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

• Published in: European journal of endocrinology Vol. 177; no. 2; pp. R85 - R97
• Main Authors: Aguiar-Oliveira, Manuel H, Souza, Anita H O, Oliveira, Carla R P, Campos, Viviane C, Oliveira-Neto, Luíz A, Salvatori, Roberto
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.08.2017; Oxford University Press
• Subjects: Arteriosclerosis; Blood pressure; C-reactive protein; Cholesterol; Dwarfism, Pituitary - diagnosis; Dwarfism, Pituitary - genetics; Dwarfism, Pituitary - metabolism; Endocrinology; Fat-free body mass; Growth hormone-releasing hormone; Growth Hormone-Releasing Hormone - genetics; Growth Hormone-Releasing Hormone - metabolism; Growth hormones; Hearing loss; Human Growth Hormone - genetics; Human Growth Hormone - metabolism; Humans; Hypoglycemia; Hypoplasia; Immune response; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor II; Liver; Low density lipoprotein; Mutation; Mutation - genetics; Neonates; Pancreas; Pituitary (anterior); Point mutation; Puberty; Receptors, Ghrelin - genetics; Receptors, Ghrelin - metabolism; Retina; Review; Spleen; Thyroid; Uterus
• ISSN: 0804-4643; 1479-683X; 1479-683X
• DOI: 10.1530/EJE-16-1047

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 −7.2, total maxillary length of −6.5, total facial height of −4.3 and cephalic perimeter of −2.7. 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.