Evidence for a Continuum of Genetic, Phenotypic, and Biochemical Abnormalities in Children with Growth Hormone Insensitivity

Abstract

GH insensitivity (GHI) presents in childhood as growth failure and in its severe form is associated with dysmorphic and metabolic abnormalities. GHI may be caused by genetic defects in the GH-IGF-I axis or by acquired states such as chronic illness. This article discusses the former category. The field of GHI due to mutations affecting GH action has evolved considerably since the original description of the extreme phenotype related to homozygous GH receptor (GHR) mutations over 40 yr ago. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The role and mechanisms of the GH-IGF-I axis in normal human growth is discussed, followed by descriptions of mutations in GHR, STAT5B, PTPN11, IGF1, IGFALS, IGF1R, and GH1 defects causing bioinactive GH or anti-GH antibodies. These defects are associated with a range of genetic, clinical, and hormonal characteristics. Genetic abnormalities causing growth failure that is less severe than the extreme phenotype are emphasized, together with an analysis of height and serum IGF-I across the spectrum of different types of GHR defects. An overall view of genotype and phenotype relationships is presented, together with an updated approach to the assessment of the patient with GHI, focusing on investigation of the GH-IGF-I axis and relevant molecular studies contributing to this diagnosis.

A new structural model of the acid-labile subunit: pathogenetic mechanisms of short stature-causing mutations

“…Formation of the ternary complex limits IGFs' passage through the endothelial barrier, restricting its presence to the blood circulation. This results in a reduced IGF availability to bind to its cell surface receptor (IGF1R) and to exert its mitogenic and metabolic effects (Boisclair et al 2001, David et al 2011.…”

PAPP-A2 nowy regulator procesu wzrastania

“…A lot of genetic defects in this axis lead to syndromes marked by impaired growth, and have helped to further our understanding of growth physiology [46]; for example, Laron syndrome with significant growth failure caused by mutation in the GH receptor gene [47]. Mutations in the STAT5B [48], IGF1 [49], and IGF1 receptor (IGF1R) [50,51]) genes cause varying degrees of pre-and postnatal growth retardation, and mutations in ALS cause mild short stature [52].…”

Deficiência da STAT5B: uma nova síndrome de insensibilidade ao hormônio de crescimento associada a acometimento imunológico

“…No entanto, o quadro clínico e laboratorial da IGH varia dentro de um espectro que vai da síndrome de Laron a apresentações mais leves que podem ser confundidas com a baixa estatura idiopática (1). As causas mais comuns de IGH são mutações no gene do receptor de GH (GHR; OMIM: *600946), sendo que mais de setenta já foram descritas até o momento (2,3), a maioria herdada de maneira autossômica recessiva (3,4).…”