ESPE Abstracts (2015) 84 FC13.1

Gain of Function STAT3 Mutation in a Boy with Early Onset Autoimmune Diabetes and Thyroid Disease, Prenatal and Postnatal Growth Impairment and Lymphoproliferation

Hana Sediva, Petra Dusatkova, Lenka Dusatkova, Zdenek Sumnik, Stanislava Kolouskova, Stepanka Pruhova & Jan Lebl


Department of Paediatrics of the 2nd Faculty of Medicine of Charles University and the University Hospital Motol, Prague, Czech Republic


Background: Recently, a new monogenic cause of multiple immune system disorders and short stature has been attributed to germline activating mutations in the STAT3 gene encoding signal transducer and activator of transcription 3. Possible pathophysiological mechanisms include enhanced proliferation and activation of T-helper 17 cells and inhibition of regulatory T-cells by STAT3, as described in in vitro studies.

Case presentation: The affected boy was born at 35th GW of a twin pregnancy with birth weight 1900 g (−1.74 SD) and birth length 44 cm (−2.06 SD). Both of his parents suffer from type 2 diabetes, his father has psoriasis and his mother autoimmune thyroiditis. He underwent transient neonatal hypoglycaemia and unconjugated hyperbilirubinaemia. After 2 months of age, he started to fail to thrive and then consecutively presented with ketoacidosis at onset of type 1 diabetes at 11 months, hepatosplenomegaly and generalized lymphadenopathy with non-specific chronic activation in the biopsy sample at 16 months, autoimmune thyroid disease at 2 years and immune thrombocytopenia at 3.5 years. He also suffered from recurrent respiratory infections. At current age 6.5 years, his height is 103 cm (−3.81 SD). His peak GH secretion is normal. He has decreased IgG (5.07 g/l) and IgM (0.29 g/l) levels as well as NK-cell count (5.5%) and higher B-lymphocyte count (22.9%). Direct Sanger sequencing of STAT3 revealed a heterozygous de novo p.Pro715Leu mutation in a highly conserved region of STAT3 gene.

Conclusion: We revealed a previously unreported, heterozygous de novo p.Pro715Leu mutation of STAT3 with a high probability of pathogenicity. We strongly recommend considering investigation for STAT3 mutations in children with early onset multiple autoimmune endocrine and non-endocrine disorders, growth impairment and lymphoproliferation.

Funding: The study was supported by grant NT 11402.

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