: Lessons from Clinical Experience","year":"2011"},{"key":"ref681","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.exger.2009.04.001","article-title":"The somatotropic axis and aging: mechanisms and persistent questions about practical implications","volume":"44","year":"2009","journal-title":"Experimental Gerontology"},{"key":"ref1221","first-page":"2699","article-title":"Hearing status in adult individuals with lifetime, untreated isolated growth hormone deficiency","volume":"150","year":"2014","journal-title":"Otolaryngology Head and Neck Surgery"},{"key":"ref1531","first-page":"285","article-title":"Premature mortality due to cardiovascular disease in hypopituitarism","volume":"336","year":"1999","journal-title":"Lancet"},{"key":"ref921","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/45230","article-title":"Ghrelin is a growth-hormone-releasing acylated peptide from stomach","volume":"402","year":"1999","journal-title":"Nature"},{"key":"ref1151","first-page":"207","article-title":"Climacteric in untreated isolated growth hormone deficiency","volume":"15","year":"2008","journal-title":"Menopause"},{"key":"ref431","first-page":"112","article-title":"Serum leptin and body composition in children with familial GH deficiency (GHD) due to a mutation in the growth hormone-releasing hormone (GHRH) receptor","volume":"51","year":"1999","journal-title":"Clinical Endocrinology"},{"key":"ref1161","first-page":"427","article-title":"Magnetic resonance imaging study of pituitary morphology in subjects homozygous and heterozygous for a null mutation of the GHRH receptor gene","volume":"148","year":"2003","journal-title":"European Journal of Endocrinology"},{"key":"ref1021","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1159\/000342760","article-title":"GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects","volume":"78","year":"2012","journal-title":"Hormone Research in Paediatrics"},{"key":"ref171","first-page":"106","article-title":"Unusual phenotypic features in a patient with a novel splice mutation in the GHRHR gene","volume":"14","year":"2008","journal-title":"Molecular Medicine"},{"key":"ref1041","first-page":"33","article-title":"Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: Dwarfism of Sindh","volume":"83","year":"1998","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1411","first-page":"175","article-title":"Low serum levels of IGF-1, BP3 and ALS are associated to severe short stature, obesity premature aging, increased cardiovascular mortality and absence of cancer in the Ecuadorian cohort of Laron syndrome subjects","volume":"68","year":"2007","journal-title":"Hormone Research"},{"key":"ref541","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/j.1365-2265.2006.02558.x","article-title":"Body composition in untreated adult patients with Laron syndrome (primary GH insensitivity)","volume":"65","year":"2006","journal-title":"Clinical Endocrinology"},{"key":"ref481","first-page":"2093","article-title":"Brazilian adult individuals with untreated isolated GH deficiency do not have accelerated subclinical atherosclerosis","volume":"5","year":"2016","journal-title":"Endocrine Connections"},{"key":"ref1311","first-page":"89","article-title":"Lack of evidence of premature atherosclerosis in untreated severe isolated growth hormone (GH) deficiency due to a GH-releasing hormone receptor mutation","volume":"91","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1081","first-page":"1031","article-title":"GH response to hypoglycemia and clonidine in the GH-releasing hormone resistance syndrome","volume":"29","year":"2006","journal-title":"Journal of Endocrinological Investigation"},{"key":"ref311","first-page":"207","article-title":"Climacteric in untreated isolated growth hormone deficiency","volume":"15","year":"2008","journal-title":"Menopause"},{"key":"ref1191","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1056\/NEJM199610313351805","article-title":"Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene","volume":"335","year":"1996","journal-title":"New England Journal of Medicine"},{"key":"ref821","first-page":"685","article-title":"Pituitary hypoplasia in patients with a mutation in the growth hormone-releasing hormone receptor gene","volume":"21","year":"2000","journal-title":"American Journal of Neuroradiology"},{"key":"ref411","first-page":"70ra13","article-title":"Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans","volume":"3","year":"2011","journal-title":"Science Translational Medicine"},{"key":"ref361","first-page":"101","article-title":"Quality of life in congenital, untreated, lifetime isolated growth hormone deficiency","volume":"34","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"ref621","first-page":"673e37","article-title":"Voice quality in short stature with and without GH deficiency","volume":"5","year":"2012","journal-title":"Journal of Voice"},{"key":"ref751","first-page":"4664","article-title":"Arrest of atherosclerosis progression after interruption of GH replacement in adults with congenital isolated GH deficiency","volume":"166","year":"2012","journal-title":"European Journal of Endocrinology"},{"key":"ref1661","first-page":"685","article-title":"Pituitary hypoplasia in patients with a mutation in the growth hormone-releasing hormone receptor gene","volume":"21","year":"2000","journal-title":"American Journal of Neuroradiology"},{"key":"ref851","first-page":"917","article-title":"Familial isolated growth hormone deficiency due to a novel mutation in the growth hormone releasing hormone receptor","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref231","first-page":"1958","article-title":"Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 4118\u20134126","volume":"89","year":"2004","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref691","first-page":"285","article-title":"Premature mortality due to cardiovascular disease in hypopituitarism","volume":"336","year":"1999","journal-title":"Lancet"},{"key":"ref871","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1172\/JCI109658","article-title":"Partial purification and characterization of a peptide with growth hormone-releasing activity from extra pituitary tumors in patients with acromegaly","volume":"65","year":"1980","journal-title":"Journal of Clinical Investigation"},{"key":"ref1391","first-page":"132","article-title":"Infectious diseases and immunological responses in adult subjects with lifetime untreated, congenital GH deficiency","volume":"54","year":"2016","journal-title":"Endocrine"},{"key":"ref141","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/ng0196-88","article-title":"Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse","volume":"12","year":"1996","journal-title":"Nature Genetics"},{"key":"ref1461","first-page":"673e37","article-title":"Voice quality in short stature with and without GH deficiency","volume":"5","year":"2012","journal-title":"Journal of Voice"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1210\/edrv-8-4-426","article-title":"Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth","volume":"8","year":"1987","journal-title":"Endocrine Reviews"},{"key":"ref521","first-page":"693","article-title":"Insulin sensitivity and \u03b2-cell function in adults with lifetime, untreated isolated growth hormone deficiency","volume":"97","year":"2012","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref721","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1210\/jc.2016-2118","article-title":"Hormonal replacement in hypopituitarism in adults: an Endocrine Society Clinical Practice Guideline","volume":"101","year":"2016","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1341","first-page":"191","article-title":"Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene","volume":"95","year":"2010","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref241","first-page":"1031","article-title":"GH response to hypoglycemia and clonidine in the GH-releasing hormone resistance syndrome","volume":"29","year":"2006","journal-title":"Journal of Endocrinological Investigation"},{"key":"ref1051","first-page":"4065","article-title":"Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins, and terna complex formation throughout life","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref441","first-page":"559","article-title":"Familial isolated growth hormone deficiency is associated with increased systolic blood pressure, central obesity, and dyslipidemia","volume":"87","year":"2002","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1321","first-page":"2093","article-title":"Brazilian adult individuals with untreated isolated GH deficiency do not have accelerated subclinical atherosclerosis","volume":"5","year":"2016","journal-title":"Endocrine Connections"},{"key":"ref881","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1126\/science.6812220","article-title":"Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly","volume":"218","year":"1982","journal-title":"Science"},{"key":"ref401","first-page":"11","article-title":"Lifetime congenital isolated GH deficiency does not protect from the development of diabetes","volume":"15","year":"2013","journal-title":"Endocrine Connections"},{"key":"ref601","doi-asserted-by":"crossref","first-page":"578","DOI":"10.2319\/102210-618.1","article-title":"Cephalometric features in isolated growth hormone deficiency","volume":"81","year":"2011","journal-title":"Angle Orthodontist"},{"key":"ref631","first-page":"13","article-title":"Voice formants in individuals with congenital, isolated, lifetime growth hormone deficiency","volume":"30","year":"2016","journal-title":"Journal of Voice"},{"key":"ref981","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/ng0196-88","article-title":"Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse","volume":"12","year":"1996","journal-title":"Nature Genetics"},{"key":"ref811","first-page":"956","article-title":"Selective lack of growth hormone (GH) response to the gh-releasing peptide hexarelin in patients with GH-releasing hormone receptor deficiency","volume":"84","year":"1999","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1171","first-page":"743","article-title":"Histopathology of the pituitary gland in neonatal little (lit) mutant mice","volume":"7","year":"1992","journal-title":"Histology and Histopathology"},{"key":"ref1351","first-page":"714","article-title":"Adipokine profile and urinary albumin excretion in isolated growth hormone deficiency","volume":"95","year":"2010","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1091","first-page":"805","article-title":"Growth hormone-releasing peptide-2 stimulates GH secretion in GH-deficient patients with mutated GH-releasing hormone receptor","volume":"86","year":"2001","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref251","first-page":"805","article-title":"Growth hormone-releasing peptide-2 stimulates GH secretion in GH-deficient patients with mutated GH-releasing hormone receptor","volume":"86","year":"2001","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref611","first-page":"369","article-title":"Laryngeal and vocal evaluation in untreated growth hormone deficient adults","volume":"140","year":"2009","journal-title":"Otolaryngology Head and Neck Surgery"},{"key":"ref421","first-page":"103","article-title":"Diabetic retinopathy in two patients with congenital IGFI deficiency (Laron syndrome)","volume":"151","year":"2004","journal-title":"European Journal of Endocrinology"},{"key":"ref641","first-page":"281","article-title":"Pathophysiological and clinical importance of insulin-like growth factor-I with respect to bone metabolism","volume":"52","year":"2003","journal-title":"Physiological Research"},{"key":"ref1521","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.exger.2009.04.001","article-title":"The somatotropic axis and aging: mechanisms and persistent questions about practical implications","volume":"44","year":"2009","journal-title":"Experimental Gerontology"},{"key":"ref531","first-page":"1013","article-title":"Liver status in congenital, untreated, isolated GH deficiency","volume":"3","year":"2014","journal-title":"Endocrine Connections"},{"key":"ref1451","first-page":"369","article-title":"Laryngeal and vocal evaluation in untreated growth hormone deficient adults","volume":"140","year":"2009","journal-title":"Otolaryngology Head and Neck Surgery"},{"key":"ref961","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1530\/EJE-16-0357","volume":"175","year":"2016","journal-title":"European Journal of Endocrinology"},{"key":"ref111","first-page":"717","article-title":"Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human","volume":"19","year":"1998","journal-title":"Endocrine Reviews"},{"key":"ref291","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1210\/jc.2005-2555","article-title":"Thyroid morphology and function in adults with untreated isolated growth hormone deficiency","volume":"91","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref391","first-page":"464","article-title":"Abnormal vascular and neural retinal morphology in congenital lifetime isolated growth hormone deficiency","volume":"27","year":"2016","journal-title":"Growth Hormone and IGF Research"},{"key":"ref951","first-page":"717","article-title":"Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human","volume":"19","year":"1998","journal-title":"Endocrine Reviews"},{"key":"ref1011","first-page":"106","article-title":"Unusual phenotypic features in a patient with a novel splice mutation in the GHRHR gene","volume":"14","year":"2008","journal-title":"Molecular Medicine"},{"key":"ref651","first-page":"657","article-title":"Pereira F de A, Oliveira CR, Pereira RM, Farias CT, Vicente TA & Salvatori R. Consequences of lifetime isolated growth hormone (GH) deficiency and effects of short-term GH treatment on bone in adults with a mutation in the GHRH-receptor gene","volume":"70","year":"2009","journal-title":"Clinical Endocrinology"},{"key":"ref791","first-page":"379","article-title":"Older individuals heterozygous for a growth hormone-releasing hormone receptor gene mutation are shorter than normal subjects","volume":"60","year":"2015","journal-title":"Journal of Human Genetics"},{"key":"ref351","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1056\/NEJM199610313351805","article-title":"Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene","volume":"335","year":"1996","journal-title":"New England Journal of Medicine"},{"key":"ref1551","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1210\/jc.2002-021938","article-title":"Reduced longevity in untreated patients with isolated growth hormone deficiency","volume":"88","year":"2003","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1211","first-page":"894","article-title":"Lifetime growth hormone deficiency: impact on growth, metabolism, body composition, and survival capacity","year":"2012","journal-title":"Handbook of Growth and Growth Monitoring in Health and Disease"},{"key":"ref551","first-page":"132","article-title":"Infectious diseases and immunological responses in adult subjects with lifetime untreated, congenital GH deficiency","volume":"54","year":"2016","journal-title":"Endocrine"},{"key":"ref831","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1210\/jc.2002-021120","article-title":"The impact of congenital, severe, untreated growth hormone (GH) deficiency on bone size and density in young adults: insights from genetic gh-releasing hormone receptor deficiency","volume":"88","year":"2003","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1381","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/j.1365-2265.2006.02558.x","article-title":"Body composition in untreated adult patients with Laron syndrome (primary GH insensitivity)","volume":"65","year":"2006","journal-title":"Clinical Endocrinology"},{"key":"ref1571","first-page":"153","article-title":"Metabolic effects of growth hormone (GH) replacement in children and adolescents with severe isolated GH deficiency due to a GHRH receptor mutation","volume":"66","year":"2007","journal-title":"Clinical Endocrinology"},{"key":"ref201","first-page":"33","article-title":"Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: Dwarfism of Sindh","volume":"83","year":"1998","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref1621","first-page":"2353","article-title":"The consequences of growth hormone-releasing hormone receptor haploinsufficiency for bone quality and insulin resistance","volume":"77","year":"2012","journal-title":"Clinical Endocrinology"},{"key":"ref1631","first-page":"379","article-title":"Older individuals heterozygous for a growth hormone-releasing hormone receptor gene mutation are shorter than normal subjects","volume":"60","year":"2015","journal-title":"Journal of Human Genetics"}],"container-title":["European Journal of Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/eje.bioscientifica.com\/view\/journals\/eje\/177\/2\/EJE-16-1047.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1530\/EJE-16-1047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T16:10:22Z","timestamp":1676391022000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ejendo\/article\/177\/2\/R85\/6655345"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8]]},"references-count":164,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.1530\/eje-16-1047","relation":{},"ISSN":["0804-4643","1479-683X"],"issn-type":[{"value":"0804-4643","type":"print"},{"value":"1479-683X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8]]}}}