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Context: In the last decade the Sanger method of DNA sequencing has been replaced by next-generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM)., Objective: To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) vs 2013-2022 (NGS)., Methods: We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM + c.SIR) of the Italian dataset., Results: Fifty-five patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103 340 (NDM) and 1:1 240 082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11, INS, ABCC8, 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6, PDX1, GATA6, HNF1B, FOXP3, IL2RA, LRBA, BSCL2) during 2013-2022 (8/42 or 19%, P = .034 vs 2003-2012). Notably, among rare genes 5 were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3, IL2RA, LRBA) were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6, PDX1) were supplemented with pancreatic enzymes, and the individual with lipodystrophy caused by BSCL2 was started on metreleptin., Conclusion: NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and c.SIR in Italy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The pathogenesis of diabetic kidney disease (DKD) is complex and involves both glomerular and tubular dysfunction. A global assessment of kidney function is necessary to stage DKD, a progressive kidney disease that is likely to begin in childhood. The present study evaluated whether kidney injury biomarkers identified as early DKD biomarkers in adults have any prognostic value in the very early stages of childhood diabetes., Methods: We measured urine free Retinol-binding protein 4 (UfRBP4), albumin (UAlb), Kidney injury molecule-1 (KIM-1) and the microRNAs miR-155, miR-126 and miR-29b in two cohorts of paediatric T1DM patients without evidence of DKD, but with diabetes of short-duration, ≤ 2.5 years (SD, n = 25) or of long-duration, ≥ 10 years (LD, n = 29); non-diabetic siblings (H, n = 26) were recruited as controls. A p value < 0.05 was considered significant for all results., Results: UfRBP4 and UAlb were not significantly different across the three groups. No differences were found in KIM-1 excretion between any of the three groups. UfRBP4 was correlated with UAlb in all three groups (r 0.49; p < 0.001), whereas KIM-1 showed no correlation with albumin excretion. Among microRNAs, miR-29b was higher in all diabetic children compared with the H control group (p = 0.03), whereas miR-155 and miR-126 were not significantly different. No differences were found between the SD and LD groups for all three microRNAs. No associations were identified between these biomarkers with sex, age, BMI, eGFR, T1DM duration or glycaemic control., Conclusions: UfRBP4, KIM-1, miR-155, and miR-126 were unaffected by the presence and duration of diabetes, whereas miR-29b showed a modest elevation in diabetics, regardless of duration. These data support the specificity of a panel of urine biomarkers as DKD biomarkers, rather than any relationship to diabetes per se or its duration, and not as early DKD biomarkers in a paediatric setting., (© 2022. The Author(s).)

Type 1 diabetes mellitus (T1D) is one of the most demanding chronic diseases for children and their families, since controlling diabetes involves a process of co-regulation with attachment figures. However, there is insufficient evidence in middle childhood on psychological mechanisms involved that might complicate the adaptation of these children. Therefore, 106 children ( N  = 31 with T1D and N  = 75 as matched healthy group [HG]) aged 8 to 13 were assessed using the Child Attachment Interview , the Child Behavior Checklist , and the measure of glycated hemoglobin. Results showed that insecure T1D children did not have worse diabetes control than the secure ones. However, T1D children differed from HG for higher levels of idealization to father and withdrawn/depressed problems. Moreover, T1D children with insecure attachment to mother scored significantly higher in anxious/depressed, withdrawn/depressed, attention problems, and rule-breaking behavior, while T1D children with insecure attachment to father scored significantly higher only in the withdrawn/depressed scale compared to the remaining children. Therefore, diabetes does not in itself determine a psychological vulnerability in middle childhood, but the presence of an insecure attachment, especially to the mother, worsens the psychological adaptation of T1D children. Psychological support should be provided for these young patients and their families.

Purpose: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce., Methods: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up., Results: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID)., Conclusions: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.

Many variables influence the outcome of growth hormone (GH) therapy (GH dose and duration, height - SDS at treatment start or at puberty onset, bone age, mid parental height, growth velocity, age, etc.). Nevertheless, all these factors only partially explain the interindividual variability in response to GH in GH deficiency (GHD) and in short non-GHD subjects. To this regard, genes coding for factors involved in GH action could play an important role. GH acts through the GH receptor (GHR), and therefore the GHR gene could be the first candidate to influence the response to GH. Polymorphisms of the GHR have been described in exons 3, 6 and 10. The first one consists in the deletion (d3) or retention (fl) of the entire exon 3. The d3 polymorphism has been recently associated with a better growth response to GH in idiopathic short stature subjects and in short children born small for gestational age. Subsequent studies on the same and other categories of short children (idiopathic short stature, small for gestational age, GHD, Turner syndrome) have reported controversial results, with some confirming the role of d3 and others showing no effect. This review analyses these studies trying to explain the apparent discrepancies, mainly due to different selection criteria and different dose regimens in treating GHD and non-GHD short subjects.