ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 4.12 | DOI: 10.1530/ey.15.4.12

Centro de Investigaciones Endocrinológicas ‘Dr César Bergadá’ (CEDIE), CONICET, FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina


To read the full abstract: Mol Cell Endocrinol 2018; 15;473:166-177

Signal transducers and activators of transcription (STAT) proteins are transcription factors transiently activated by different ligands such as cytokines, growth factors, or peptides, which trigger intracellular tyrosine phosphorylation along the JAK-STAT signaling pathway. Phosphorylated STAT induces target gene expression, influencing cell proliferation, differentiation, and apoptosis. The activation of STATs is strictly regulated, whereas their deregulation leads to several disorders, ranging from susceptibility to infection, autoimmunity, and growth impairment.

STAT3 is a cytosolic protein involved in intracellular signaling transduction from cytokines, including several interleukins (IL), interferons (IFN a/b and g) and growth factors and is involved in cell growth, apoptosis, organogenesis, inflammation, infection and oncogenesis. Activating mutations in the STAT3 gene are associated with multiple early-onset autoimmune conditions and growth failure. For example, a recent case report described a heterozygous de novo variant within the transactivation domain of STAT3 in an SGA boy with progressive postnatal growth failure, late infancy onset type 1 diabetes and autoimmune thyroid disease, bicytopenia, and lymphoproliferative disease in subsequent years [47].

Here, Gutiérrez et al. describe two unrelated children, sharing clinical features such as short stature and immunological abnormalities. Patient 1 showed congenital autoimmune hypothyroidism, eczema, chronic diarrhea, recurrent oral candidiasis, severe respiratory infections. Patient 2 had history of IPEX-like syndrome with dermatitis, chronic diarrhea, colitis, autoimmune hypothyroidism. After ruling out anomalies in two candidate genes (STAT5B and FOXP3), whole exome sequencing was performed and identified two de novo STAT3 mutations. Both mutations were GOF and increased STAT3 transcriptional responses to GH. Both patients partially shared features with previously reported cases with STAT3 GOF mutations, and had undetectable IGF-1 levels with relatively high GH concentrations.

Activating mutations of STAT3 and inactivating mutations of STAT5b result in overlapping clinical features, including endocrine and immunological abnormalities [48]. Here, the authors discovered that both de novo STAT3 GOF mutations had a negative effect on STAT5b transcriptional activity. The mechanisms underlying this interaction have not been elucidated. SOCS3 may play a role as it is activated by STAT3 and negatively regulates STAT5. In conclusion, this study reveals a new form of IGF-1 deficiency and indicates an inhibitory role of STAT3 in the GH signalling pathway.

47. Sediva H, Dusatkova P, Kanderova V, Obermannova B, Kayserova J, Sramkova L, et al. Short Stature in a Boy with Multiple Early-Onset Autoimmune Conditions due to a STAT3 Activating Mutation: Could Intracellular Growth Hormone Signalling Be Compromised? Horm Res Paediatr. 2017;88:160-6.

48. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349:1139-47.

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