Adolescent gender dysphoria management: position paper from the Italian Academy of Pediatrics, the Italian Society of Pediatrics, the Italian Society for Pediatric Endocrinology and Diabetes, the Italian Society of Adolescent Medicine and the Italian Society of Child and Adolescent Neuropsychiatry.

BACKGROUND: In response to the imperative need for standardized support for adolescent Gender Dysphoria (GD), the Italian Academy of Pediatrics, in collaboration with the Italian Society of Pediatrics, the Italian Society for Pediatric Endocrinology and Diabetes, Italian Society of Adolescent Medicine and Italian Society of Child and Adolescent Neuropsychiatry is drafting a position paper. The purpose of this paper is to convey the author's opinion on the topic, offering foundational information on potential aspects of gender-affirming care and emphasizing the care and protection of children and adolescents with GD. MAIN BODY: Recognizing that adolescents may choose interventions based on their unique needs and goals and understanding that every individual within this group has a distinct trajectory, it is crucial to ensure that each one is welcomed and supported. The approach to managing individuals with GD is a multi-stage process involving a multidisciplinary team throughout all phases. Decisions regarding treatment should be reached collaboratively by healthcare professionals and the family, while considering the unique needs and circumstances of the individual and be guided by scientific evidence rather than biases or ideologies. Politicians and high court judges should address discrimination based on gender identity in legislation and support service development that aligns with the needs of young people. It is essential to establish accredited multidisciplinary centers equipped with the requisite skills and experience to effectively manage adolescents with GD, thereby ensuring the delivery of high-quality care. CONCLUSION: Maintaining an evidence-based approach is essential to safeguard the well-being of transgender and gender diverse adolescents.

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.

Differences in Plasma 25-Hydroxyvitamin D Levels at Diagnosis of Celiac Disease and Type 1 Diabetes.

AIM: The aim of this work is to assess the vitamin D levels, evaluated as plasma 25-hydroxyvitamin D of children with a new diagnosis of celiac disease (CD), of children with a new onset of type 1 diabetes (T1D) and in children with CD at diagnosis of T1D (T1D&CD). METHODS: In this single-center observational study, we collected data for four groups of children and adolescents: T1D, CD, T1D&CD, and a control group (CG). The CG included schoolchildren who had negative results during a mass screening campaign for CD and were not diagnosed for T1D, according to RIDI Marche registry data, were considered for the purposes of this study. Plasma 25-hydroxyvitamin D, 25(OH)D2, and 25(OH)D3 were considered as the parameters for evaluating vitamin D nutritional status, and the date of measurement was recorded to analyze vitamin D level seasonality. Vitamin D nutritional status was categorized as follows: severe deficiency (<10 ng/mL), deficiency (<20 ng/mL), insufficiency (20-29 ng/mL), or sufficiency/adequacy (≥30 ng/mL). The Kruskal-Wallis test was used to compare the groups. The association of 25(OH)D levels with health conditions and seasonal differences of 25(OH)D levels was analyzed using a multiple linear regression model. RESULTS: The number of children enrolled for the present study was 393: 131 in the CG, 131 CD, 109 T1D, and 22 T1D&CD. Significantly lower levels of vitamin D were displayed for children with CD, T1D, or both the diseases. Interestingly, severe vitamin D deficiency was detected in no children with CD, 1.5% of children in the CG, in 24.4% with T1D, and 31.8% with T1D&CD (p < 0.001). As expected, the CG children vitamin D levels were significantly influenced by seasonality. Contrarily, no seasonal differences were reported in children with CD, T1D, and T1D&CD. Multiple regression analysis showed that children with T1D and T1D&CD had lower 25(OH)D levels of 9.9 ng/mL (95% CI: 5.4; 14.5) and 14.4 ng/mL (95% CI: 6.2-22.7) compared to CG children (p < 0.001). CONCLUSIONS: Our results showed low levels of vitamin D diagnosis of T1D, CD, and T1D&CD; however, severe deficiency was only reported in children with T1D and T1D&CD. More studies are needed to better understand the role of this deficiency in children newly diagnosed with CD and T1D.

Central Precocious Puberty in Italian Boys: Data From a Large Nationwide Cohort.

CONTEXT: There are only a few nationwide studies on boys with central precocious puberty (CPP) and the last Italian study is a case series of 45 boys that dates back to 2000. OBJECTIVE: We aimed to evaluate the causes of CPP in boys diagnosed during the last 2 decades in Italy and the relative frequency of forms with associated central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) compared to idiopathic ones. METHODS: We performed a national multicenter retrospective study collecting data from 193 otherwise normal healthy boys with a diagnosis of CPP. Based on MRI findings, the patients were divided into: Group 1, no CNS abnormalities; Group 2, mild abnormalities (incidental findings) unrelated to CPP; and Group 3, causal pathological CNS abnormalities. RESULTS: The MRI findings show normal findings in 86%, mild abnormalities (incidental findings) in 8.3%, and causal pathological CNS abnormalities in 5.7% of the cases. In Group 3, we found a higher proportion of patients with chronological age at diagnosis < 7 years (P = .00001) and body mass index greater than +2 SDS (P < .01). Gonadotropin-releasing hormone analogue therapy was started in 183/193 subjects. The final height appeared in the range of the target height in all groups and in 9 patients in whom the therapy was not started. CONCLUSION: In our study on a large nationwide cohort of boys referred for precocious puberty signs, the percentage of forms associated with CNS abnormalities was one of the lowest reported in the literature.

Satisfaction with continuous glucose monitoring is associated with quality of life in young people with type 1 diabetes regardless of metabolic control and treatment type.

AIMS: While continuous glucose monitoring (CGM) and associated technologies have positive effects on metabolic control in young people with type 1 diabetes (T1D), less is known about their impact on quality of life (QoL). Here, we quantified CGM satisfaction and QoL in young people with T1D and their parents/caregivers to establish (i) the relationship between QoL and CGM satisfaction and (ii) the impact of the treatment regimen on QoL. METHODS: This was a cross-sectional study of children and adolescents with T1D on different treatment regimens (multiple daily injections, sensor-augmented pumps and automated insulin delivery). QoL was assessed with the KINDL instrument, and CGM satisfaction with the CGM-SAT questionnaire was evaluated in both youths with T1D and their parents. RESULTS: Two hundred and ten consecutively enrolled youths with T1D completed the KINDL and CGM-SAT questionnaires. The mean total KINDL score was greater than neutral in both subjects with T1D (3.99 ± 0.47) and parents (4.06 ± 0.40), and lower overall CGM-SAT scores (i.e., higher satisfaction) were significantly associated with higher QoL in all six KINDL subscales (p < 0.05). There were no differences in KINDL scores according to delivery technology or when participants were grouped according to optimal and sub-optimal glucose control. CONCLUSIONS: Higher satisfaction with recent CGMs was associated with better QoL in all dimensions. QoL was independent of both the insulin delivery technology and glycaemic control. CGM must be further disseminated. Attention on perceived satisfaction with CGM should be incorporated with the clinical practice to improve the well-being of children and adolescents with T1D and their families.

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.

Satisfaction with continuous glucose monitoring is positively correlated with time in range in children with type 1 diabetes.

AIMS: Continuous glucose monitoring (CGM) can improve glucometrics in children with type 1 diabetes (T1D), and its efficacy is positively related to glucose sensor use for at least 60% of the time. We therefore investigated the relationship between CGM satisfaction as assessed by a robust questionnaire and glucose control in pediatric T1D patients. METHODS: This was a cross-sectional study of children and adolescents with T1D using CGM. The CGM Satisfaction (CGM-SAT) questionnaire was administered to patients and demographic, clinical, and glucometrics data were recorded. RESULTS: Two hundred and ten consecutively enrolled patients attending 14 Italian pediatric diabetes clinics completed the CGM-SAT questionnaire. CGM-SAT scores were not associated with age, gender, annual HbA1c, % of time with an active sensor, time above range (TAR), time below range (TBR), and coefficient of variation (CV). However, CGM satisfaction was positively correlated with time in range (TIR, p < 0.05) and negatively correlated with glycemia risk index (GRI, p < 0.05). CONCLUSIONS: CGM seems to have a positive effect on glucose control in patients with T1D. CGM satisfaction is therefore an important patient-reported outcome to assess and it is associated with increased TIR and reduced GRI.

Autoantibody test for type 1 diabetes in children: are there reasons to implement a screening program in the general population? A statement endorsed by the Italian Society for Paediatric Endocrinology and Diabetes (SIEDP-ISPED) and the Italian Society of Paediatrics (SIP).

In recent years screening of type 1 diabetes (T1D) in both at risk children and general population has been widely discussed with the aim of increasing awareness of the importance to early detect (and possibly treat) at-risk children in early stages of the chronic autoimmune progression to T1D.In fact, it is well known that first-degree relatives have the highest risk of T1D, but up to 90% of children who develop T1D do not have a family history and belong to the general population.The reasons for screening children well before the clinical onset of T1D include prevention of DKA (still up to 60% children are diagnosed with DKA) and related morbidities and mortality, reducing the need for hospitalisation, time to provide emotional support and education to ensure a smooth transition to insulin treatment, and opportunities for new treatments to prevent or delay progression.There are pros and cons of screening of T1D in children, but recent evidences suggest that it is now time to consider possible a screening for T1D in children.Recently, the European Society for Paediatric Endocrinology (ESPE) has endorsed a Position Statement, discussing the pros and cons of screening for T1D in the general population; ESPE supports national Societies for Paediatric Endocrinology to spread information on this important issue in various countries throughout Europe; the Italian Society for Paediatric Endocrinology and Diabetes (SIEDP-ISPED) and the Italian Society of Paediatrics (SIP) endorse this document with the specific aim of increasing awareness on screening for paediatric T1D in the general population.

Adjustment of octreotide dose given via insulin pump based on continuous glucose monitoring (CGM) in a child with congenital hyperinsulinism.

OBJECTIVES: CHI is a relevant cause of persistent and severe hypoglycemia and the ABCC8 gene mutation is one of most common cause of the disease. Two main types of CHI have been described, diffuse and focal form. Octreotide is a medication utilized in case of diazoxide-unresponsive forms of CHI. For those CHI focal forms where is decided either to manage medically or until resolutive surgery is completed, octreotide can be administered as subcutaneous injection or as continuous subcutaneous infusion via insulin pump. However, it is unclear how to adjust the drug's daily basal pattern when a pump is used. CASE PRESENTATION: We present a case of an infant with a diazoxide-unresponsive focal form of CHI, due to ABCC8 mutation ABCC8, treated with octreotide. To better evaluate the glycemic trend, a CGM was placed. In order to achieve a better personalization of the therapy we utilized an insulin pump for octreotide administration. CONCLUSIONS: The adoption of the CGM and insulin pump, allowed a better personalization of the therapy and a reduction of acute carbohydrate intake, promoting a good auxological growth before resolutive surgery. What is new? Octreotide administered with an insulin pump in patient with CHI allows a wide modulation of the daily therapy. The CGM allows a continuous and a less painful control of the glycemic trend in a patient with CHI. Different basal rates, given via insulin pump may allow a better personalization of the therapy. Prevention of hypoglycemia reduces the acute introduction of carbohydrates, promoting normal growth..

A Risk Profile for Disordered Eating Behaviors in Adolescents with Type 1 Diabetes: A Latent Class Analysis Study.

(1) Background: This multi-center study aimed to identify a risk profile for disordered eating behaviors (DEBs) in youth with type 1 diabetes (T1D) based on their dietary intake, lipid profile, body mass index (BMI-SDS), and glycometabolic control. (2) Methods: Adolescents aged 11 to 18 years from five centers across Italy were recruited. Lipid profile, HbA1c, BMI-SDS, and dietary intake data were collected. The risk for developing DEBs was assessed via the Diabetes Eating Problems Survey-R (DEPS-R) questionnaire. A latent class analysis (LCA) was performed using a person-centered approach. (3) Results: Overall, 148 participants aged 11-18 (12.1, ±3.34), 52% males with a mean diabetes duration of 7.2 (±3.4), were enrolled. Based on the results of the DEBS-R score, LCA allowed us to highlight two different classes of patients which were defined as "at-risk" and "not at-risk" for DEB. The risk profile for developing DEBs is characterized by higher BMI-SDS (23.9 vs. 18.6), higher HbA1c (7.9 vs. 7.1%), higher LDL cholesterol (99.9 vs. 88.8 mg/dL), lower HDL cholesterol (57.9 vs. 61.3 mg/dL), higher proteins (18.2 vs. 16.1%), and lower carbohydrates (43.9 vs. 45.3%). Adolescents included in the "at-risk" class were significantly older (p = 0.000), and their parents' SES was significantly lower (p = 0.041). (4) Conclusions: This study allowed us to characterize a risk profile for DEBs based on dietary behavior and clinical parameters. Early identification of the risk for DEBs allows timely intervention and prevention of behavior disorders.

Trends and cyclic variation in the incidence of childhood type 1 diabetes in two Italian regions over 33 years and during the COVID-19 pandemic.

AIM: There is conflicting evidence about the impact of the COVID-19 pandemic on the incidence of type 1 diabetes. Here, we analysed long-term trends in the incidence of type 1 diabetes in Italian children and adolescents from 1989 to 2019 and compared the incidence observed during the COVID-19 pandemic with that estimated from long-term data. MATERIALS AND METHODS: This was a population-based incidence study using longitudinal data from two diabetes registries in mainland Italy. Trends in the incidence of type 1 diabetes from 1 January 1989 to 31 December 2019 were estimated using Poisson and segmented regression models. RESULTS: There was a significant increasing trend in the incidence of type 1 diabetes of 3.6% per year [95% confidence interval (CI): 2.4-4.8] between 1989 and 2003, a breakpoint in 2003, and then a constant incidence until 2019 (0.5%, 95% CI: -1.3 to 2.4). There was a significant 4-year cycle in incidence over the entire study period. The rate observed in 2021 (26.7, 95% CI: 23.0-30.9) was significantly higher than expected (19.5, 95% CI: 17.6-21.4; p = .010). CONCLUSION: Long-term incidence analysis showed an unexpected increase in new cases of type 1 diabetes in 2021. The incidence of type 1 diabetes now needs continuous monitoring using population registries to understand better the impact of COVID-19 on new-onset type 1 diabetes in children.

Italian translation and validation of the CGM satisfaction scale questionnaire.

AIMS: Patient-reported outcomes (PROs) are increasingly important for assessing patient satisfaction with diabetes technologies. PROs must be assessed with validated questionnaires in clinical practice and research studies. Our aim was to translate and validate the Italian version of the continuous glucose monitoring (CGM) Satisfaction (CGM-SAT) scale questionnaire. METHODS: Questionnaire validation followed MAPI Research Trust guidelines and included forward translation, reconciliation, backward translation, and cognitive debriefing. RESULTS: The final version of the questionnaire was administered to 210 patients with type 1 diabetes (T1D) and 232 parents. The completion rate was excellent, with almost 100% of items answered. The overall Cronbach's coefficient was 0.71 and 0.85 for young people (patients) and parents indicating moderate and good internal consistency, respectively. Parent-young people agreement was 0.404 (95% confidence interval: 0.391-0.417), indicating moderate agreement between the two assessments. Factor analysis identified that factors assessing the "benefits" and "hassles" of CGM accounted for 33.9% and 12.9% of score variance in young people and 29.6% and 19.8% in parents, respectively. DISCUSSION: We present the successful Italian translation and validation of the CGM-SAT scale questionnaire, which will be useful for assessing satisfaction with Italian T1D patients using CGM systems.

Association of Achieving Time in Range Clinical Targets With Treatment Modality Among Youths With Type 1 Diabetes.

Importance: Continuous glucose monitoring (CGM) devices have demonstrated efficacy in adults and more recently in youths and older adults with type 1 diabetes. In adults with type 1 diabetes, the use of real-time CGM compared with intermittently scanned CGM was associated with improved glycemic control, but there are limited data available for youths. Objective: To assess real-world data on achievement of time in range clinical targets associated with different treatment modalities in youths with type 1 diabetes. Design, Setting, and Participants: This multinational cohort study included children, adolescents, and young adults younger than 21 years (hereinafter referred to collectively as youths) with type 1 diabetes for a duration of at least 6 months who provided CGM data between January 1, 2016, and December 31, 2021. Participants were enrolled from the international Better Control in Pediatric and Adolescent Diabetes: Working to Create Centers of Reference (SWEET) registry. Data from 21 countries were included. Participants were divided into 4 treatment modalities: intermittently scanned CGM with or without insulin pump use and real-time CGM with or without insulin pump use. Exposures: Type 1 diabetes and the use of CGM with or without an insulin pump. Main Outcomes and Measures: Proportion of individuals in each treatment modality group achieving recommended CGM clinical targets. Results: Among the 5219 participants (2714 [52.0%] male; median age, 14.4 [IQR, 11.2-17.1] years), median duration of diabetes was 5.2 (IQR, 2.7-8.7) years and median hemoglobin A1c level was 7.4% (IQR, 6.8%-8.0%). Treatment modality was associated with the proportion of individuals achieving recommended clinical targets. Adjusted for sex, age, diabetes duration, and body mass index standard deviation score, the proportion achieving the recommended greater than 70% time in range target was highest with real-time CGM plus insulin pump use (36.2% [95% CI, 33.9%-38.4%]), followed by real-time CGM plus injection use (20.9% [95% CI, 18.0%-24.1%]), intermittently scanned CGM plus injection use (12.5% [95% CI, 10.7%-14.4%]), and intermittently scanned CGM plus insulin pump use (11.3% [95% CI, 9.2%-13.8%]) (P < .001). Similar trends were observed for less than 25% time above (real-time CGM plus insulin pump, 32.5% [95% CI, 30.4%-34.7%]; intermittently scanned CGM plus insulin pump, 12.8% [95% CI, 10.6%-15.4%]; P < .001) and less than 4% time below range target (real-time CGM plus insulin pump, 73.1% [95% CI, 71.1%-75.0%]; intermittently scanned CGM plus insulin pump, 47.6% [95% CI, 44.1%-51.1%]; P < .001). Adjusted time in range was highest among real-time CGM plus insulin pump users (64.7% [95% CI, 62.6%-66.7%]). Treatment modality was associated with the proportion of participants experiencing severe hypoglycemia and diabetic ketoacidosis events. Conclusions and Relevance: In this multinational cohort study of youths with type 1 diabetes, concurrent use of real-time CGM and an insulin pump was associated with increased probability of achieving recommended clinical targets and time in range target as well as lower probability of severe adverse events compared with other treatment modalities.

Impact of the COVID-19 pandemic on long-term trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes: an international multicentre study based on data from 13 national diabetes registries.

BACKGROUND: An increased prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in children was observed in various diabetes centres worldwide during the COVID-19 pandemic. We aimed to evaluate trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes before and during the COVID-19 pandemic, and to identify potential predictors of changes in diabetic ketoacidosis prevalence during the pandemic. METHODS: For this international multicentre study, we used data from 13 national diabetes registries (Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA [Colorado], and Wales). The study population comprised 104 290 children and adolescents aged 6 months to younger than 18 years, who were diagnosed with type 1 diabetes between Jan 1, 2006, and Dec 31, 2021. The observed diabetic ketoacidosis prevalence in 2020 and 2021 was compared to predictions based on trends over the pre-pandemic years 2006-19. Associations between changes in diabetic ketoacidosis prevalence and the severity of the COVID-19 pandemic and containment measures were examined with excess all-cause mortality in the whole population and the Stringency Index from the Oxford COVID-19 Government Response Tracker. FINDINGS: 87 228 children and adolescents were diagnosed with type 1 diabetes between 2006 and 2019, 8209 were diagnosed in 2020, and 8853 were diagnosed in 2021. From 2006 to 2019, diabetic ketoacidosis at diagnosis of type 1 diabetes was present in 23 775 (27·3%) of 87 228 individuals and the mean annual increase in the prevalence of diabetic ketoacidosis in the total cohort from 2006 to 2019 was 1·6% (95% CI 1·3 to 1·9). The adjusted observed prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes was 39·4% (95% CI 34·0 to 45·6) in 2020 and 38·9% (33·6 to 45·0) in 2021, significantly higher than the predicted prevalence of 32·5% (27·8 to 37·9) for 2020 and 33·0% (28·3 to 38·5) for 2021 (p<0·0001 for both years). The prevalence of diabetic ketoacidosis was associated with the pandemic containment measures, with an estimated risk ratio of 1·037 (95% CI 1·024 to 1·051; p<0·0001) per ten-unit increase in the Stringency Index for 2020 and 1·028 (1·009 to 1·047; p=0·0033) for 2021, but was not significantly associated with excess all-cause mortality. INTERPRETATION: During the COVID-19 pandemic, there was a marked exacerbation of the pre-existing increase in diabetic ketoacidosis prevalence at diagnosis of type 1 diabetes in children. This finding highlights the need for early and timely diagnosis of type 1 diabetes in children and adolescents. FUNDING: German Federal Ministry for Education and Research, German Robert Koch Institute, German Diabetes Association, German Diabetes Foundation, Slovenian Research Agency, Welsh Government, Central Denmark Region, and Swedish Association of Local Authorities and Regions.