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Background and aimsCystic fibrosis related diabetes (CFRD) is correlated with worsening of nutritional status and greater deterioration of lung function. The role of new technologies for the treatment of CFRD is little explored. The aim of the study was to evaluate the efficacy of Advanced Hybrid Closed Loop (AHCL) systems on glycemic control in CF patients.MethodsA single-center retrospective study on CFRD patients using AHCL systems was performed. Glycated hemoglobin (HbA1c) values and Continuous Glucose Monitoring (CGM) metrics were collected at T0 (AHCL placement), T1 (1-month), T2 (6-months) and T3 (1-year) to evaluate glycemic control.Results10 patients were included in the study. Data showed a reduction of HbA1c value (7.31 ± 0.34 to 6.35 ± 1.00; p=0.03), glycemic variability (p=0.05) and insulin requirement (p=0.03). The study population reached American Diabetes Association (ADA) recommended glycemic targets at 1-year. An increase in the Time in Range (TIR) and a reduction in time in hyperglycemia were also observed, although not statistically significant.ConclusionsIn patients with CFRD, the use of AHCL leads to an improvement in glycemic control in terms of HbA1c and glycemic variability. The increase in TIR and the reduction of time in hyperglycemia, although not statistically significant, are extremely encouraging from a clinical point of view. Further studies with a larger population and a longer follow-up are needed. The results of this study demonstrate the importance of proposing the use of AHCL even in CF patients, who could benefit from glycemic improvement also in terms of nutritional status and respiratory function.

Introduction: The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial. Aim: The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population. Materials and methods: A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T3mo), 6 months (T6mo) and 12 months (T12mo) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del). Results: Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T3mo and T6mo, but not at T12mo, whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly. Conclusion: We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

The case report shows the safety and efficacy of insulin treatment with Advanced Hybrid Closed Loop (AHCL) system in a young patient affected by permanent neonatal diabetes mellitus (PNDM) due to chromosome 8 deletion syndrome involving the GATA4 gene. In the first days of life, he presented hyperglycaemia and started an intravenous insulin infusion therapy, replaced by a continuous subcutaneous insulin infusion (CSII) with Medtronic Minimed 780G® insulin pump (Medtronic, Northridge, CA, USA). At the age of 2 years, the off-label activation of SmartGuard® automated insulin delivery mode led to a great improvement in glycaemic control, reaching all recommended targets. At the 1-month follow-up visit, Time in Range (TIR) increased from 66% to 79%, with a Time in Tight Range (TTIR) of 55% and a reduction of 11% in time in hyperglycaemia and of 2% in time in hypoglycaemia. During the entire follow-up, no episodes of ketoacidosis or severe hypoglycaemia were observed and the patient maintained the glycaemic recommended targets reached at 1 month. Maintaining optimal glycaemic control and reducing hyperglycaemia are essential for brain growth and neurocognitive development in young patients. AHCL use should be considered to ensure good glycaemic control in patients affected by neonatal diabetes.

Abstract 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.

Background and aimsSince 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.MethodsThe 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.Results225 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

Background and aimsThe 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.MethodsAn 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.ResultsWe 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).ConclusionTelemedicine 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.

ObjectiveTandem 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 methodsWe 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.ResultsGroup 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).ConclusionsThis 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.

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.

ContextData on pubertal timing in Silver Russell syndrome (SRS) are limited.Design and methodsRetrospective 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-β-estradiol, testosterone], and bone age progression were evaluatedResultsPubertal 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-β-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.ConclusionTiming 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.

Aim/HypothesisTo 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.MethodsForty-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.ResultsOverall, 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

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 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.

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.

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.

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.

AimsDiabetic 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 MethodsWe 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).ResultsWe 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).ConclusionsAn 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.

Tandem Control-IQ and Minimed 780G represent the most Advanced Hybrid Closed Loop (AHCL) systems currently available in pediatric and adult subjects with Type 1 Diabetes (T1D). We retrospectively compared clinical and continuous glucose monitoring data from 51 patients who upgraded to Minimed 780G system and have completed 1-month observation period with data from 39 patients who upgraded to Tandem Control-IQ. Inverse probability weighting was used to minimize the basal characteristics imbalances. Both AHCL systems showed a significant improvement in glycemic parameters. Minimed 780G group achieved higher TIR increase (p= 0.004) and greater reduction of blood glucose average (p= 0.001). Tandem Control-IQ system significantly reduced the occurrence of TBR (p= 0.010) and the Coefficient of Variation of glucose levels (p= 0.005). The use of ACHL systems led to a significant improvement of glycemic control substantially reaching the International recommended glycemic targets. Minimed 780G appears to be more effective in managing hyperglycemia, while Tandem Control-IQ seems to be more effective in reducing time in hypoglycemia.

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 β-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.

Wieacker-Wolff syndrome (WWS) is an X-linked Arthrogryposis Multiplex Congenita (AMC) disorder associated with broad neurodevelopmental impairment. The genetic basis of WWS lies in hemizygous pathogenic variants in ZC4H2, encoding a C4H2 type zinc-finger nuclear factor abundantly expressed in the developing human brain. The main clinical features described in WWS families carrying ZC4H2 pathogenic variants encompass having a short stature, microcephaly, birth respiratory distress, arthrogryposis, hypotonia, distal muscle weakness, and broad neurodevelopmental delay. We hereby report a Sicilian family with a boy clinically diagnosed with WWS and genetically investigated with exome sequencing (ES), leading to the identification of a c.593G>A (p. R198Q) hemizygous pathogenic variant in the ZC4H2 gene. During the first year of life, the onset of central hypoadrenalism led to recurrent hypoglycemic events, which likely contributed to seizure susceptibility. Also, muscle biopsy studies confirmed a pathology of the muscle tissue and revealed peculiar abnormalities of the neuromuscular junction. In conclusion, we expand the phenotypic spectrum of the WWS-related neurodevelopmental disorders and discuss the role of ZC4H2 in the context of the potential neuroendocrinological and neuromuscular features associated with this condition.

AimsThe purpose of the study was to evaluate the impact of the lockdown established by the Italian government to limit the spread of Coronavirus disease (COVID-19) on glycemic control in a large sample of patients with type 1 diabetes (T1D) based on age, type of insulin therapy, number of telemedicine visits and physical activity.Material and MethodsWe retrospectively evaluated glycemic control in young T1D patients using the DexcomG6® system before the Italian lockdown (February 10–23, 2020—Time 0) and during lockdown (April 17–30, 2020—Time 1). Data on age, type of insulin therapy, number of telemedicine visits and physical activity of 202 patients with T1D and a median age of 18.2 years (range: 6–39) were collected.ResultsData showed a significant improvement of TIR from 54.58% at T0 to 59.09% at T1 (p ≤0.0001). Glycemic control improved significantly in patients ≥14 years old, showing the best outcome in the “university students and young adults” group (55.40% at T0 and 61.37% at T1, p ≤0.001). All patients reduced physical activity during lockdown; in the 56 patients of “intense physical activity” group both at T0 and T1 TIR increased from ±56.91 to 64.11% (p ≤0.0001).ConclusionsOverall, the lockdown led to an unexpected improvement in glycemic control of young patients with T1D. A healthier and stressless lifestyle changes in association with the maintenance of physical activity resulted in a significant age-proportional improvement in glycemic control.

Cystic fibrosis related diabetes (CFRD) is a comorbidity of cystic fibrosis (CF) that negatively impacts on its clinical course. Prediabetes is an important predictor of either CFRD development and unfavorable prognosis of CF in both pediatric and adult patients. International guidelines recommend insulin only in case of CFRD diagnosis. Whether early detection and treatment of prediabetes may contribute to improve the clinical course of CF is still debated. A subgroup of pediatric diabetologists of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED) performed a systematic review of the literature based on predefined outcomes: impact of pre-diabetes on clinical outcomes and on the risk of developing CFRD; diagnosis of diabetes and pre-diabetes under 10 years of age; effectiveness of therapy on glycemic control, impact of therapy on pulmonary function and nutritional status. Thirty-one papers were selected for the analysis data presented in these papers were reported in tables sorted by outcomes, including comprehensive evidence grading according to the GRADE approach. Following the grading of the quality of the evidence, the entire ISPED diabetes study group achieved consensus for the Italian recommendations based on both evidence and clinical experience. We concluded that in patients with CF, prediabetes should be carefully considered as it can evolve into CFRD. In patients with CF and prediabetic conditions, after complete evaluation of the OGTT trend, glucometrics, glycemic values measured during pulmonary exacerbations and/or steroid therapy, early initiation of insulin therapy could have beneficial effects on clinical outcomes of patients with CF and prediabetes.

This study aims to compare the frequency of Diabetic Ketoacidosis (DKA) at diagnosis in 2014–2016 with the one previously reported in 2004–2013; and to assess the association between family socioeconomic status and DKA at type 1 diabetes (T1D) diagnosis in children

Assessment of endothelial dysfunction in cancer survivors may have a role in the early identification of non-communicable diseases and cardiovascular late effects. Oncological therapies may impair endothelial function. Therefore, in patients such as childhood cancer survivors who could benefit from early cardioprotective pharmacological interventions, it is essential to monitor endothelial function, even if the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, as well as invasive and non-invasive tools with and without pharmacological stimuli have been studied. Human clinical studies that have examined lifestyle or cancer treatment protocols have yielded evidence showing the involvement of lipid and lipoprotein levels, glycemic control, blood pressure, adiposity, inflammation, and oxidative stress markers on the state of endothelial health and its role as an early indicator of cardiometabolic risk. However, with regards to pharmacological interventions, cautious interpretation of the result attained whilst monitoring the endothelial function is warranted due to methodological limitations and substantial heterogeneity of the results reported in the published studies. In this narrative review, an overview of evidence from human clinical trials examining the effects of cancer therapies on endothelial disease is provided together with a discussion of endothelial function assessment using the different non-invasive techniques available for researchers and clinicians, in recent years.

Our objective is to emphasize the important role of continuous glucose monitoring (CGM) in suggesting adrenal insufficiency in patients affected by type 1 diabetes. We describe an adolescent girl with type 1 diabetes and subsequent latent Addison’s disease diagnosed based on a recurrent hypoglycemic trend detected by CGM. In patients with type 1 diabetes, persistent unexplained hypoglycemic episodes at dawn together with reduced insulin requirement arouse souspicionof adrenal insufficiency. Adrenal insufficiency secondary to autoimmune Addison’s disease, even if rarely encountered among young patients, may be initially symptomless and characterized by slow progression up to acute adrenal crisis, which represents a potentially life-threatening condition. Besides glycometabolic assessment and adequate insulin dosage adjustment, type 1 diabetes needs prompt recognition of potentially associated autoimmune conditions. Among these, Addison’s disease can be suspected, although latent or paucisymptomatic, through periodic and careful evaluation of CGM data.

We conducted a retrospective survey in pediatric centers belonging to the Italian Society for Pediatric Diabetology and Endocrinology. The following data were collected for all new-onset diabetes patients aged 0–18 years: DKA (pH < 7.30), severe DKA (pH < 7.1), DKA in preschool children, DKA treatment according to ISPAD protocol, type of rehydrating solution used, bicarbonates use, and amount of insulin infused. Records (n=2453) of children with newly diagnosed diabetes were collected from 68/77 centers (87%), 39 of which are tertiary referral centers, the majority of whom (n=1536, 89.4%) were diagnosed in the tertiary referral centers. DKA was observed in 38.5% and severe DKA in 10.3%. Considering preschool children, DKA was observed in 72%, and severe DKA in 16.7%. Cerebral edema following DKA treatment was observed in 5 (0.5%). DKA treatment according to ISPAD guidelines was adopted in 68% of the centers. In the first 2 hours, rehydration was started with normal saline in all centers, but with different amount. Bicarbonate was quite never been used. Insulin was infused starting from third hour at the rate of 0.05–0.1 U/kg/h in 72% of centers. Despite prevention campaign, DKA is still observed in Italian children at onset, with significant variability in DKA treatment, underlying the need to share guidelines among centers.

Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells. The role played by autoantibodies directed against beta cells antigens in the pathogenesis of the disease is still unclear. Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet. To clarify these issues, we screened a random peptide library with sera obtained from 58 patients with recent onset type 1 diabetes, before insulin therapy. We identified an immunodominant peptide recognized by the majority of individual patients'sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis. Antibodies against the peptide affinity-purified from patients' sera, recognized the viral protein and autoantigens; moreover, such antibodies induced apoptosis of the beta cells upon binding the L-type calcium channels expressed on the beta cell surface, suggesting a calcium dependent mechanism. Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.

BACKGROUND: Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym "DIDMOAD". The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. METHODOLOGY/PRINCIPAL FINDINGS: We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. CONCLUSIONS/SIGNIFICANCE: Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA).

Acute or perforated appendicitis within inguinal hernia is rarely encountered and it is known as Amyand’s hernia. We report on the first case occurring in a 4-year-old boy affected by permanent neonatal diabetes mellitus due to pancreatic agenesis, an extremely rare condition. The initial suspicion of inguinal hernia was confirmed by ultrasound examination of the right inguinal region which revealed omental layers inside a swollen inguinal canal; this finding and the clinical presentation allowed a prompt and appropriate surgical management. The careful evaluation of this patient and early recognition of this unique presentation of appendicitis allowed trans-hernial appendectomy and immediate herniorrhaphy. Ultrasonography played a pivotal role to reach the correct diagnosis and to start a prompt treatment.