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. 2011 Dec 12:2:95.
doi: 10.3389/fendo.2011.00095. eCollection 2011.

Genetic Defects in the Growth Hormone-IGF-I Axis Causing Growth Hormone Insensitivity and Impaired Linear Growth

Martin O Savage  1 , Vivian Hwa, Alessia David, Ron G Rosenfeld, Louise A Metherell
Affiliations

Genetic Defects in the Growth Hormone-IGF-I Axis Causing Growth Hormone Insensitivity and Impaired Linear Growth

Martin O Savage et al. Front Endocrinol (Lausanne). .

Abstract

Human genetic defects in the growth hormone (GH)-IGF-I axis affecting the IGF system present with growth failure as their principal clinical feature. This is usually associated with GH insensitivity (GHI) presenting in childhood as severe or mild short stature. Dysmorphic features and metabolic abnormalities may also be present. The field of GHI due to mutations affecting GH action has evolved rapidly since the first description of the extreme phenotype related to homozygous GH receptor (GHR) mutations in 1966. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The mechanisms of the GH-IGF-I axis in the regulation of normal human growth is discussed followed by descriptions of mutations in GHR, STAT5B, IGF-I, IGFALS, IGF1R, and GH1 defects causing bio-inactive GH or anti-GH antibodies. These GH-IGF-I axis defects are associated with a range of clinical, and hormonal characteristics. An up-dated approach to the clinical assessment of the patient with GHI focusing on investigation of the GH-IGF-I axis and relevant molecular studies contributing to the identification of causative genetic defects is also discussed.

Keywords: childhood linear growth; genetic defects; growth hormone insensitivity; growth hormone–IGF-I axis mutations.

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Figures

Figure 1
Figure 1
The GH–IGF-I axis in human growth. Solid arrows, activation processes; dashed arrows, translocation processes. P, phosphorylated residue; Y, tyrosine; AKT, v-akt murine thymoma viral oncogene homolog, also known as PKB, protein kinase B; ALS, acid-labile subunit; IGFBP-3, IGF-binding protein-3; IGFIR, IGF-I receptor; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; STAT, signal transducer and activator of transcription.
Figure 2
Figure 2
Homozygous STAT5B mutations identified in patients with GH insensitivity, IGF-I deficient, severely growth retarded, and immune compromised. Schematic of the STAT5b protein modular structure encoded by corresponding exons is as indicated. CCD, coiled-coiled domain; DBD, DNA binding domain; L, linker; ND, N-terminal domain; SH2, Src-homology 2-domain; STAT, signal transducer and activator of transcription; TAD, transactivation domain.
Figure 3
Figure 3
Schematic representation of the ALS protein indicating the location of identified human IGFALS mutations. The IGFALS is composed of two exons, with five amino residues of the ALS signal peptide encoded by exon 1 and the first five amino residues of exon 2 and the remainder of the ALS protein encoded by exon 2. ALS, acid-labile subunit; NH2, N-terminal region.
Figure 4
Figure 4
Algorithm showing key steps in the investigation of genetic GH–IGF-I axis defects. SD, standard deviation; IGHD, isolated growth hormone deficiency; ALS, acid-labile subunit; IGFBP-3, IGF-binding protein-3.
See this image and copyright information in PMC

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