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An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the coexpression of CD3 and CD56 molecules (TR3-56), is reduced in individuals with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating TR3-56 cells is associated with reduced beta-cell function and with the presence of diabetic ketoacidosis. Since autoreactive CD8+ T cells mediate disruption of insulin-producing beta cells1–3, we demonstrate that TR3-56 cells can suppress CD8+ T cell functions in vitro by reducing the levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of TR3-56 cells are also altered in children with T1D. Together, our findings indicate that TR3-56 cells constitute a regulatory cell population that controls CD8+ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D. Low numbers of circulating CD3+CD56+ regulatory T cells are associated with reduced beta-cell function and diabetic ketoacidosis in three separate cohorts of children with type 1 diabetes.

Objective Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design Retrospective analysis of the Italian data set of patients with TNDM. Methods Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; −2.27 SD) than those with KATP mutations (4.0 weeks; −1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (TR3-56), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating TR3-56 cells is associated with reduced β-cell function and with the presence of diabetic ketoacidosis. As autoreactive CD8+ T cells mediate disruption of insulin-producing β-cells1–3, we demonstrate that TR3-56 cells can suppress CD8+ T cell functions in vitro by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of TR3-56 cells are also altered in T1D children. Together, our findings indicate that TR3-56 cells constitute a regulatory cell population that controls CD8+ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D.

Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls. Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative RT-PCR. The associations between immune cell frequency, plasmatic microRNAs, and the parameters of pancreatic loss, glycemic control, and diabetic ketoacidosis were assessed by logistic regression models and correlation analyses. We found that the increase in specific plasmatic microRNAs was associated with T1D disease onset (let-7c-5p, let-7d-5p, let-7f-5p, let-7i-5p, miR-146a-5p, miR-423-3p, and miR-423-5p), serum C-peptide concentration (miR-142-5p and miR-29c-3p), glycated hemoglobin (miR-26a-5p and miR-223-3p) and the presence of ketoacidosis (miR-29c-3p) more strongly than the evaluated immune cell subset frequency. Some of these plasmatic microRNAs were shown to positively correlate with numbers of blood circulating B lymphocytes (miR-142-5p) and CD4+CD45RO+ (miR-146a-5p and miR-223-3p) and CD4+CD25+ cells (miR-423-3p and miR-223-3p) in children with T1D but not in healthy controls, suggesting a disease-specific microRNA association with immune dysregulation in T1D. In conclusion, our results suggest that, while blood co-circulating extracellular microRNAs and immune cell subsets may be biologically linked, microRNAs may better provide powerful information about T1D onset and severity.

Aims/hypothesis: We aimed to analyse the association between plasma circulating microRNAs (miRNAs) and the immunometabolic profile in children with type 1 diabetes and to identify a composite signature of miRNAs/immunometabolic factors able to predict type 1 diabetes progression. Methods: Plasma samples were obtained from children at diagnosis of type 1 diabetes (n = 88) and at 12 (n = 32) and 24 (n = 30) months after disease onset and from healthy control children with similar sex and age distribution (n = 47). We quantified 60 robustly expressed plasma circulating miRNAs by quantitative RT-PCR and nine plasma immunometabolic factors with a recognised role at the interface of metabolic and immune alterations in type 1 diabetes. Based on fasting C-peptide loss over time, children with type 1 diabetes were stratified into the following groups: those who had lost >90% of C-peptide compared with diagnosis level; those who had lost

Diabetes mellitus is the most common comorbidity in cystic fibrosis (CF). Recently, more attention has been paid to early glucose metabolism derangements (GMDs). The subject of this report is a female patient, affected by CF since 3 months of age. She presented with intermittent diabetes during early childhood. At the age of 10 years, oral glucose tolerance test (OGTT) was performed and showed glucose intolerance (IGT) status; glargine insulin therapy was started. At the age of 13 years, CF-related diabetes with fasting hyperglycemia occurred, so rapid insulin at meals was added. During the following year, clinical and nutritional status improved. Stable clinical conditions were observed in the following 3 years. This is the first case of very long-term follow-up concerning a CF patient with GMDs. Our case confirms the importance of paying attention to early GMDs in very young CF patients and seems to suggest that earlier therapy could ameliorate CF natural history.

Aims To analyze the factors associated with non-albuminuric reduced estimated glomerular filtration rate (NAeGFR-) phenotype in young people with type 1 diabetes (T1DM). Methods In this cross-sectional study were enrolled 140 outpatient diabetic children (age 7–18 years), consecutively observed in the period 2016–2017. Eighteen subjects with microalbuminuria (defined as albumin excretion rate ≥ 30 mg/24 h) were excluded. Fasting HbA1c, uric acid (UA), neutrophils and lymphocytes count were recorded. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz’s bed-side formula and reduced eGFR was defined by a value Results Out of 122 subjects analyzed, 76 (62%) showed normal eGFR and 46 (38%) showed NAeGFR- phenotype. They were characterized by higher prevalence of male sex (57% vs 33%, p = 0.010), autoimmune diseases (26% vs 12%, p = 0.043), high UA levels (4.0 ± 0.9 vs 3.3 ± 0.9 mg/dl, p Conclusions In our population, the prevalence on NAeGFR- phenotype is 38% and it is associated with male sex, high levels of UA, presence of other autoimmune diseases and low-grade inflammation. It should encourage pediatricians to monitor early both eGFR and UA in order to intercept diabetic youth more likely prone to develop progressive renal impairment.

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.

Purpose of review: Non-diabetic hyperglycemia (NDHY) is a pathological condition that is not yet well known. The aim of this review is to examine approaches for management of this condition. Recent findings: While it is well known that persistent hyperglycemia in diabetes affects immune response and risk for diabetes-related micro- and macrovascular complications, little is known about the biological effects of transient NDHY, particularly in the pediatric age group. Summary: Stress HY (SHY) is typically defined as blood glucose > 8.33 mmol/L (150 mg/dL) during physical stress, resolving spontaneously after dissipation of acute illness in patients without known diabetes. Based on the literature and clinical practice, two situations can be classified: (1) SHY1, which occurs during severe and prolonged illness and under serious life-threatening conditions, mainly in emergency situations and in resuscitation areas; and (2) SHY2, which occurs during acute illness, mainly in non-life-threatening conditions. Furthermore, (NDHY) among pediatric patients can be induced by drugs; the most frequent conditions are secondary to (1) steroid therapy and (2) antineoplastic/immunosuppressive therapy

Sleep-related disordered breathing (SDB) is very common in paediatric patients affected by Prader-Willi Syndrome (PWS). However, data addressing SBD patterns and their management are lacking. The aim of the present study was to analyse SDB features in 14 PWS patients (age range, 8 months-17 years). Polygraphic registration (PG) during a 12-h nocturnal sleep was performed in all patients. Obstructive and central apnoea indices and oxygen saturation (SpO2) were recorded along with demographic and clinical data. Obstructive sleep apnoea (OSA) was diagnosed in 13/14 patients (92.9%); the mean obstructive apnoea-hypopnea index (OAHI) was 7.6 ± 4.2 events/h with a mean central apnoea index (CAI) of 0.7 ± 1.04 events/h. Time spent with SpO2 < 90% was of 0.02% [range 0–23%], with a mean oxygen desaturation index of 12.1 ± 6.9 events/h. No correlation was found between OAHI and body mass index (mean BMI 28 ± 9.8 kg/m2 and BMI z-score 2.7 ± 1.7). Conclusion: OSA was the predominant sleep-related disorder in our PWS patients, not associated with age or obesity, and appeared more severe than previously reported. Further studies addressing the underlying mechanisms are necessary in larger study populations to better design the most appropriate clinical approach.What is Known:• Sleep-related patterns and their management are very limited in patients with Prader-Willi syndrome.What is New:• Severe obstructive sleep apnoea is the most frequent sleep-related disorder in our case series.

Diabetes mellitus is the most common comorbidity in cystic fibrosis (CF), occurring in a variable number of children and adolescents. Glucose metabolism derangements (GMDs) are responsible for a negative impact on the general health status of CF patients. Screening of GMDs is important since the youngest age and should be performed by means of OGTT, including its intermediate times, that could detect other non-traditional GMDs. Insulin treatment, administered before overt diabetes, could be beneficial in reducing the number of pulmonary infections, in improving both pulmonary function and nutritional status. Early screening of GMDs in pediatric age can exert an important preventing role regarding all aspects of health status of patients with CF.

Diabetic ketoacidosis (DKA) may be associated with neurologic complications: the most common is cerebral edema while the risk of venous and arterial stroke is rare. There is a pathogenetic link between DKA, hypercoagulability and stroke, whose risk is underestimated by clinicians. Our cases present a wide spectrum of cerebral accidents during DKA, the first one being diffuse cerebral edema, the second one venous stroke after 5 days of DKA resolution, while the third one multifocal edema suspected to be extrapontine myelinolysis although without electrolyte imbalance. Our cases suggest that DKA requires very accurate treatment, particularly at an early age, and it can be complicated by cerebral accidents even with appropriate medical care.

Thiamine-responsive megaloblastic anemia (TRMA) syndrome (OMIM No. 249270) is an autosomal recessive disorder and an example of a rare form of monogenic diabetes coexisting with anemia and deafness. T

In childhood, several rare genetic diseases have overlapping symptoms and signs, including those regarding growth alterations, thus the differential diagnosis is sometimes difficult. The proband, aged 3 years, was suspected to have Silver–Russel syndrome because of intrauterine growth retardation, postnatal growth retardation, typical facial dysmorphic features, macrocephaly, body asymmetry, and bilateral fifth finger clinodactyly. Other features were left atrial and ventricular enlargement and patent foramen ovale. Total X-ray skeleton showed hypoplasia of the twelfth rib bilaterally and of the coccyx, slender long bones with thick cortex, and narrow medullary channels. The genetic investigation did not confirm Silver–Russel syndrome. At the age of 5 the patient developed an additional sign: hepatomegaly. Array CGH revealed a 147 kb deletion (involving TRIM 37 and SKA2 genes) on one allele of chromosome 17, inherited from his mother. These results suggested Mulibrey nanism. The clinical features were found to fit this hypothesis. Sequencing of the TRIM 37 gene showed a single base change at a splicing locus, inherited from his father that provoked a truncated protein. The combined use of Array CGH and DNA sequencing confirmed diagnosis of Mulibrey nanism. The large deletion involving the SKA2 gene, along with the increased frequency of malignant tumours in mulibrey patients, suggests closed monitoring for cancer of our patient and his mother. Array CGH should be performed as first tier test in all infants with multiple anomalies. The clinician should reconsider the clinical features when the genetics suggests this. © 2016 Wiley Periodicals, Inc.

Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disease caused by loss of function mutations in the SLC19A2 gene. TRMA is characterized by anemia, deafness, and diabetes. In some cases, optic atrophy or more rarely retinitis pigmentosa is noted. We now report two sisters, the eldest of which presented to a different hospital during childhood with sensorineural deafness, which was treated with a hearing prosthesis, insulin requiring diabetes, retinitis pigmentosa, optic atrophy, and macrocytic anemia. These features initially suggested a clinical diagnosis of Wolfram syndrome (WS). Therapy with thiamine was initiated which resulted in the resolution of the anemia. The younger sister, who was affected with sensorineural deafness, was referred to our hospital for non-autoimmune diabetes. She was found to have macrocytosis and ocular abnormalities. Because a diagnosis of TRMA was suspected, therapy with insulin and thiamine was started. Sequencing analysis of the SLC19A2 gene identified a compound heterozygous mutation p.Y81X/p.L457X (c.242insA/c.1370delT) in both sisters. Non-autoimmune diabetes associated with deafness and macrocytosis, without anemia, suggests a diagnosis of TRMA. Patients clinically diagnosed with WS with anemia and/or macrocytosis should be reevaluated for TRMA.

Celiac Disease (CD) occurs in patients with Type 1 Diabetes (T1D) ranging the prevalence of 4.4-11.1% versus 0.5% of the general population. The mechanism of association of these two diseases involves a shared genetic background: HLA genotype DR3-DQ2 and DR4-DQ8 are strongly associated with T1D, DR3-DQ2 with CD. The classical severe presentation of CD rarely occurs in T1D patients, but more often patients have few/mild symptoms of CD or are completely asymptomatic (silent CD). In fact diagnosis of CD is regularly performed by means of the screening in T1D patients. The effects of gluten-free diet (GFD) on the growth and T1D metabolic control in CD/T1D patient are controversial. Regarding of the GFD composition, there is a debate on the higher glycaemic index of gluten-free foods respect to gluten-containing foods; furthermore GFD could be poorer of fibers and richer of fat. The adherence to GFD by children with CD-T1D has been reported generally below 50%, lower respect to the 73% of CD patients, a lower compliance being more frequent among asymptomatic patients. The more severe problems of GFD adherence usually occur during adolescence when in GFD non compliant subjects the lowest quality of life is reported. A psychological and educational support should be provided for these patients.

2.1 Genetic associations Patients with type 1 diabetes (T1D) have an increased risk of other autoimmune conditions, such as autoimmune thyroid disease (AIT), celiac disease (CD), Addison’s disease (AD) and vitiligo. These diseases are associated with organ-specific autoantibodies: AIT with thyroid peroxidase (TPO) and thyroglobulin autoantibodies (TG), CD with endomysial (EMA) and transglutaminase (TTG) autoantibodies, and AD with adrenal autoantibodies. Using these autoantibodies, organ-specific autoimmunity may be often detected before the development of clinical disease, in order to prevent significant morbidity related to unrecognized disease (Barker, 2006). The probable mechanism of these associations involves a shared genetic background (Myśliwiec et al., 2008; Smyth et al., 2008). The majority of autoimmune endocrinopathies, including T1D, are inherited as complex genetic traits. Multiple genetic and environmental factors interact with each other to confer susceptibility to these disorders. Genetic risk factors associated with T1D, ATD, CD and AD include HLA genes and non-HLA genes.

Cystic fibrosis–related diabetes (CFRD) is considered the most common comorbidity in patients affected by cystic fibrosis (CF), with a prevalence increasing with age (1). Recently, more attention has been turned to other less severe glucose metabolism derangements (GMD), since prediabetes may be related to increased morbidity (1), and early treatment may improve the clinical course in patients with CF (2). According to recent guidelines released by the Cystic Fibrosis Foundation, the American Diabetes Association, and the Pediatric Endocrine Society, the oral glucose tolerance test (OGTT) is recommended yearly in patients with CF over 10 years of age (3). Some authors recommend annual OGTT after the age of 6 years in CF patients with pancreatic insufficiency (4). In …