IGF-I in Human Growth: Lessons from Defects in the GH-IGF-I Axis

Abstract

The IGF system plays a critical role in all phases of human growth, including intrauterine, childhood and pubertal. The importance of IGF-I for both in utero as well as postnatal human growth is highlighted by rare human homozygous IGF1 mutations, which are characterized by intrauterine growth retardation (IUGR), microcephaly, mental retardation and severe postnatal growth failure. Clinical conditions of IGF-I resistance due to mutations in the IGF-I receptor (IGFIR) similarly lead to IUGR and postnatal growth retardation. Postnatal regulation of IGF-I production is predominantly GH dependent. Defects in the GH-IGF-I axis, including mutations in the GHR, STAT5B and IGFALS genes, lead to postnatal IGF deficiency and GH insensitivity. Patients are of normal birth size but present with severe postnatal growth failure, despite normal or elevated levels of GH. Other phenotypic features - immune deficiency for STAT5B defects and insulin insensitivity for IGFALS defects - are of note. Mutations identified have been predominantly recessive. The identification and assessment of genetic defects in the GH-IGF axis has greatly enhanced our understanding of the critical importance of IGF-I in human linear growth. Continued evaluations will facilitate better diagnosis and management of children presenting with abnormal growth and development.

Global effects of income and income inequality on adult height and sexual dimorphism in height

“…Also listed are some of the Functional Consequences (Box 4) of height variation for individuals, communities, and populations (Steckel, 2012). Detailed discussion of the categories and factors of Figure 1 are available in the literature (Eveleth and Tanner, 1991;Komlos and Baten, 1998;Bogin, 1999;Steckel, 2009;Kuzawa and Quinn, 2009;Blum et al, 2011;Muñoz-Hoyos et al, 2011;Dubois et al, 2012;Hermanussen, 2013;Hwa et al, 2013;Simeone and Alberti, 2014;McDade et al, 2016).…”

“…. Martin, 2012;Eveleth and Tanner, 1991;Hermanussen, 2013;Hwa, Fang, Derr, Fiegerlova, & Rosenfeld, 2013;Komlos and Baten, 1998;Kuzawa and Quinn, 2009;McDade, Georgiev, & Kuzawa 2016; Muñoz-Hoyos, Molina-Carballo, Augustin-Morales, Contreras-Chova, Naranjo-G omez, Justicia-Martínez, & Uberos, 2011;Simeone and Alberti, 2014;Steckel, 2009).…”

Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy

“…Neurotrophic factors, such as insulin-like growth factor 1 and its type 1 receptor (IGF-1R), are known to modulate the synaptic activity of dopamine and glutamate in the developing and adult nervous systems (Guevara-Aguirre, 1996; Mattson, 2008; Mattson, 1990; Pehar et al, 2010). Moreover, alterations in neural IGF-1 have been described in the cause and progression of several neuropsychiatric disorders associated with development, aging, degeneration and malformation of cytoskeletal proteins in neurons (Guevara-Aguirre, 1996; Hwa et al, 2013; Pehar et al, 2010). Additionally, other reports have shown that loss of neurotrophins, and associated receptors are pivotal to a compromised synaptic integrity, abnormal neurotransmitter signaling events and activation of inflammatory pathways in traumatic stress (Su et al, 2015; Finsterwald et al, 2015).…”

Targeted Resequencing of Putative Growth-Related Genes Using Whole Exome Sequencing in Patients with Severe Primary IGF-I Deficiency

“…Since then, several proteins and their coding regions in the genome have been identified that affect postnatal growth [4, 5]. The GH–IGF-I axis is involved in all phases of human growth, including intrauterine growth, childhood and pubertal development.…”

“…Laron syndrome and severe GH deficiency probably represent the 2 extreme ends of molecular defects covering the GH–IGF-I axis. Since the description of Laron syndrome, several conditions have been identified with a less severe phenotype, which make a biochemical continuum from GH deficiency towards GH insensitivity likely [5]. The prevalence for individuals with SPIGFD has been estimated to be about 1: 50.000.…”