Growth Hormone Pathways in Short Stature Disorders

The regulation of human growth relies fundamentally on the growth hormone (GH) axis, in which GH released from the anterior pituitary binds to its cognate receptor (GHR) on target cells to initiate intracellular signalling. Activation of the JAK–STAT pathway, notably via STAT5B, drives transcription of insulin-like growth factor-1 (IGF-1) in the liver and peripheral tissues. Circulating IGF-1, in complex with IGF-binding proteins (principally IGFBP3) and the acid-labile subunit (ALS), mediates endocrine and paracrine effects on chondrocytes and myocytes to promote linear growth. Disruption at any point—from GHR mutations in Laron syndrome to defects in STAT5B or disturbances of IGF-1 bioavailability—manifests as short stature disorders. Recent advances have illuminated the structural basis of ternary complex assembly, clarified genotype–phenotype correlations in imprinting syndromes such as Silver–Russell, and refined animal and cellular models of GH insensitivity. Emerging insights into the molecular choreography of GH signalling are guiding targeted interventions, including recombinant IGF-1 therapy and genetic correction strategies, with global implications for paediatric endocrinology and therapeutic development.

Research from Nature Portfolio

Recent studies have characterised dominant-negative STAT5B variants that retain phosphorylation capacity but fail to translocate to the nucleus or bind canonical DNA elements, thereby attenuating GH-induced transcription and giving rise to a milder form of GH insensitivity with relative preservation of immune function. Structural analysis by cryo-electron microscopy has revealed the parachute-like architecture of the IGF-1/IGFBP3/ALS ternary complex and identified key interfaces whose proteolytic disruption liberates IGF-1, enhancing its bioavailability. These findings not only clarify the mechanistic underpinnings of conditions such as complete ALS deficiency and IGF-1 paucity, but also suggest avenues for therapeutic modulation of IGF-1 release in growth disorders.

Growth Hormone Pathways in Short Stature Disorders publication trend

The graph below shows the total number of articles in growth hormone pathways in short stature disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Growth hormone (GH): a pituitary-derived peptide that triggers anabolic and growth-promoting responses via receptor engagement and intracellular kinase activation.

Insulin-like growth factor-1 (IGF-1): a liver-synthesised peptide hormone mediating the growth-stimulating effects of GH in autocrine, paracrine and endocrine fashions.

Growth hormone insensitivity (GHI): a clinical syndrome in which target tissues fail to respond adequately to GH, often resulting from receptor, signalling or post-receptor defects.

Signal transducer and activator of transcription 5B (STAT5B): a transcription factor activated by GH-induced tyrosine phosphorylation that regulates IGF-1 gene expression.

IGF-binding protein 3 (IGFBP3): the principal carrier protein for IGF-1 in circulation, modulating its half-life and tissue access.

Acid-labile subunit (ALS): a glycoprotein that forms a ternary complex with IGF-1 and IGFBP3, stabilising circulating IGF-1 levels.

Laron syndrome: an autosomal recessive condition characterised by GH receptor mutations leading to insensitivity, low IGF-1 and marked postnatal growth failure.

References

1. A zebrafish model of growth hormone insensitivity syndrome with immune dysregulation 1 (GHISID1). Cellular and Molecular Life Sciences (2023).
2. Pathogenic sequence variant and microdeletion affecting HMGA2 in Silver–Russell syndrome: case reports and literature review. Clinical Epigenetics (2024).
3. Short stature related to Growth Hormone Insensitivity (GHI) in childhood. Frontiers in Endocrinology (2023).
4. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nature Communications (2018).
5. Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex. Nature Communications (2022).