Glucometrics and device satisfaction in children and adolescents with type 1 diabetes using different treatment modalities: A multicenter real-world observational study.

AIMS: To analyze metabolic outcomes, diabetes impact and device satisfaction in children and adolescents with type 1 diabetes in Italy who used different treatment modalities for diabetes care in a real-life context. METHODS: In this multicenter, nationwide, cross-sectional study, 1464 participants were enrolled at a routine visit. The following treatment modalities were considered MDI + SMBG; MDI + CGM; Sensor Augmented Pump Therapy; predictive management of low glucose; Hybrid Closed Loop (HCL); Advanced Hybrid Closed Loop (AHCL). Health related quality of life was evaluated by the Italian version of the Diabetes Impact and Device Satisfaction Scale (DIDS) questionnaire. RESULTS: Patients treated with AID systems were more likely to have HbA1c ≤ 6.5 %, higher percentage of time with glucose levels between 70 and 180 mg/dL, lower percentage of time with glucose levels above 180 mg/dL, higher device satisfaction, and reduced impact of diabetes. All the therapeutic modalities with respect to MDI + CGM, except for MDI + SMBG, contributed to increase the device satisfaction. HCL and AHCL respect to MDI + CGM were associated with lower diabetes impact. CONCLUSION: Real-life use of automated insulin delivery systems is associated with reduced type 1 diabetes impact, increased device satisfaction, and achievement of glycemic goals.

The changing landscape of neonatal diabetes mellitus in Italy between 2003-2022.

CONTEXT: In the last decade Sanger method of DNA sequencing has been replaced by next generation sequencing (NGS).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) versus 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: Fiftyfive 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= 0.034 vs 2003-2012). Notably, five among rare genes 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. CONCLUSIONS: NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and congenital SIR in Italy.

The real-life management of glucose homeostasis abnormalities in pediatric onco-hematological diseases: data from a national survey.

Glycemic abnormalities are a frequent finding in pediatric oncological patients, both during treatment and after its discontinuation. Moreover, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG) and diabetes mellitus (DM) are not rarely diagnosed in non-oncological hematological diseases. To explore the current pediatric Italian approach to the diagnosis and the management of the glycemic alterations in this clinical setting and, thus, to identify and enforce current clinical needs, we submitted an online 23-items survey to all the Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers, and surveys were descriptively analyzed. Thirty-nine AIEOP centers were involved in the study. In 2021, among 75278 children and adolescents affected by an oncological or a hematological disease, 1.2 and 0.65% developed DM, while IGT or IFG were widespread in 2.3 and 2.8%, respectively. The main causes of DM were the use of corticosteroids in patients with cancer and the iron overload in patients with thalassemia. Venous fasting plasma glycemia was the most used tool to detect glycemic abnormalities. The performance of oral glucose tolerance test (OGTT) was extremely limited, except when IFG occurred. Despite the diagnosis of DM, ∼45% of patients with cancer and 30% of patients with one hematological disease did not receive an appropriate treatment. In the other cases, insulin was the drug of first choice. Emerging technologies for diabetes care (glucose sensors and insulin pumps) are not largely used yet. The results of our study support the standardization of the care of the glycemic abnormalities during or after onco-hematologic diseases in the pediatric age. Despite the scarce data in pediatric literature, proper guidelines are needed.

Endocrine immune-related adverse effects of immune-checkpoint inhibitors.

INTRODUCTION: Immune-checkpoint inhibitor therapy modulates the response of the immune system acting against cancer. Two pathways impacted by this kind of treatment are the CTLA4 and the PD-1/PD-L1 pathways. ICI therapy can trigger autoimmune adverse effects, known as immune-related Adverse Events (irAEs). AREAS COVERED: This review focuses on irAEs which affect the endocrine system. This review elucidates the pathways used by these drugs with a focus on the hypothetical pathogenesis at their basis. In fact, the pathophysiology of irAEs concerns the possibility of an interaction between cellular autoimmunity, humoral immunity, cytokines, chemokines, and genetics. The endocrine irAEs examined are thyroid dysfunctions, immune related-hypophysitis, diabetes, peripheral adrenal insufficiency, and hypoparathyroidism. EXPERT OPINION: There is still much to investigate in endocrine irAES of checkpoint inhibitors. In the future, checkpoint inhibitors will be increasingly utilized therapies, and therefore it is crucial to find the proper diagnostic-therapeutic program for irAEs, especially as endocrine irAEs are nonreversible and require lifelong replacement therapies.

The treatment of obesity in children and adolescents: consensus position statement of the Italian society of pediatric endocrinology and diabetology, Italian Society of Pediatrics and Italian Society of Pediatric Surgery.

This Position Statement updates the different components of the therapy of obesity (lifestyle intervention, drugs, and surgery) in children and adolescents, previously reported in the consensus position statement on pediatric obesity of the Italian Society of Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Lifestyle intervention is the first step of treatment. In children older than 12 years, pharmacotherapy is the second step, and bariatric surgery is the third one, in selected cases. Novelties are available in the field of the medical treatment of obesity. In particular, new drugs demonstrated their efficacy and safety and have been approved in adolescents. Moreover, several randomized control trials with other drugs are in process and it is likely that some of them will become available in the future. The increase of the portfolio of treatment options for obesity in children and adolescents is promising for a more effective treatment of this disorder.

Perinatal and postnatal exposure to phthalates and early neurodevelopment at 6 months in healthy infants born at term.

Background: Phthalates are non-persistent chemicals largely used as plasticizers and considered ubiquitous pollutants with endocrine disrupting activity. The exposure during sensible temporal windows as pregnancy and early childhood, may influence physiological neurodevelopment. Aims and Scope: The aim of this study is to analyze the relationship between the urinary levels of phthalate metabolites in newborn and infants and the global development measured by the Griffiths Scales of Children Development (GSCD) at six months. Methods: Longitudinal cohort study in healthy Italian term newborn and their mothers from birth to the first 6 months of life. Urine samples were collected at respectively 0 (T0), 3 (T3), 6 (T6) months, and around the delivery for mothers. Urine samples were analyzed for a total of 7 major phthalate metabolites of 5 of the most commonly used phthalates. At six months of age a global child development assessment using the third edition of the Griffith Scales of Child Development (GSCD III) was performed in 104 participants. Results: In a total of 387 urine samples, the seven metabolites analyzed appeared widespread and were detected in most of the urine samples collected at any time of sampling (66-100%). At six months most of the Developmental Quotients (DQs) falls in average range, except for the subscale B, which presents a DQ median score of 87 (85-95). Adjusted linear regressions between DQs and urinary phthalate metabolite concentrations in mothers at T0 and in infants at T0, T3 and T6 identified several negative associations both for infants' and mothers especially for DEHP and MBzP. Moreover, once stratified by children's sex, negative associations were found in boys while positive in girls. Conclusions: Phthalates exposure is widespread, especially for not regulated compounds. Urinary phthalate metabolites were found to be associated to GSCD III scores, showing inverse association with higher phthalate levels related to lower development scores. Our data suggested differences related to the child's sex.

Skeptical Look at the Clinical Implication of Metabolic Syndrome in Childhood Obesity.

Metabolic syndrome (MetS) is defined by a cluster of several cardio-metabolic risk factors, specifically visceral obesity, hypertension, dyslipidemia, and impaired glucose metabolism, which together increase risks of developing future cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D). This article is a narrative review of the literature and a summary of the main observations, conclusions, and perspectives raised in the literature and the study projects of the Working Group of Childhood Obesity (WGChO) of the Italian Society of Paediatric Endocrinology and Diabetology (ISPED) on MetS in childhood obesity. Although there is an agreement on the distinctive features of MetS, no international diagnostic criteria in a pediatric population exist. Moreover, to date, the prevalence of MetS in childhood is not certain and thus the true value of diagnosis of MetS in youth as well as its clinical implications, is unclear. The aim of this narrative review is to summarize the pathogenesis and current role of MetS in children and adolescents with particular reference to applicability in clinical practice in childhood obesity.

Endocrine Disrupting Chemicals' Effects in Children: What We Know and What We Need to Learn?

Thousands of natural or manufactured chemicals were defined as endocrine-disrupting chemicals (EDCs) because they can interfere with hormone activity and the endocrine system. We summarize and discuss what we know and what we still need to learn about EDCs' pathogenic mechanisms of action, as well as the effects of the most common EDCs on endocrine system health in childhood. The MEDLINE database (PubMed) was searched on 13 May 2022, filtering for EDCs, endocrine diseases, and children. EDCs are a group of compounds with high heterogeneity, but usually disrupt the endocrine system by mimicking or interfering with natural hormones or interfering with the body's hormonal balance through other mechanisms. Individual EDCs were studied in detail, while humans' "cocktail effect" is still unclear. In utero, early postnatal life, and/or pubertal development are highly susceptible periods to exposure. Human epidemiological studies suggest that EDCs affect prenatal growth, thyroid function, glucose metabolism, obesity, puberty, and fertility through several mechanisms. Further studies are needed to clarify which EDCs can mainly act on epigenetic processes. A better understanding of EDCs' effects on human health is crucial to developing future regulatory strategies to prevent exposure and ensure the health of children today, in future generations, and in the environment.

The impact of BMI on long-term anthropometric and metabolic outcomes in girls with idiopathic central precocious puberty treated with GnRHas.

Background: Gonadotropin-releasing hormone analogs (GnRHas) are effective in increasing the final height of children with idiopathic central precocious puberty (ICPP). However, in previous years, some transient metabolic complications have been described during this treatment, for which there are no long-term outcome data. Our study aimed to evaluate the efficacy of GnRHas and clarify if body mass index (BMI) at diagnosis of ICPP could influence long-term outcomes. Methods: This was an observational, retrospective study that recruited a cohort of girls with ICPP. Data for anthropometric measures, fasting lipid profile, and glucose metabolism were collected at baseline [when GnRHas treatment started (T1)], at the end of the treatment (T2), and near-final height (nFH) or final height (FH) (T3). Predicted adult height (PAH) was calculated at T1 following Bayley and Pinneau's method. Analysis was carried out using BMI standard deviation score (SDS) categories at T1 (group A, normal weight, vs. group B, overweight/obese). Results: Fifty-seven girls with ICPP who were treated with GnRHas were enrolled in the study (group A vs. group B: 33 vs. 24 patients, aged 7.86 ± 0.81 vs. 7.06 ± 1.61 years, respectively; p < 0.05). In the study population, nFH/FH was in line with the target height (TH) (p = 0.54), with a mean absolute height gain of 11.82 ± 5.35 cm compared with PAH. Even if the length of therapy was shorter (group A vs. group B: 1.84 ± 2.15 vs. 2.10 ± 0.81 years, respectively; p < 0.05) and the age at menarche was younger (group A vs. group B: 10.56 ± 1.01 vs. 11.44 ± 0.85 years, respectively; p < 0.05) in group B than in group A, the nFH/FH gain was still comparable between the two groups (p = 0.95). At nFH/FH, BMI SDS was still greater in group B than in group A (p = 0.012), despite the fact that BMI SDS significantly increased in group A only (p < 0.05). Glucose metabolism got worst during GnRHa with a complete restoring after it, independently from pre-treatment BMI. The ratio of low-density to high-density lipoprotein cholesterol transiently deteriorated during treatment with GnRHas in group A only (p = 0.030). Conclusions: Our results confirm the effectiveness of treatment with GnRHas on growth and do not support the concern that being overweight and obese can impair the long-term outcomes of GnRHas therapy. However, the observed transient impairment of metabolic parameters during treatment suggests that clinicians should encourage ICPP girls treated with GnRHas to have a healthy lifestyle, regardless of their pretreatment BMI.

Corrigendum: The silent epidemic of diabetic ketoacidosis at diagnosis of type 1 diabetes in children and adolescents in italy during the covid-19 pandemic in 2020.

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Challenges in the growth and development of newborns with extra-uterine growth restriction.

INTRODUCTION: Extra-uterine growth restriction (EUGR) is a condition caused by the failure of very preterm infants to reach their potential growth during the NICU hospital stay. Despite enormous improvements in nutritional support and strategies, the growth pattern of preterm infants is still far from the one expected. AREAS COVERED: This review focuses on what EUGR is, highlighting controversial aspects of this topic. EUGR is still missing a univocal definition, and the international debate is also open on what is the best growth chart to use. Moreover, professionals in NICU may not be trained on how to perform anthropometric measurements, increasing the risk of over- or underestimation, especially for length assessment. EUGR has recently been described as one of the main comorbidities in NICU, influencing growth, metabolism, and neurodevelopment later in life. EXPERT OPINION: There is still much to investigate about what the best growth pattern in the NICU should be. What is known so far is that the majority of preterm neonates develop EUGR, and this leads to several short- and long-term consequences. It is imperative that neonatologists and pediatric endocrinologists work together, to modulate growth in the NICU.

The Silent Epidemic of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents in Italy During the COVID-19 Pandemic in 2020.

Aim/Hypothesis: To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019. Methods: Forty-seven pediatric diabetes centers caring for >90% of young people with diabetes in Italy recruited 4,237 newly diagnosed children with type 1 diabetes between 2017 and 2020 in a longitudinal study. Four subperiods in 2020 were defined based on government-imposed containment measures for COVID-19, and the frequencies of DKA and severe DKA compared with the same periods in 2017-2019. Results: Overall, the frequency of DKA increased from 35.7% (95%CI, 33.5-36.9) in 2017-2019 to 39.6% (95%CI, 36.7-42.4) in 2020 (p=0.008), while the frequency of severe DKA increased from 10.4% in 2017-2019 (95%CI, 9.4-11.5) to 14.2% in 2020 (95%CI, 12.3-16.4, p<0.001). DKA and severe DKA increased during the early pandemic period by 10.4% (p=0.004) and 8% (p=0.002), respectively, and the increase continued throughout 2020. Immigrant background increased and high household income decreased the probability of presenting with DKA (OR: 1.55; 95%CI, 1.24-1.94; p<0.001 and OR: 0.60; 95 CI, 0.41-0.88; p=0.010, respectively). Conclusions/Interpretation: There was an increase in the frequency of DKA and severe DKA in children newly diagnosed with type 1 diabetes during the COVID-19 pandemic in 2020, with no apparent association with the severity of COVID-19 infection severity or containment measures. There has been a silent outbreak of DKA in children during the pandemic, and preventive action is required to prevent this phenomenon in the event of further generalized lockdowns or future outbreaks.

Specific miRNAs Change After 3 Months of GH treatment and Contribute to Explain the Growth Response After 12 Months.

Context: There is growing evidence of the role of epigenetic regulation of growth, and miRNAs potentially play a role. Objective: The aim of this study is to identify changes in circulating miRNAs following GH treatment in subjects with isolated idiopathic GH deficiency (IIGHD) after the first 3 months of treatment, and verify whether these early changes can predict growth response. Design and Methods: The expression profiles of 384 miRNAs were analyzed in serum in 10 prepubertal patients with IIGHD (5 M, 5 F) at two time points before starting GH treatment (t-3, t0), and at 3 months on treatment (t+3). MiRNAs with a fold change (FC) >+1.5 or <-1.5 at t+3 were considered as differentially expressed. In silico analysis of target genes and pathways led to a validation step on 8 miRNAs in 25 patients. Clinical and biochemical parameters were collected at baseline, and at 6 and 12 months. Simple linear regression analysis and multiple stepwise linear regression models were used to explain the growth response. Results: Sixteen miRNAs were upregulated and 2 were downregulated at t+3 months. MiR-199a-5p (p = 0.020), miR-335-5p (p = 0.001), and miR-494-3p (p = 0.026) were confirmed to be upregulated at t+3. Changes were independent of GH peak values at testing, and levels stabilized after 12 months. The predicted growth response at 12 months was considerably improved compared with models using the common clinical and biochemical parameters. Conclusions: MiR-199a-5p, miR-335-5p, and miR-494-3p changed after 3 months of GH treatment and likely reflected both the degree of GH deficiency and the sensitivity to treatment. Furthermore, they were of considerable importance to predict growth response.

Significant and persistent improvements in time in range and positive emotions in children and adolescents with type 1 diabetes using a closed-loop control system after attending a virtual educational camp.

OBJECTIVE: To evaluate the six-month impact of the advanced automated functions of a closed-loop control (CLC) system (Control-IQ) and a virtual educational camp (vEC) on emotions and time in range (TIR) of children and adolescents with type 1 diabetes. METHODS: Children and their parents participated in a three-day vEC. Clinical, glucose, and emotion data were evaluated before, just after, and six months after the vEC. Emotions were evaluated using adapted Plutchik's and Geneva Emotion Wheels. RESULTS: Forty-three children and adolescents (7-16 years) showed significant improvements in positive emotions immediately and six months after the vEC (67% and 65% vs 38%, p < 0.05, respectively), while mixed emotions were reduced (32% and 15% vs 61%, p < 0.05 and p < 0.001, respectively). The median percentage TIR increased from 64% (IQR 54-72) to 75% (IQR 70-82) with Control-IQ (p < 0.001) six months after the vEC. CONCLUSIONS: Positive emotions (joy, serenity, and satisfaction) significantly improved while mixed emotions were significantly worse six months after the initiation of a CLC system (Control-IQ) and a vEC.

A comparative study on the incidence of type 1 diabetes mellitus between children of North African migrants and Italian children in Emilia-Romagna region, Italy.

In the last few decades, many studies have reported an increasing global incidence of type 1 diabetes. Studies on migrant populations have underlined the importance of both environmental and genetic factors. AIMS: Evaluate the incidence of type 1 diabetes in North African vs Italian children aged 0-14 years from 1 January 2015, to 31st December 2018, in Emilia-Romagna region, Italy. METHODS: Clinical and epidemiological data about childhood onset type 1 diabetes in Emilia Romagna region were retrospectively collected by the regional centers of pediatric diabetology and matched using 3 different data sources. RESULTS: 365 new cases were diagnosed. Total cumulative incidence was 15.4/100,000/year. North African cases showed a cumulative incidence of 53.8/100,000/year, statistically significant compared to cumulative incidence of the Italian cases alone 13.1/100,000/year (p value < 0.001). The annual incidence did not differ in the 4 years for both groups.  Conclusion: The incidence of type 1 diabetes in the pediatric age (0 14 years) was significantly higher in the North African population than in the Italian one, suggesting that a mix of genetic and environmental factors may have caused the increase in newly diagnosed cases. WHAT IS KNOWN: • The incidence of type 1 diabetes largely varies worldwide. • Study on immigrants helped to better understand the interplay role between genetics and environment. WHAT IS NEW: • This is the first study focused on the incidence of children and adolescents of North African migrants in Italy. • The incidence of children and adolescents of North African migrants in Emilia Romagna region, Italy, seems to be higher than that reported in the host countries, and, above all, than that reported in highest-incidence countries in Europe and in the world.

Growth hormone deficiency in a child with benign hereditary chorea caused by a de novo mutation of the TITF1/NKX2-1 gene.

OBJECTIVES: Benign Hereditary Chorea (BHC) (MIM 118700) is a rare childhood-onset movements disorder characterized by non-progressive chorea. It is usually caused by variants in the thyroid transcription factor 1 (TITF-1/NKX2-1) gene and it is associated with thyroid dysfunction and pulmonary symptoms in the brain-lung-thyroid syndrome. CASE PRESENTATION: We reported the clinical case of a toddler presenting with neurological symptoms (hypotonia, delayed motor milestones, and axial dystonia) and subclinical hypothyroidism in which we found a 'de novo' variant in the NKX2-1 gene. CONCLUSIONS: The peculiarity of our case is that the mild alteration of thyroid-stimulating hormone (TSH) levels, hypotonia, and delayed motor milestones were associated with growth hormone deficiency.

New insights on the effects of endocrine-disrupting chemicals on children.

OBJECTIVE: Endocrine disrupting chemicals (EDCs) are present in many areas and materials of the common life, and exposure to these chemicals can occur from products to personal care, from air and food. This review aims to summarize the more recent epidemiological findings for the impact of EDCs on endocrine system health in children, including effects in growth, metabolism, sexual development, and reproduction. SOURCES: The MEDLINE database (PubMed) was searched on August 24th, 2021, filtering for EDCs, endocrine disruptors, children, and humans. SUMMARY OF THE FINDINGS: Intrauterine exposure of EDCs can have transgenerational effects, thus laying the foundation for disease in later life. The dose-response relationship may not always be predictable as even low-level exposures that may occur in everyday life can have significant effects on a susceptible individual. Although individual compounds have been studied in detail, the effects of a combination of these chemicals are yet to be studied to understand the real-life situation where human beings are exposed to a "cocktail effect" of these EDCs. Epidemiological studies in humans suggest EDCs' effects on prenatal growth, thyroid function, glucose metabolism, obesity, puberty, and fertility mainly through epigenetic mechanisms. CONCLUSIONS: EDCs cause adverse effects in animals, and their effects on human health are now known and irrefutable. Because people are typically exposed to multiple endocrine disruptors, assessing public health effects is difficult. Legislation to ban EDCs and protect especially pregnant women and young children is required and needs to be revised and adjusted to new developments on a regular basis.