Supplementary Material for: Short Stature in a Boy with Multiple Early-Onset Autoimmune Conditions due to a STAT3 Activating Mutation: Could Intracellular Growth Hormone Signalling Be Compromised?

<i>Background:</i> Germline <i>STAT3</i> 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 <i>STAT3</i> GOF mutations results mostly from GH insensitivity via involving activation of STAT5. <i>Case Report:</i> A boy with a novel <i>STAT3</i> 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 µg/L (–2.22 SD) but stimulated GH was 27.7 µg/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 µg/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. <i>Conclusions:</i> Our findings confirm the effect of <i>STAT3</i> GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity

Supplementary Material for: Glycemic control by treatment modalities: national registry-based population data in children and adolescents with type 1 diabetes

AIMS To assess the differences in key parameters of type 1 diabetes (T1D) control associated with treatment and monitoring modalities including newly introduced hybrid closed-loop (HCL) algorithm in children and adolescents with T1D (CwD) using the data from the population-wide pediatric diabetes registry ČENDA. MATERIALS AND METHODS CwD younger than 19 years with T1D duration > 1 year were included and divided according to the treatment modality and type of CGM used: multiple daily injection (MDI), insulin pump without (CSII) and with HCL function, intermittently scanned continuous glucose monitoring (isCGM), real-time CGM (rtCGM), and intermittent or no CGM (noCGM). HbA1c, times in glycemic ranges, and glucose risk index (GRI) were compared between the groups. RESULTS Data of a total of 3251 children (mean age 13.4± years) were analyzed. 2187 (67.3%) were treated with MDI, 1064 (32.7%) with insulin pump, 585/1064 (55%) with HCL. The HCL users achieved the highest median TIR 75.4% (IQR 6.3), and GRI 29.1 (7.8), both p<0.001 compared to other groups, followed by MDI rtCGM and CSII groups with TIR 68.8% (IQR 9.0) and 69.0% (7.5), GRI 38.8 (12.5) and 40.1 (8.5), respectively (non-significant to each other). These three groups did not significantly differ in their HbA1c medians (51.8 (IQR 4.5), 50.7 (4.5), and 52.7 (5.7) mmol/mol, respectively). NoCGM groups had the highest HbA1c and GRI and lowest TIR regardless of the treatment modality. CONCLUSIONS This population-based study shows that the HCL technology is superior to other treatment modalities in CGM-derived parameters and should be considered as a treatment of choice in all CwD fulfilling the indication criteria

Supplementary Material for: Short Stature in a Boy with Multiple Early-Onset Autoimmune Conditions due to a STAT3 Activating Mutation: Could Intracellular Growth Hormone Signalling Be Compromised?

<i>Background:</i> Germline <i>STAT3</i> 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 <i>STAT3</i> GOF mutations results mostly from GH insensitivity via involving activation of STAT5. <i>Case Report:</i> A boy with a novel <i>STAT3</i> 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 µg/L (–2.22 SD) but stimulated GH was 27.7 µg/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 µg/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. <i>Conclusions:</i> Our findings confirm the effect of <i>STAT3</i> GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity