Hypothalamic abnormalities: Growth failure due to defects of the GHRH receptor
GROWTH HORMONE & IGF RESEARCH
Authors: Aguiar-Oliveira, Manuel H.; Davalos, Caridad; Tampos, Vivian C.; Oliveira Neto, Luiz A.; Marinho, Cindi G.; Oliveira, Carla R. P.
Several acquired or congenital hypothalamic abnormalities may cause growth failure (GF). We described two of these congenital abnormalities. First, a case of CHARGE syndrome, an epigenetic disorder mostly caused by heterozygous mutations in the gene encoding CHD7, a chromatin remodeling protein, causing several malformations, some life-threatening, with additional secondary hypothalamus-hypophyseal dysfunction, including GF. Second, a cohort of individuals with genetic isolated severe GH deficiency (IGHD), due to a homozygous mutation in the GH-releasing hormone (GHRH) receptor gene described in Itabaianinha County, in northeast Brazil. In this IGHD, with marked reduction of serum concentrations of IGF-I, and an up regulation of IGF-II, GF is the principal finding in otherwise normal subjects, with normal quality of life and longevity. This IGHD may unveil the effects of GHRH, pituitary GH and IGF-I, IGF-II and local GH and growth factor on the size and function of body and several systems. For instance, anterior pituitary hypoplasia, and impairment of the non-REM sleep may be due to GHRH resistance. Proportionate short stature, doll facies, high-pitched pre-pubertal voice, and reduced muscle mass reflect the lack of the synergistic effect of pituitary GH and IGF-I in bones and muscles. Central adiposity may be due to a direct effect of the lack of GH. Brain, eyes and immune system may also involve IGF-II and local GH or growth factors. A concept of physiological hierarchy controlling body size and function by each component of the GH system may be drawn from this model.
Genetic causes of isolated and combined pituitary hormone deficiency
BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM
Authors: Giordano, Mara
Research over the last 20 years has led to the elucidation of the genetic aetiologies of Isolated Growth Hormone Deficiency (IGHD) and Combined Pituitary Hormone Deficiency (CPHD). The pituitary plays a central role in growth regulation, coordinating the multitude of central and peripheral signals to maintain the body's internal balance. Naturally occurring mutation in humans and in mice have demonstrated a role for several factors in the aetiology of IGHD/CPHD. Mutations in the GH1 and GHRHR genes shed light on the phenotype and pathogenesis of IGHD whereas mutations in transcription factors such as HESX1, PROP1, POU1F1, LHX3, LHX4, GLI2 and SOX3 contributed to the understanding of CPHD. Depending upon the expression patterns of these molecules, the phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly. Although numerous monogenic causes of growth disorders have been identified, most of the patients with IGHD/CPHD remain with an explained aetiology as shown by the relatively low mutation detection rate. The introduction of novel diagnostic approaches is now leading to the disclosure of novel genetic causes in disorders characterized by pituitary hormone defects. (C) 2016 Published by Elsevier Ltd.