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STAT5b Deficiency: An Unsuspected Cause of Growth Failure, Immunodeficiency, and Severe Pulmonary Disease

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First Cases of STAT5b Deficiency

The cardinal feature of GH insensitivity (GHI) is severe growth failure, associated with elevated serum concentrations of GH, resulting in a clinical phenotype that is essentially indistinguishable from that of congenital GH deficiency. The phenotype of GHI has been attributed to more than 70 mutations in the GHR gene, encoding the GH receptor (GHR).7 GHI in the presence of normal GHR, in contrast to classic GHI, has remained largely uninvestigated. The molecular basis has been determined in

STAT 5 Genes and Proteins

STAT5a and STAT5b have been implicated in cellular functions of proliferation, differentiation, and apoptosis, with relevance to processes of hematopoiesis, immunoregulation, reproduction, prolactin production, and lipid metabolism. STAT5A and STAT5B genes are collocated on 17q21, are approximately 10 kb apart, and are regulated by a Sp-1 Cis-element.9 Although STAT5a and STAT5b show peptide sequence similarities of >90%, the human STAT5b and STAT5a proteins differ by 6 amino acids in the DNA

Animal Studies

STAT5b protein, as demonstrated in Stat5 knock-out models, is essential for the biological response to GH. In the Stat5b−/− mouse model, targeted disruption of the Stat5b gene resulted in loss of the sexual dimorphic body growth rates characteristic of normal mice, with Stat5b−/− male mice reduced to the size of female mice, whereas the size of female mice remained unaltered.15 When both Stat5b and Stat5a were ablated in mice, growth retardation was even more pronounced, resulting in mice

Role of STAT5b in Growth Hormone Signaling

The postnatal growth-promoting actions of GH in humans is mediated through regulation of IGF-I production, as repeatedly demonstrated in clinical conditions of GH deficiency and GHI. The interaction of GH with the cell surface GHR activates signaling cascades that include four STAT pathways, STAT1, -3, 5a, and 5b, leading to regulation of multiple genes, such as IGF-1, IGF binding protein-3 (IGFBP-3), and IGFBP, acid labile subunit (IGFALS). IGF-I circulates in serum complexed to IGFBP-3 and

Auxology

In general, gestational growth and birth size in subjects with STAT5b deficiency were within normal limits, as is also commonly observed with mutations of GHR (Table I). Patients with STAT5b deficiency, however, typically display severe growth failure after birth, with height SDS ranging from −3.0 to −9.9 in girls and boys, respectively (Figure 2 and Table I). In those cases with appropriate clinical information, modestly delayed puberty was noted (Table I). It is interesting to note that the

Implications: Is This Disorder Undiagnosed?

Knowledge and understanding of this disease are important to the field of pediatrics because the pediatric health care worker, in monitoring growth frequently in the first 3 years of life, is often the first medical caregiver to document poor growth (and chronic infection) and is in position to initiate the appropriate diagnostic evaluation. Because the STAT5B gene defect leads to growth failure and growth hormone insensitivity, it is possible to diagnose children early, so that much of their

Clinical Aspects of STAT5b Overexpression

STAT5 is activated in a broad spectrum of human hematologic malignancies. Using a genetic approach, Schwaller et al26 addressed whether activation of STAT5 is necessary for the myeloproliferative and lymphoproliferative disease induced by the TEL/JAK2 fusion gene. Myeloproliferative disease was induced by reconstitution with bone marrow cells expressing a constitutively active mutant, Stat5a or a single Stat5a target, murine Osm (oncostatin M). These data defined a critical role for Stat5a/b

Management

Optimizing early diagnosis will be critical to the prevention and improvement in clinical outcomes for subjects with STAT5 defects. To manage growth failure in these patients, growth hormone therapy is ineffective. It is presumed that IGF-I therapy, on the other hand, would be effective, unless the presence of severe chronic infection limits the growth response. Clinical trials of IGF-I therapy in these patients have not, to date, been performed. Any signs and symptoms of immunodeficiency

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References (29)

  • R. Zeiser et al.

    Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells

    Blood

    (2008)
  • S.E. Turvey et al.

    Primary immunodeficiency diseases: a practical guide for clinicians

    Postgrad Med J

    (Dec 2009)
  • V. Hwa et al.

    Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene

    Horm Res

    (2007)
  • E.M. Kofoed et al.

    Growth hormone insensitivity associated with a STAT5b mutation

    N Engl J Med

    (2003)
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    The authors declare no conflicts of interest.

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