Journal
HORMONE RESEARCH IN PAEDIATRICS
Volume 88, Issue 2, Pages 160-166Publisher
KARGER
DOI: 10.1159/000456544
Keywords
STAT3; Activating mutation; Short stature; Growth hormone; Growth hormone signal transduction; Growth hormone sensitivity; STAT5
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Funding
- research project of the Agency for Health Care Research, Ministry of Health of the Czech Republic [16-31211A]
- Ministry of Health of the Czech Republic [00064203/6001]
- Grant Agency of the Czech Republic [GBP302/12/G101]
- Ministry of Education, Youth and Sports NPU I [LO1604]
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Background: Germline STAT3 gain-of-function (GOF) mutations cause multiple endocrine and haematologic autoimmune disorders, lymphoproliferation, and growth impairment. As the JAK-STAT pathway is known to transduce the growth hormone (GH) signalling, and STAT3 interacts with STAT5 in growth regulation, we hypothesised that short stature in STAT3 GOF mutations results mostly from GH insensitivity via involving activation of STAT5. Case Report: A boy with a novel STAT3 c.2144C>T (p.Pro715Leu) mutation presented with short stature (-2.60 SD at 5.5 years). He developed diabetes mellitus at 11 months, generalised lymphoproliferation, autoimmune thyroid disease, and immune bicytopenia in the subsequent years. At 5.5 years, his insulin-like growth factor-1 (IGF-I) was 37 mu g/L (-2.22 SD) but stimulated GH was 27.7 mu g/L. Both a standard IGF-I generation test (GH 0.033 mg/kg/day sc; 4 days) and a high-dose prolonged IGF-I generation test (GH 0.067 mg/kg/day sc; 14 days) failed to significantly increase IGF-I levels (37-46 and 72-87 mu g/L, respectively). The boy underwent haematopoietic stem cell transplantation at 6 years due to severe neutropenia and massive lymphoproliferation, but unfortunately deceased 42 days after transplantation from reactivated generalised adenoviral infection. Conclusions: Our findings confirm the effect of STAT3 GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity. (C) 2017 S. Karger AG, Basel
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