Type I diabetes (T1D) is the most common chronic autoimmune disease in children, driven by a breakdown in self-tolerance and T cell-mediated immune attack of pancreatic β-cells. There are no biomarkers to effectively diagnose autoimmunity before disease onset and clinical symptom development. Here, we applied deep multi-parametric immunophenotyping to compare immune landscapes in thirty-eight new-onset patients with T1D, 24 siblings, and 18 healthy controls (HC). T1D subjects underwent clinical and metabolic evaluations. Immune populations were analyzed on fresh whole blood using a panel of 26 antibodies, detecting 39 different cell populations. Memory regulatory T cells (memory Tregs) were significantly increased in T1D subjects (p<0.05) and siblings (p<0.01) compared with HC but not between T1D subjects and siblings. Memory Tregs were associated with disease status and age in multivariable analysis. There was a positive correlation between age and memory Tregs in HC and siblings but not in patients with T1D. Baseline siblings’ memory Treg levels resembled those of patients with T1D. These findings highlight the existence of an age-independent, disease-specific immune fingerprint that could serve as a minimally invasive biomarker for early diagnosis and personalized immunotherapy. Further studies are needed to confirm memory Tregs as a pathogenic trait through functional and single-cells analysis.

Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes—such as NR0B1 pathogenic variants in men—can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.

BACKGROUND/OBJECTIVES:Human endogenous retroviruses (HERVs) are genomic elements derived from ancient retroviral infections and are increasingly recognized for their roles in gene regulation and immune modulation. Obesity is characterized by chronic low-grade inflammation and metabolic dysregulation, which may influence HERV expression. SUBJECTS/METHODS:In this study, we evaluated the transcriptional levels of HERV-H-pol, HERV-K-pol, and HERV-W-pol in peripheral blood from adolescents with obesity as compared to healthy normal weight controls (HC). Total RNA was extracted from whole blood samples, and gene expression was assessed using quantitative reverse-transcription PCR (RT-qPCR), with GAPDH as a reference gene. RESULTS:HERV-H-pol and HERV-K-pol were significantly upregulated in adolescents with obesity as compared to HC, whereas HERV-W-pol was downregulated. No significant associations were observed between HERV expression levels and age, sex, or metabolic parameters. CONCLUSIONS:These findings suggest that obesity in adolescents is associated with a differential regulation of HERV elements, possibly reflecting the impact of chronic inflammatory and metabolic stress. HERV dysregulation may represent a novel molecular feature of obesity and warrants further investigation as a potential biomarker or contributor to obesity-related complications.

BACKGROUND & AIMS:Among diet, microbiota, and obesity exists a close correlation that remains insufficiently explored, particularly within the pediatric age. We aimed to deeply investigate the relationship between dietary composition and microbiota in pediatric subjects with obesity before an educational training in a Mediterranean-style diet. METHODS:55 subjects (10-18 years) with overweight or obesity and visceral adiposity, diet naïve, or failure to a previous weight loss program were phenotypically described through clinical and metabolic parameters, including circulating LPS levels. 16S DNA sequencing was used to profile the microbiota. Lifestyle habits (KIDMED score, 24-h recall, International Physical Activity Questionnaire for Adolescents) and diet composition were assessed. RESULTS:Five different main enterotypes were found. Females at the end of puberty were well separated from the other subjects in the principal component analysis. Microbiota composition changed with the progression of puberty, and LPS levels negatively correlated with Tanner stages. Gut microbiota composition, considering all the clinical parameters, was significantly modulated mostly by the percentage of carbohydrate intake and insulin resistance. Carbohydrate intake ranging from 45 to 55 % determined a high number of species, but with a reduction of biodiversity (Shannon and Simpson indexes). Bacteroides dorei, Turicibacter sanguinis, and B. vulgatus were among the main species involved in signatures of carbohydrate intake, whereas an enrichment in Bacteroides stercoris was found in subjects with a low fiber intake. Adherence to the Mediterranean diet was associated with a great presence of dietary fiber metabolizers, including Faecalibacterium prausnitzii and Lachnospira sp. Alistipes finegoldii and Akkermansia muciniphila were more represented in low insulin resistance, while Bifidobacterium pseudocatenulatum and Clostridium clostridioforme were enriched in patients with high insulin resistance. CONCLUSION:Carbohydrate content of the diet, insulin resistance, and microbiota are strictly related in children with obesity. A certain degree of dysbiosis could link obesity to a severe phenotype. Since gender and puberty status impact the microbiota signature, clustering pediatric patients for diet intervention is a challenge.

Introduzione. Il diabete mellito di tipo 1 (T1D) è una condizione cronica comune nei bambini e negli adolescenti, con incidenza in aumento. Una gestione adeguata è fondamentale per il controllo glicemico e la prevenzione delle complicanze. La transizione dai centri di cura pediatrica a quelli per adulti è una fase critica e la sua efficacia è variabile tra i diversi Paesi e in diverse aree dello stesso Paese. Materiali e metodi. In questo studio qualitativo svolto nel 2023, sono stati invitati a partecipare almeno 30 pazienti con T1D, che avessero affrontato la transizione dal 2017 al 2022, attraverso compilazione di un questionario semi-strutturato online sull’esperienza del passaggio. Ulteriori questionari sono stati somministrati ai professionisti sanitari per raccogliere informazioni su barriere organizzative e aspettative dei pazienti. Risultati. L’indagine, condotta su 52 giovani adulti con T1D, provenienti da 5 centri diabetologici italiani, ha rivelato che la transizione all’assistenza per adulti avviene mediamente a 19,6 anni. Al momento della rilevazione, il 73% dei partecipanti non aveva manifestato complicanze acute e il 55,7% aveva un compenso metabolico ottimale prima della transizione. Tuttavia molti pazienti hanno riscontrato problemi nella gestione operativa del passaggio e circa il 40% ha giudicato il processo come difficile, evidenziando in alcuni casi un senso di “abbandono” e un desiderio di maggiore supporto e comunicazione tra i servizi pediatrici e quelli per adulti. La maggior parte degli intervistati ha riportato un aumento dell’autonomia nella gestione del diabete. Discussione e conclusioni. Sebbene il processo di transizione per i pazienti con T1D sia strutturato, dallo studio emergono alcune lacune nella comunicazione e nel supporto tra i centri di assistenza pediatrica e quelli degli adulti. È essenziale un percorso ben coordinato che consideri le esigenze individuali dei pazienti e che preveda il potenziamento della collaborazione tra i team di cura.

Cardiovascular and cerebrovascular diseases (CVDs), primarily driven by atherosclerosis, remain the leading cause of mortality worldwide and represent a major healthcare burden. Mounting evidence demonstrates that atherosclerotic processes begin in childhood, with lipid streaks detectable as early as the first decade of life. The increasing prevalence of obesity, hypertension, dyslipidemia, insulin resistance, and other modifiable cardiovascular risk factors (CVRFs) in children and adolescents highlights the urgent need for prevention strategies starting early in life. This document, jointly produced by the Italian Society of Pediatrics (SIP), the Italian Society of Hypertension (SIIA), the Italian Society for the Study of Atherosclerosis (SISA), and the Italian Society for Cardiovascular Prevention (SIPREC), emphasizes that atherosclerosis should be considered a disease with its roots in childhood and that true primary prevention must begin from pregnancy and birth. Two possible and complementary levels of intervention should be considered: (1) population-wide promotion of healthy diets, lifestyles, and supportive environments; and (2) early identification and management of specific CVRFs in children and adolescents. The involvement of multiple stakeholders—families, pediatricians, schools, healthcare professionals, policymakers, patient associations, and the media—is crucial to ensure the effectiveness of prevention interventions. Particular attention must be given to obesity, as both an independent risk factor and a driver of additional metabolic and vascular risks. Fighting CVDs requires a paradigm shift: preventive action must start early, be comprehensive, and mobilize all sectors of society. Only by addressing cardiovascular risk during childhood can the future burden of CVDs be effectively reduced.

The objective of this study was to identify clinical and/or metabolic predictive factors of genetic obesity. Subjects aged ≤ 18 years with obesity (BMI ≥ 97 th percentile) followed-up at the Paediatric Endocrinology Clinic of Maggiore Hospital in Novara, Italy were screened for genes associated with obesity by next-generation sequencing. Anamnestic, anthropometric, and biochemical data were collected, and parents completed two questionnaires, to screen for hyperphagia and daytime sleepiness, respectively. The study included 50 patients. Six genetic variants (6/50 patients,12%) were classified as pathogenic/likely pathogenic, three (3/50 patients,6%) as polygenic, and 16 (13/50 patients,26%) as variants of uncertain clinical significance (VUS). Eight patients carried > 1 variant. All pathogenic mutations were in genes implicated in the hypothalamic melanocortin pathway or responsible for syndromic obesity. All subjects with definitive genetic diagnosis developed obesity before five years of age. There were no statistically significant differences in auxological nor metabolic parameters between the three genetic patterns of absent genetic mutations, VUS, and pathogenic/likely pathogenic mutations. Finally, a Genetic Obesity Risk Score was developed using logistic regression analysis, selecting Hyperphagia Questionnaire score, age of onset of obesity, and family history as variables. Genetic screening of our cohort of children and adolescents with severe obesity revealed pathogenic/polygenic variants in 18% of cases, with PCSK1 the most frequently mutated gene and with a definitive genetic diagnosis in 3 patients. Identifying clinical, behavioral, and metabolic features predictive of genetic obesity would facilitate early diagnosis and tailored management.

Childhood obesity is a growing global health concern, with established links to physical activity, nutrition, and, increasingly, to prenatal and perinatal factors. Emerging evidence highlights the significant role of maternal conditions such as obesity, comorbidities, nutrition, and environmental exposures in predisposing offspring to long-term metabolic and cardiovascular diseases. The “Developmental Origins of Health and Disease” (DOHaD) paradigm provides a framework for understanding how early life environmental exposures, particularly during the periconceptional, fetal, and neonatal periods, can program future health outcomes through epigenetic mechanisms. Epigenetic modifications alter gene expression without changing the DNA sequence and are increasingly recognized as key mediators in the development of obesity. This narrative review summarizes current findings on the early determinants of childhood obesity, emphasizing the molecular and epigenetic pathways involved. A comprehensive literature search was conducted across multiple databases and international sources, focusing on recent studies from the past decade. Both human and animal research were included to provide a broad perspective. This review aims to consolidate recent insights into early life influences on obesity, underscoring the need for preventive strategies starting as early as the preconception period.

Omnitrope® (a somatropin biosimilar), used to treat growth disturbances, is considered to have a good safety profile in children. Here, we present the analysis of final data of the Italian cohort of the PAtients TReated with Omnitrope® (PATRO) Children study. This multicenter, open-label, longitudinal, post-marketing surveillance study enrolled eligible children during 2010–2018. The primary objective was to assess the long-term safety of Omnitrope® by recording all adverse events (AEs), serious AEs, and adverse drug reactions (ADRs). A secondary objective was to evaluate the long-term effectiveness of Omnitrope® using height measurements. A total of 375 patients were included in the Italian cohort of the PATRO Children study. After a mean ± standard deviation (SD) follow-up duration of 40.9 ± 24.6 months, 607 AEs were reported in 58.4

AIM:To assess the efficacy of the combined administration of myo-inositol and zinc, a mineral involved in the insulin pathway, in paediatric obesity with insulin resistance on HOMA-IR, glucose-insulin metabolism, and lipid profile. MATERIALS AND METHODS:Double-blind, randomized, placebo-controlled study conducted in North Italy. Fifty-six patients (10-18 years, Tanner stage ≥3) with obesity and insulin resistance were randomized to myo-inositol (2000 mg), zinc gluconate (5 mg), and galactooligosaccharides (GOS) from plant-based origin (1000 mg) (TRT) or placebo (PLC) containing only GOS from plant-based origin (1000 mg). All patients received an isocaloric diet following the Mediterranean diet style. Data were collected at baseline (V0) and after 3 months (V1). The primary outcome was the insulin resistance index (HOMA-IR). RESULTS:Fifty out of 56 recruited subjects completed the study. TRT improved HDL cholesterol level compared to PLC (p = 0.05) but not insulin resistance. A stratified post hoc analysis was performed by sex, BMI, and subgroups of adherence to the Mediterranean diet. Subjects were divided for obesity grade, fasting insulin (p = 0.0137) and HOMA-IR (p = 0.0273) were lower in TRT than in PLC patients, with a greater effect on severe obesity. No adverse events were detected. CONCLUSION:Three months of supplementation with myo-inositol and zinc were beneficial on lipid profile and in managing obesity complications at least in subjects with severe phenotype. Thus, myo-inositol and zinc could be used as non-pharmacological agents. This work suggests a long-term study with a larger sample size to enrich the findings.

Abstract Disclosure: V. Antoniotti: None. V. Mancioppi: None. A. Solito: None. C. Partenope: None. A. Petri: None. I. Rabbone: None. L. Scotti: None. F. Prodam: None. Background: In the last decades, pediatric obesity and cardiovascular-associated risks have been relevant challenges. The first treatment against obesity is a lifestyle change, nevertheless, no intervention seems to be effective in the evolution of the condition, especially in the long term. Thus, the interest in non-pharmaceutical as well as pharmaceutical compounds is growing. Inositol compounds have recently been studied in adults with obesity and insulin resistance but have never been investigated in the pediatric age where insulin resistance is a specific trait of puberty. Furthermore, zinc is critical for insulin secretion and growth. Methods. This is a double-blind, randomized, placebo-controlled study aiming to explore the efficacy of 3 months of combined administration of Zinc (5 mg/die) and Myo-inositol (2000 mg/die) in children and adolescents with obesity. 56 patients aged 10- 17.9 years (starting from Tanner 3) with obesity and insulin resistance have been enrolled. The treatment group received 5 mg of Zinc, 2000 mg of Myo-inositol, and 1000 mg of galactooligosaccharides from Pisum sativum, while the placebo group only received 1000 mg of galactooligosaccharides from Pisum sativum. All patients were subjected to an isocaloric diet following the Mediterranean diet style consisting of 55% carbohydrates, 30-35% fat, and 15% protein. Clinical and biochemical evaluations were carried out for the determination of weight, lipid profile, liver function, and glucose-insulin metabolism. Results. At the end of the study, BMI, fasting insulin, and insulin resistance (HOMA-IR) were significantly improved in both groups, while the treatment group also had an increase in HDL cholesterol (p=0.0426). On the other hand, the placebo group significantly improved its eating habits showing greater adherence to the Mediterranean diet than the treatment group. Moreover, subjects were divided according to the degree of obesity. Fasting insulin (p= 0.0137), HOMA-IR (p= 0.0273), and systolic blood pressure (p= 0.0349) showed a significant improvement in treated patients with severe obesity compared to treated patients with low-grade obesity. Thus, subjects with a higher level of obesity respond better to both treatment and lifestyle change than those with a lower grade of obesity. Also, the improvement of the lifestyle and the presence of fiber allow an increase in the metabolic framework in placebo subjects. Conclusions. Supplementation with Zinc and Myo-inositol could be used as a non-pharmacological compound for the control of complications related to obesity also in the pediatric age. Presentation: 6/1/2024