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.

Advanced Hybrid Closed Loop users' satisfaction of telemedicine and telenursing in pediatric and young adult type 1 diabetes.

Background and aims: The aim of the study was to evaluate the satisfaction of the use of telemedicine and telenursing in children and young adults with Type 1 Diabetes (T1D) using Advanced Hybrid Closed Loop systems (AHCL) with a focus on the role of connectivity, data download and the ease of technical steps in the set and sensor change procedures. Methods: An online anonymous survey was administered to AHCL users. The questionnaire consisted of five Clusters: Cluster A-B-C included questions related to the general satisfaction in the use of telemedicine, Cluster D was focused on the role of data download and connectivity, Cluster E was related to satisfaction in telenursing and Cluster F to the perception of ease of execution of the technical steps like changing the infusion set and the sensor. Results: We collected 136 completed questionnaires. 83.8% of AHCL users were overall satisfied with the quality of the telemedicine service. 88.2% of patients downloaded AHCL data before visits and the overall quality of televisits (data sharing, connectivity, ease of use) was satisfactory for 85.3% of users. Telenursing support during set and sensor change procedures was considered effective by 98% of AHCL users. The sensor and insulin infusion set change procedure is perceived as different for the two systems: set change simpler for Medtronic (p = 0.011) users, while sensor change was simpler for Tandem users (p = 0.009). Conclusion: Telemedicine and telenursing have an essential role in diabetology and are highly appreciated in AHCL users. The nurse support in the education of the use of AHCL systems is effective and must be implemented. Unfortunately, not all patients have the technological tools needed for downloading data at home and using telemedicine services; this represents an important challenge for the future of diabetology and for the equity in accessibility to care.

Blood Lymphocyte Subsets and Proinflammatory Cytokine Profile in ROHHAD(NET) and non-ROHHAD(NET) Obese Individuals.

Context: Rapid-onset obesity with central hypoventilation, hypothalamic dysfunction, and autonomic dysregulation with neural crest tumors (ROHHAD-NET) syndrome pathophysiology remains elusive. Acquired neuroimmunological dysfunction has been proposed as a possible pathogenetic pathway. Objective: The aim of our study was to characterize lymphocyte subpopulations subsets in peripheral blood (PB) and to evaluate a panel of proinflammatory cytokines/chemokines in ROHHAD(NET) patients vs controls. Methods: We included 11 ROHHAD(NET) patients, 7 ROHHAD and 4 ROHHAD-NET, selected by clinical criteria. Controls were 11 simple obese children, matched for age and sex. Flow cytometric analysis and enzyme-linked immunosorbent assay were performed on PB and serum samples of the 2 groups. Results: Analysis revealed that T lymphocytes are significantly increased in ROHHAD(NET) patients (P = .04) with a prevalence of CD4-T cells (P = .03) and a lower number of activated CD8-T cells (P = .02). With regard to regulatory subset, patients displayed increased regulatory B cells (P = .05) and type-1 regulatory T cells (P = .03). With regard to CD8-T cells, a lower number of T effector memory was observed (P = .02). In contrast, among CD4-T cells, we found a higher number of T naive (P = .04) and T effector (P = .0008). Interleukin-8 (IL-8) levels and monocyte chemotactic protein-1 were increased in patients vs controls (P = .008 and P = .01, respectively). Furthermore, IL-8 levels were higher in the subgroup with neural tumor (P = .0058) (ROHHAD-NET) than in patients without neural tumor (ROHHAD). Soluble HLA-G was significantly lower in patients vs controls (P = .03). Conclusion: Our findings contribute to support the hypothesis of immune dysregulation, which may underlie this complex, often fatal disease. Because ROHHAD(NET) syndrome is an ultra-rare disease, multicentric studies are needed to improve the effect of our data in the management of this condition.

Gut-microbiota in children and adolescents with obesity: inferred functional analysis and machine-learning algorithms to classify microorganisms.

The fecal microbiome of 55 obese children and adolescents (BMI-SDS 3.2 ± 0.7) and of 25 normal-weight subjects, matched both for age and sex (BMI-SDS - 0.3 ± 1.1) was analysed. Streptococcus, Acidaminococcus, Sutterella, Prevotella, Sutterella wadsworthensis, Streptococcus thermophilus, and Prevotella copri positively correlated with obesity. The inferred pathways strongly associated with obesity concern the biosynthesis pathways of tyrosine, phenylalanine, tryptophan and methionine pathways. Furthermore, polyamine biosynthesis virulence factors and pro-inflammatory lipopolysaccharide biosynthesis pathway showed higher abundances in obese samples, while the butanediol biosynthesis showed low abundance in obese subjects. Different taxa strongly linked with obesity have been related to an increased risk of multiple diseases involving metabolic pathways related to inflammation (polyamine and lipopolysaccharide biosynthesis). Cholesterol, LDL, and CRP positively correlated with specific clusters of microbial in obese patients. The Firmicutes/Bacteroidetes-ratio was lower in obese samples than in controls and differently from the literature we state that this ratio could not be a biomarker for obesity.

Next Generation Sequencing (NGS) Target Approach for Undiagnosed Dysglycaemia.

Next-generation sequencing (NGS) has revolutionized the field of genomics and created new opportunities for basic research. We described the strategy for the NGS validation of the "dysglycaemia panel" composed by 44 genes related to glucose metabolism disorders (MODY, Wolfram syndrome) and familial renal glycosuria using Ion AmpliSeq technology combined with Ion-PGM. Anonymized DNA of 32 previously genotyped cases with 33 different variants were used to optimize the methodology. Standard protocol was used to generate the primer design, library, template preparation, and sequencing. Ion Reporter tool was used for data analysis. In all the runs, the mean coverage was over 200×. Twenty-nine out of thirty three variants (96.5%) were detected; four frameshift variants were missed. All point mutations were detected with high sensitivity. We identified three further variants of unknown significance in addition to pathogenic mutations previously identified by Sanger sequencing. The NGS panel allowed us to identify pathogenic variants in multiple genes in a short time. This could help to identify several defects in children and young adults that have to receive the genetic diagnosis necessary for optimal treatment. In order not to lose any pathogenic variants, Sanger sequencing is included in our analytical protocol to avoid missing frameshift variants.

Corrigendum: Pubertal timing in children with Silver Russell syndrome compared to those born small for gestational age.

[This corrects the article DOI: 10.3389/fendo.2022.975511.].

Automated Insulin Delivery (AID) Systems: Use and Efficacy in Children and Adults with Type 1 Diabetes and Other Forms of Diabetes in Europe in Early 2023.

Type 1 diabetes (T1D) patients' lifestyle and prognosis has remarkably changed over the years, especially after the introduction of insulin pumps, in particular advanced hybrid closed loop systems (AHCL). Emerging data in literature continuously confirm the improvement of glycemic control thanks to the technological evolution taking place in this disease. As stated in previous literature, T1D patients are seen to be more satisfied thanks to the use of these devices that ameliorate not only their health but their daily life routine as well. Limited findings regarding the use of new devices in different age groups and types of patients is their major limit. This review aims to highlight the main characteristics of each Automated Insulin Delivery (AID) system available for patients affected by Type 1 Diabetes Mellitus. Our main goal was to particularly focus on these systems' efficacy and use in different age groups and populations (i.e., children, pregnant women). Recent studies are emerging that demonstrate their efficacy and safety in younger patients and other forms of diabetes.

"Pesto" Mutation: Phenotypic and Genotypic Characteristics of Eight GCK/MODY Ligurian Patients.

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes mellitus (DM) that accounts for around 2-5% of all types of diabetes. Autosomal dominant inheritance in pathogenic variations of 14 genes related to ß-cell functions can lead to monogenic types of diabetes. In Italy, GCK/MODY is the most frequent form and it is caused by mutations of the glucokinase (GCK). Patients with GCK/MODY usually have stable mild fasting hyperglycaemia with mildly elevated HbA1c levels and rarely need pharmacological treatment. Molecular analysis of the GCK coding exons was carried out by Sanger sequencing in eight Italian patients. All the probands were found to be heterozygous carriers of a pathogenic gross insertion/deletion c.1279_1358delinsTTACA; p.Ser426_Ala454delinsLeuGln. It was previously described for the first time by our group in a large cohort of Italian GCK/MODY patients. The higher levels of HbA1c (6.57% vs. 6.1%), and the higher percentage of patients requiring insulin therapy (25% vs. 2%) compared to the previously studied Italian patients with GCK/MODY, suggest that the mutation discovered could be responsible for a clinically worse form of GCK/MODY. Moreover, as all the patients carrying this variant share an origin from the same geographic area (Liguria), we postulate a possible founder effect and we propose to name it the "pesto" mutation.

Management of Type 1 Diabetes in a school setting: effectiveness of an online training program for school staff.

Background and aims: Since Type 1 Diabetes (T1D) onset usually occurs at a young age, a relevant number of affected people attend school for most of their time; it is necessary that school personnel receive appropriate education and training. We aimed to evaluate the effectiveness of the online training program offered by IRCCS Istituto Giannina Gaslini during and after COVID-19 pandemic. Methods: The Institute's Diabetes team offered an online training program to school staff of the Region during COVID-19 pandemic. A validated questionnaire was proposed to all the schools in which training meetings were held in the previous 2 years (2020-2021 and 2021-2022). The questionnaire consisted of four sections: Section 1 (Socio-demographical data), Section 2 (Theoretical knowledge on T1D), Section 3 (Confidence in handling T1D), and Section 4 (Practical skills and Glucagon Administration). To evaluate the effectiveness of the online training program, the answers between participants (Group A) and non-participants (Group B) were then compared. Results: 225 subjects from 19 schools participated in the survey. People who participated to the training (Group A, n = 53) demonstrated better T1D theoretical knowledge compared to non-participants (Group B, n = 154; p < 0.001). Group A revealed to feel more confident in the management of children with T1D during scholastic (p = 0.006) and extra-scholastic activities (p = 0.01), in supporting the children in the administration of insulin (p < 0.001) and in recognizing hypoglycaemia (p = 0.006). Moreover, results confirmed good levels of confidence among scholastic personnel who participated in the training of administration of glucagon in case of severe hypoglycaemia. Conclusion: School staff who took part in the online training program on management of T1D showed better theoretical knowledge and better confidence in the management of daily needs and possible emergencies of students with T1D. It appears essential to offer educational programs on T1D for school staff by implementing the use of technological tools to reach a wider population. Moreover, it is advisable to offer a more practical approach, involving educational nurses.

To sleep or not to sleep: An Italian Control-IQ-uestion.

Objective: Tandem Control-IQ is an advanced hybrid closed loop (AHCL) system with a Sleep Activity Mode to intensify glycemic control overnight. The aim of the study is to evaluate the effectiveness of using Sleep Mode or not among Tandem Control-IQ users. Research design and methods: We performed a retrospective Tandem Control-IQ data download for patients followed at IRCCS G. Gaslini Pediatric Diabetes Centre. We divided the patients into group 1 (Sleep Mode users) and group 2 (non-users) and compared their overall glycemic data, particularly during nighttime. Results: Group 1 (n = 49) does not show better nocturnal glycemic control as expected when compared with group 2 (n = 34). Group 2 shows a nighttime TIR% of 69.50 versus 66.25 (p = 0.20). Only the patients who do not use Sleep Mode and with sensor and automatic mode use ≥90% reached TIR >70% during nighttime, as well as lower nocturnal TAR% (18.80 versus 21.78, p = 0.05). Conclusions: This is the first study that evaluates the real-life effectiveness of the use of Sleep Mode in young patients with T1D. Control-IQ Sleep Activity Mode may not be as effective in Italian patients as in American patients due to the different habits.

Infectious diseases associated with pediatric type 1 diabetes mellitus: A narrative review.

Diabetes mellitus (DM) has been frequently associated with an impaired immune response against infectious agents, making affected patients at risk for more severe disease and sometimes causing worse outcomes. The recent COVID-19 pandemic has seriously affected patients with both diabetes, in particular those carrying comorbidities or with poor glycemic control. As regards pediatric diabetes mellitus, the availability of more accurate and technological tools for glycemic management and the improved markers of metabolic control might mitigate the negative impact of infections. Notably, good metabolic control of diabetes since its diagnosis reduces not only the risk of microangiopathic complications but also of impaired immune response to infectious diseases. Therefore, vaccinations are strongly recommended. Our paper aims to provide the most updated evidence regarding infectious diseases in type 1 pediatric DM.

Pubertal timing in children with Silver Russell syndrome compared to those born small for gestational age.

Context: Data on pubertal timing in Silver Russell syndrome (SRS) are limited. Design and methods: Retrospective observational study including twenty-three SRS patients [11p15 loss of methylation, (11p15 LOM, n=10) and maternal uniparental disomy of chromosome 7 (mUPD7, n=13)] and 21 small for gestational age (SGA). Clinical (thelarche in females; testis volume ≥ 4 ml in males; pubarche), BMI SD trend from the age of 5 to 9 years to the time of puberty, biochemical parameters of puberty onset [Luteinizing hormone (LH), 17-ß-estradiol, testosterone], and bone age progression were evaluated. Results: Pubertal onset and pubarche occurred significantly earlier in children with SRS than in SGA (p 0.03 and p 0.001, respectively) and clinical signs of puberty onset occurred earlier in mUPD7 than in 11p15LOM group (p 0.003). Five SRS children experienced central precocious puberty and LH, 17-ß-estradiol, testosterone were detected earlier in SRS than in SGA (p 0.01; p 0.0001). Bone age delay in SRS children was followed by rapid advancement; the delta between bone age and chronological age in SRS group became significantly higher than in SGA group at the age of 9-11 years (p 0.007). 11p15LOM patients were underweight at the age of 5 years and showed a progressive normalization of BMI that was significantly higher than in mUPD7 (p 0.04) and SGA groups (p 0.03) at puberty onset. Conclusion: Timing of puberty is affected in SRS and occurred earlier in mUPD7 compared to 11p15LOM. The impact of early puberty on adult height and metabolic status deserves long-term evaluation.

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.

[This corrects the article .].

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.

Diabetes Mellitus Diagnosed in Childhood and Adolescence With Negative Autoimmunity: Results of Genetic Investigation.

Monogenic diabetes is a rare form of diabetes, accounting for approximately 1% to 6% of pediatric diabetes patients. Some types of monogenic diabetes can be misdiagnosed as type 1 diabetes in children or adolescents because of similar clinical features. Identification of the correct etiology of diabetes is crucial for clinical, therapeutic, and prognostic issues. Our main objective was to determine the prevalence of monogenic diabetes in patients with diabetes mellitus, diagnosed in childhood or in adolescence, and negative autoimmunity. We retrospectively analyzed clinical data of 275 patients diagnosed with insulin-dependent diabetes at age <18yr in the last 10 years. 8.4% of subjects has negative autoimmunity. Their DNA was sequenced by NGS custom panel composed by 45 candidate genes involved in glucose metabolism disorder. Two novel heterozygous pathogenic or likely pathogenic variants (10,5% of autoantibody negative subjects) were detected: the frameshift variant c.617_618insA in NEUROD1 exon 2 and the missense change c.116T>C in INS exon 2. Our study corroborates previous results of other reports in literature. NGS assays are useful methods for a correct diagnosis of monogenic diabetes, even of rarest forms, highlighting mechanisms of pediatric diabetes pathogenesis.

Patient Satisfaction of Telemedicine in Pediatric and Young Adult Type 1 Diabetes Patients During Covid-19 Pandemic.

The aim of this study was to evaluate the satisfaction of the use of telemedicine and telenursing in children and young adults with Type 1 Diabetes and their families followed in the Regional Pediatric Diabetes Center of Giannina Gaslini Institute (Liguria, Italy). An anonymous survey form was administered to 290 patients (138 filled out by caregivers and 152 by patients). The questionnaire consisted of two parts: the first one included a series of questions related to the patient's personal and medical data; the second one was directed toward the satisfaction in the use of telemedicine and telenursing during Covid-19 pandemic. The data collected showed that 92.4% of the population was overall very satisfied with the quality of the service provided. Satisfaction was much higher especially in those who live outside of the province of Genoa (p = 0.017) and in those on insulin pump treatment (p = 0.037). Telemedicine and telenursing have an essential role in diabetology and are highly appreciated in our Center, where most patients prefer to continue regular follow-up via video-call as well as in person. Telenursing was also proved to be an effective and appreciated tool for educating and supporting patients using insulin pumps and glucose sensors.

An Atypical Case of Late-Onset Wolfram Syndrome 1 without Diabetes Insipidus.

Wolfram syndrome 1, a rare autosomal recessive neurodegenerative disease, is caused by mutations in the WFS1 gene. It is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD), and other clinical manifestations such as urological and neurological disorders. Here we described the case of a patient with an atypical late-onset Wolfram syndrome 1 without DI. Our WS1 patient was a c.1620_1622delGTG (p.Trp540del)/c.124 C > T (p.Arg42*) heterozygous compound. The p.Arg42* nonsense mutation was also found in heterozygosity in his sister and niece, both suffering from psychiatric disorders. The p.Arg42* nonsense mutation has never been found in WS1 and its pathogenicity is unclear so far. Our study underlined the need to study a greater number of WS1 cases in order to better understand the clinical significance of many WFS1 variants.

Increased Frequency of Diabetic Ketoacidosis: The Link With COVID-19 Pandemic.

Aims: Diabetic ketoacidosis is the most severe metabolic derangement due to prolonged insulin deficiency as in type 1 diabetes. Diabetic ketoacidosis, a life-threatening condition, is often diagnosed late. A timely diagnosis is mandatory to prevent its consequences, mainly neurological. The COVID-19 pandemic and lockdown have reduced the availability of medical care and access to hospitals. The aim of our retrospective study was to compare the frequency of ketoacidosis at the diagnosis of type 1 diabetes between the lockdown-post lockdown period and the previous two calendar years, in order to evaluate the impact of the COVID-19 pandemic. Patients and Methods: We retrospectively assessed the clinical and metabolic data at the diagnosis of type 1 diabetes in children in the Liguria Region during 3 different time periods: calendar year 2018 (Period A), calendar year 2019 until February 23,2020 (Period B) and from February 24, 2020 onwards to March 31, 2021 (Period C). Results: We analyzed 99 patients with newly-diagnosed T1DM from 01/01/2018 to 31/03/2021. Briefly, a younger age at diagnosis of T1DM was observed in Period 2 compared to Period 1 (p = 0.03). The frequency of DKA at clinical onset of T1DM was similar in Period A (32.3%) and Period B (37.5%), while it significantly increased in Period C (61.1%) compared to Period B (37.5%) (p = 0.03). PH values were similar in Period A (7.29 ± 0.14) and Period B (7.27 ± 0.17), while they were significantly lower in Period C (7.21 ± 0.17) compared to Period B (p = 0.04). Conclusions: An increase in the frequency of diabetic ketoacidosis has been documented in newly diagnosed pediatric patients in the Liguria Region during and after the lockdown period compared to previous calendar years. This increase could have been caused by the delay in diagnosis following the restrictions imposed by the lockdown with consequently reduced access to health care facilities. More information on the risks of ketoacidosis is desirable by means of social and medical awareness campaigns.

Urinary Tract Involvement in Wolfram Syndrome: A Narrative Review.

Wolfram Syndrome (WS) is a rare neurodegenerative disease with autosomal recessive inheritance and characterized by juvenile onset, non-autoimmune diabetes mellitus and later followed by optic atrophy leading to blindness, diabetes insipidus, hearing loss, and other neurological and endocrine dysfunctions. A wide spectrum of neurodegenerative abnormalities affecting the central nervous system has been described. Among these complications, neurogenic bladder and urodynamic abnormalities also deserve attention. Urinary tract dysfunctions (UTD) up to end stage renal disease are a life-threatening complication of WS patients. Notably, end stage renal disease is reported as one of the most common causes of death among WS patients. UTD have been also reported in affected adolescents. Involvement of the urinary tract occurs in about 90% of affected patients, at a median age of 20 years and with peaks at 13, 21 and 33 years. The aim of our narrative review was to provide an overview of the most important papers regarding urological impairment in Wolfram Syndrome. A comprehensive search on PubMed including Wolfram Syndrome and one or more of the following terms: chronic renal failure, bladder dysfunction, urological aspects, and urinary tract dysfunction, was done. The exclusion criteria were studies not written in English and not including urinary tract dysfunction deep evaluation and description. Studies mentioning general urologic abnormalities without deep description and/or follow-up were not considered. Due to the rarity of the condition, we considered not only papers including pediatric patients, but also papers with pediatric and adult case reports.