STAT5B – Growth Hormone Insensitivity Syndrome

Signal transducer and activator of transcription 5B (STAT5B) mediates growth hormone (GH)–induced IGF-I expression via the GH receptor–JAK2 pathway. Pathogenic variants in STAT5B are causally linked to growth hormone insensitivity syndrome (growth hormone insensitivity syndrome), manifesting as IGF-I deficiency, growth failure, and immune dysregulation.

Autosomal recessive (AR) STAT5B deficiency is defined by homozygous, inactivating mutations. To date, seven distinct homozygous loss-of-function alleles have been reported in ten probands presenting with severe postnatal growth retardation and marked IGF-I deficiency (10 probands) (PMID:26703237). One recurrent frameshift, c.1191dup (p.Asn398fs), segregates in multiple consanguineous pedigrees with complete penetrance and absence in healthy controls (PMID:26703237).

In addition to AR loss-of-function, six heterozygous, dominant-negative missense variants have been identified in patients with milder GH insensitivity, eczema, and elevated IgE but without fatal pulmonary disease (6 probands) (PMID:29844444). A representative allele, c.2171C>T (p.Thr724Met), demonstrates tyrosine phosphorylation upon GH stimulation yet fails nuclear translocation and DNA binding, thereby inhibiting wild-type STAT5B transcriptional activity (PMID:29844444).

Phenotypically, AR patients exhibit severe postnatal growth retardation (HP:0008850), chronic lung disease (HP:0006528), and primary immunodeficiency. Dominant-negative carriers present with mild growth delay, eczematoid dermatitis (HP:0000964), and increased circulating IgE (HP:0003212), highlighting a spectrum of STAT5B-related endocrinopathy and immune dysregulation.

Functional assays corroborate the mechanism of pathogenicity. SH2 domain missense mutations such as c.1888G>C (p.Ala630Pro) abolish GH-induced STAT5B phosphorylation and transcriptional output (PMID:16464942). Protein folding studies reveal reduced stability and rapid proteasomal degradation of mutant STAT5B, with cytoplasmic aggregation of inactive protein (PMID:16303763). Dominant-negative variants form heterodimers with wild-type STAT5B, blocking canonical DNA response element binding (PMID:29844444).

No conflicting evidence has been reported to date. Collectively, genetic and experimental data delineate STAT5B haploinsufficiency and dominant-negative effects as key drivers of growth hormone insensitivity syndrome. STAT5B genetic testing should be incorporated into the diagnostic workup for unexplained GH insensitivity, guiding endocrine and immunological management.

Key Take-home: Biallelic and heterozygous STAT5B mutations underlie a spectrum of GH insensitivity with IGF-I deficiency and immune dysfunction, warranting targeted genetic screening to inform diagnosis and treatment.

References

• Growth Hormone & IGF Research • 2016 • STAT5B deficiency: Impacts on human growth and immunity. PMID:26703237
• Nature Communications • 2018 • Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. PMID:29844444
• The Journal of Clinical Endocrinology and Metabolism • 2006 • A mutant signal transducer and activator of transcription 5b, associated with growth hormone insensitivity and insulin-like growth factor-I deficiency, cannot function as a signal transducer or transcription factor. PMID:16464942
• The Journal of Clinical Endocrinology and Metabolism • 2012 • A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease. PMID:22419735

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