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Summary: Background: The diagnosis of monogenic obesity is burdened by frequent variants of uncertain significance (VUS). We describe our real‐life approach of variant reassessment over time and we assess whether inconclusive variants are decreasing in monogenic obesity. Methods: We tested for monogenic obesity (genes: LEPR, POMC, ADCY3, PCSK1, CARTPT, SIM1, MRAP2, LEP, NTRK2, BDNF, KSR2, MAGEL2, SH2B1, MC4R, MC3R) in 101 children/adolescents (11.7 [7.3–13.7] years, 3.6 [3.3–4.0] z‐BMI) in Verona and 183 (11.3 [8.4–12.2] years, 3.2 [2.7–3.9] z‐BMI) in Naples from January 2020 to February 2023. In March–July 2024 we reassessed the baseline variants by updated software interpretation and literature renavigation. Results: We initially found 20 VUS, 4 Likely Pathogenic (LP), 5 Likely Benign (LB) and 1 benign variant in 33 individuals. At follow‐up, 6 VUS were reclassified as benign/LB, one LP as pathogenic and 3 LB as benign. Overall, 10/30 variants (6/18 in Verona, 3/11 in Naples and a variant found in both centres) were reclassified, leading to a less uncertain report for 13 of 33 variant‐carrying patients. Monogenic obesity was diagnosed in 3 probands in Verona and 4 in Naples, carrying variants at MC4R or NTRK2. Conclusion: Our variant reassessment was effective to improve classification certainty for the 39% of patients and suggested that the molecular diagnosis of monogenic obesity is becoming more accurate over time. [ABSTRACT FROM AUTHOR]

Aim: To assess the prevalence and determinants of failure to thrive (FTT) among patients with vesico‐ureteral reflux (VUR) and evaluating the effects of supplementation on growth in patients with urinary solute losses. Methods: We retrospectively enrolled 1277 patients with VUR (mean age at diagnosis = 6.5 months). Patients with FTT were screened for renal tubular function impairment (TFI). If fractional excretion of sodium (FENa) >2% or blood bicarbonate <20 mmol/L, supplementation was provided. Results: Among 1277 patients, 56 (4.4%) had FTT. Of these, 42 (75%) presented extrarenal causes of FTT, 3 (5.4%) had chronic kidney disease (CKD), 9 (16.1%) had TFI, and 2 (3.5%) had CKD and TFI. FTT occurred in 8/208 patients (3.8%) with and in 48/1069 patients (4.5%) without (p = 0.68) recurrent urinary tract infections (UTIs). At multiple logistic regression, birthweight <10th percentile, preterm birth, TFI, identified or suspected syndromes and other diseases were predictors of FTT. Eleven (19.6%) patients with FTT had TFI; five with increased FENa and/or acidosis received supplementation and showed catch‐up growth. The remaining six patients exhibited spontaneous catch‐up growth. Conclusion: FTT was found in <5% of children with VUR. It was not determined by recurrent UTIs and was mainly associated with extrarenal causes. Supplementation with sodium and bicarbonates could be useful in selected cases. [ABSTRACT FROM AUTHOR]

Aim: To determine (i) prevalence and the risk factors for acute kidney injury (AKI) in children hospitalised for febrile urinary tract infection (fUTI) and (ii) role of AKI as indicator of an underlying VUR. AKI, in fact, is favoured by a reduced nephron mass, often associated to VUR. Methods: This retrospective Italian multicentre study enrolled children aged 18 years or younger (median age = 0.5 years) discharged with a primary diagnosis of fUTI. AKI was defined using Kidney Disease/Improving Global Outcomes serum creatinine criteria. Results: Of 849 children hospitalised for fUTI (44.2% females, median age 0.5 years; IQR = 1.8), 124 (14.6%) developed AKI. AKI prevalence rose to 30% in the presence of underlying congenital anomalies of the kidney and urinary tract (CAKUT). The strongest AKI predictors were presence of CAKUT (OR = 7.5; 95%CI: 3.8–15.2; p = 9.4e‐09) and neutrophils levels (OR = 1.13; 95%CI: 1.08–1.2; p = 6.8e‐07). At multiple logistic regression analysis, AKI during fUTI episode was a significant indicator of VUR (OR = 3.4; 95%CI: 1.7–6.9; p = 0.001) despite correction for the diagnostic covariates usually used to assess the risk of VUR after the first fUTI episode. Moreover, AKI showed the best positive likelihood ratio, positive predictive value, negative predictive value and specificity for VUR. Conclusion: AKI occurs in 14.6% of children hospitalised for fUTI and is a significant indicator of VUR. [ABSTRACT FROM AUTHOR]

Objective: Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity who were homozygous for the lncOb rs10487505 leptin lowering allele. Methods: Enrolled children underwent an anthropometrical evaluation, biochemical assessment, and genotyping for lncOb rs10487505. Plasma leptin levels were assessed in 150 participants. A total of 434 patients were included and divided into two groups according to rs10487505 recessive inheritance (CC vs. GG/GC). Results: Children who were homozygous for the C allele showed higher fasting insulin (p = 0.01), homeostasis model assessment of insulin resistance (p = 0.01), lower whole‐body insulin sensitivity index (p = 0.02), and lower disposition index (p = 0.03). Moreover, CC patients presented with a higher prevalence of prediabetes (9.3% vs. 3.4%, p = 0.04) and a 2.9‐fold (95% CI: 1.1–7.9, p = 0.04) higher risk of prediabetes compared with G‐carriers independently from confounders. Leptin plasma levels were significantly lower in the CC group (p = 0.002). Hormone levels correlated with BMI z score (r = 0.19, p = 0.04), fasting insulin (r = −0.34, p < 0.0001), homeostasis model assessment of insulin resistance (r = −0.33, p < 0.0001), and disposition index (r = 0.20, p = 0.04). Conclusions: The lncOb rs10487505 polymorphism affects leptin circulating levels, worsens insulin resistance, and heightens the risk of prediabetes in children and adolescents with obesity. [ABSTRACT FROM AUTHOR]

Aims: To compare the association of high serum uric acid (HUA) or metabolic syndrome (MetS) with fatty liver disease (FLD) in youths with overweight/obesity (OW/OB). Materials and Methods: Cross‐sectional study of anthropometrics, biochemical variables, and liver ultrasound of 3104 individuals with OW/OB (age 5–17 years). Metabolic syndrome was defined by ≥ 3 criteria among (1) high waist circumference; (2) high triglycerides; (3) low high‐density lipoproteins; (4) fasting glucose ≥100 mg/dl; (5) blood pressure ≥95th percentile in children, and ≥130/80 mmHg in adolescents. High serum uric acid was defined as serum UA value ≥ 75th percentile adjusted for sex. Fatty liver disease was determined by echography. Results: The sample was stratified in four categories: (1) no HUA, no MetS (reference category); (2) MetS; (3) HUA; (4) HUA and MetS (HUA + MetS). The prevalence of FLD increased across the four categories from 29.9%, 44.0%, 52.2%, to 67.1%, respectively (p < 0.0001). The ORs for the categorical variables were 1.33 (1.06–1.68) for MetS (p = 0.02), 3.19 (2.51–4.05) for HUA (p < 0.0001) and 3.72 (2.65–5.21) for HUA + MetS (p < 0.0001), versus the reference category regardless of the body mass index. Conclusions: HUA represents a useful marker of FLD in youths with OW/OB, given its greater ability to identify those at increased risk of the disease compared to MetS. The ability of both to predict incident FLD must be investigated in longitudinal study. [ABSTRACT FROM AUTHOR]

Abbreviations JADAS-10 Juvenile Arthritis Disease Activity Score JIA juvenile idiopathic arthritis NSAIDs non-steroidal anti-inflammatory drugs Patients with autoimmune diseases have a higher risk of COVID-19, hospitalisation and death than the general population and are a priority for vaccination.1 Two messenger ribonucleic acid vaccines from Pfizer and Moderna have been approved for patients with rheumatic disease.1 It is not completely clear whether these vaccines could make underlying rheumatic disease flare up, as a result of immune activation, but adult studies have reported that they are safe and effective.1 Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatic disease.2 The Pfizer vaccine has been shown to be safe and effective in adolescents with JIA.3 In spring 2021, the Pfizer vaccine was approved for children aged 12 years and above with rheumatic disease,4 but data about the Pfizer vaccine for children with JIA have been lacking. Preliminary observations on the immunogenicity and safety of vaccines to prevent COVID-19 in patients with juvenile idiopathic arthritis The vaccine coverage and vaccine immunity status and risk factors of non-protective levels of antibodies against vaccines in children with juvenile idiopathic arthritis: cross-sectional Russian tertiary Centre study. [Extracted from the article]

Aim: This study assessed the prevalence of wrongly diagnosed non-febrile urinary tract infections in patients who had not been toilet trained and presented with poor feeding and, or, failure to thrive. The diagnostic value of these signs in predicting non-febrile UTIs was also explored.Methods: We focused on 59 outpatients (56.7% male) with these criteria, who had positive urine cultures and were referred to our Italian University hospital from January 2017 to January 2019. None were on antibiotics and all underwent urine cultures by bladder catheterisation. Wrongly diagnosed non-febrile UTIs were defined by sterile urine cultures. The predictive value was evaluated using logistic regression.Results: The mean age was 8.5 ± 5.7 months and 72.9% had wrongly diagnosed non-febrile UTIs. Poor feeding was significantly higher among the 16 patients with true non-febrile UTIs (P = .04). It was significantly predictive of non-febrile UTIs (odds ratio 4.1, 95% confidence interval 1.1-16.6), especially when leucocyturia was present (odds ratio 9.7, 95% confidence interval 2.3-40.7).Conclusion: Wrongly diagnosed non-febrile UTIs were high in children with poor feeding and, or, failure to thrive. Only poor feeding and, in particular, the combination of poor feeding and leucocyturia, significantly increased the odds of non-febrile UTI. [ABSTRACT FROM AUTHOR]

Therefore, the ideal sedation regimen should obviate the need for an intravenous access, but still enable the completion of the MRI without deep sedation and subsequent complications. Keywords: adverse effects; dexmedetomidine; infant; magnetic resonance imaging; midazolam EN adverse effects dexmedetomidine infant magnetic resonance imaging midazolam 79 81 3 12/09/21 20220101 NES 220101 Magnetic resonance imaging (MRI) has been consistently indicated as the imaging modality of choice in children and neonates. While feed and wrap technique may be used to perform MRI scans without sedation, this is not always possible due to MRI sensitivity to motion artifacts and long duration of the procedure. [Extracted from the article]

Type 1 diabetes mellitus (DM) is characterized by irreversible, autoimmune, pancreatic β-cell destruction. During the disease, some patients experience a phase of Partial Clinical Remission (PCR) known as "honeymoon." This is a transitory period that is characterized by insulin production by residual β cells following DM diagnosis and initiating the insulin therapy. In this study, we aimed to evaluate the influence of insulin production on immune system after the onset of diabetes, and we showed that the duration of honeymoon period could be related to the onset of other autoimmune conditions. For this retrospective study, 159 children aged between 11 and 18 years with type 1 DM were eligible. They have been diagnosed diabetes at least 10 years ago and use exogenous insulin. Our results showed that younger age at the onset of Type 1 DM in children, predicts Celiac Disease. Female sex and low HCO3 levels at the onset of DM had a high predictive value on patients who did not experience longer Partial Clinical Remission phase. Patients with higher BMI at the diagnosis of DM experienced shorter honeymoon period than the average. Smaller of our patients who diagnosed just DM have more than 297 days honeymoon period with respect to patients with one associated autoimmune disease. This may be due to a continuous and prolonged stimulation of immune system during the period of honeymoon that predispose the patient to develop other TH1 diseases. The patients who experienced more than 297 days Partial Clinical Remission seem under risk of developing one other autoimmune disease more than the patients who experienced less than 297 days Partial Clinical Remission. We have to consider that this observation is very intriguing because many protocols spring-up to try prolonging the honeymoon period in patients with autoimmune DM. If this aim is important from a metabolic point of view, long follow-ups are needed to be sure that the risk of other autoimmune diseases does not increase. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS) has been recently linked to Dent disease 2 (DD2) because DD2 could facilitate staphylococcal cutaneous infections and could impair dermo-epidermal junctions.[1] An adolescent affected by DD2 and HS - previously included in the first case series of DD2-associated HS[1] - showed polyclonal gammopathy (PG) during the follow-up. Immunoglobulin G (IgG) was 3980 mg/dl (Fig.). In conclusion, clinicians should keep in mind that an association between HS and PG in DD2 patients might be possible. [Extracted from the article]

Background: The non‐classical HLA‐class I molecule‐g (HLA‐G) gene shows a deletion/insertion (del/ins) polymorphism of a 14‐base‐pair sequence (14 bp) in the exon 8 at the 3′ untranslated region. The presence of the 14 bp insertion allele has been associated to lower soluble HLA‐G protein production, a protein with anti‐inflammatory activities. So far, no studies have investigated the relationship between HLA‐G 14 bp del/ins polymorphism and metabolic features of obese children and adolescents. We aimed to assess if the HLA‐G ins/del polymorphism, and in particular the HLA‐G ins/ins genotype determining lower sHLA‐G production, is associated to insulin resistance (evaluated by homeostasis model assessment [HOMA]) in a population of obese children. Methods: We enrolled 574 obese children and adolescents. Anthropometric and laboratory data were collected. The white blood cell (WBC) count was evaluated as surrogate marker of inflammation. C‐reactive protein (CRP) was available in 48 patients. HOMA was calculated. Patients were genotyped for the HLA‐G del/ins polymorphism. Results: Subjects carrying the HLA‐G ins/ins genotype, presented with higher HOMA, WBC and CRP values, compared to del/ins and del/del genotypes (P ≤ 0.0009, ≤0.02 and ≤0.0001, respectively). Comparison of the regression line slopes, performed for HOMA and WBC on the basis of HLA‐G genotypes, showed that subjects carrying the HLA‐G ins/ins genotype presented with a stronger correlation between HOMA and WBC, compared to the other genotypes (Model r2 3.13%, P ≤ 0.006). Conclusions: We showed a strong association between HLA‐G 14 bp ins/ins genotype and HOMA in obese children and adolescents. This association could be hypothetically modulated by subclinical inflammation. [ABSTRACT FROM AUTHOR]

Background Bisphenol A (BPA) exposure has been associated with increased incidence of diabetes and obesity in adults. Objectives To evaluate whether an association between BPA urinary levels and insulin resistance as well as adiponectin and resistin production and serum concentrations may occur in obese children. Methods Clinical and biochemical features of 141 obese children were collected. Serum resistin and adiponectin were evaluated. Insulin resistance and urinary BPA levels were assessed. Moreover, the effect of BPA on adiponectin and resistin gene expression in adipocytes from eight normal weight prepubertal children was investigated by quantitative real-time RT-PCR (qPCR). Results Direct association between BPA and homeostasis model assessment ( r = 0.23; p: 0.0069) and a strong inverse association between BPA and adiponectin have been found ( r = −0.48; p < 0.0001). In adipocytes, resistin expression was detected only after BPA treatment, while adiponectin expression resulted down-regulated after BPA exposure ( p < 0.05 at both 10 and 100 nM BPA concentrations). Conclusions We suggest the involvement of BPA in the development of insulin resistance in childhood obesity highlighting that urinary BPA levels are directly associated with insulin resistance regardless of BMI. This association may be explained, at least partly, by the findings that BPA affects resistin and adiponectin production in adipose tissue cultures. [ABSTRACT FROM AUTHOR]

Background The N-acetyltransferase 2 ( NAT2) A803G polymorphism has been associated with decreased insulin sensitivity in a large adult population with the A allele associated with insulin-resistance-related traits. Objective Evaluate the association of this polymorphism with anthropometric and metabolic parameters in obese children and adolescents. Subjects A total of 748 obese children and adolescents were enrolled. Methods Anthropometric and laboratory data were collected. During oral glucose tolerance test, the presence of a possible exaggerated plasma glucose excursion at 1 h ( 1HPG) or impaired glucose tolerance ( IGT) was considered. Homeostasis model assessment, oral disposition index ( oDI) and insulinogenic index ( IDI) were calculated. Patients were genotyped for the NAT2 A803G polymorphism. Results The prevalence of both IGT and elevated- 1HPG was higher in children carrying the A803 allele ( P = .02 and P = .03). Moreover, this allele was associated with both oDI and IGI reduction ( P = .01). No differences among the NAT2 A803G genotypes for the other parameters were shown. Children homozygous for the A allele presented an odds ratio ( OR), to show IGT of 4.9 ( P = .01). Children both homozygous and heterozygous for the A allele had higher risk to show elevated- 1HPG ( OR of 2.7, P = .005; and OR = 2.3, P = .005) compared with patients homozygous for the NAT2 803G allele. Conclusions NAT2 A803 allele seems to play a role in worsening the destiny of obese children carrying it, predisposing them to elevated- 1HPG and IGT and then to a possible future type 2 diabetes mellitus throughout an impairment of pancreatic β-cellular insulin secretion as suggested by oDI and IGI reduction. [ABSTRACT FROM AUTHOR]

Background & Aims A common non-synonymous polymorphism, E167K, in transmembrane six superfamily member 2 ( TM6 SF2) gene has been recently associated with an increased hepatic triglyceride content, dyslipidemia and liver fibrosis in NAFLD patients. We investigated possible associations between the TM6 SF2 variants and liver lesions in chronic hepatitis C. Patients and Methods 148 consecutive patients with biopsy proven anti- HCV/ HCV- RNA-positive chronic hepatitis, naive for antiviral therapy, were genotyped for TM6 SF2 E167K and PNPLA3 I148M variants. Results The score of liver steatosis was higher in the 18 patients with TM6 SF2 E167K variant (mean 1.9 ± 1.3) than in the 130 homozygotes for TM6 SF2 167E allele (1.1 ± 1.1, P = 0.02), and the prevalence of a steatosis score ≥ 3 was 33.3% vs. 12.3% respectively ( P = 0.02). No difference in necroinflammatory or fibrosis scores was found between the two groups. A general linear model identified as independent predictors of steatosis TM6 SF2 E167K and PNPLA3 M148M variants and waist circumference ( P = 0.0376, P = 0.0069 and P = 0.0273 respectively). Conclusions This is the first demonstration that TM6 SF2 E167K variant is an independent predictor of liver steatosis in chronic hepatitis C. [ABSTRACT FROM AUTHOR]

This report represents an attempt to define the rate of β-spectrin de novo mutations affecting mRNA accumulation in patients with hereditary spherocytosis (HS). 19 HS children with haematologically normal parents and varying degrees of spectrin deficiency were studied. 13 of the 19 cases who were heterozygous at the genomic level for polymorphisms in the β-spectrin coding region were further studied. However, in an analysis of reverse-transcripted amplified cDNA from the regions of the polymorphisms, seven patients appeared to be homozygous, suggesting the occurrence of de novo mutational events affecting expression of one β-spectrin allele. We conclude that in HS patients with isolated spectrin reduction and normal parents the apparently recessive pattern of inheritance may frequently be associated with de novo monoallelic expression of β-spectrin. [ABSTRACT FROM AUTHOR]

About 75% of hereditary spherocytosis (HS) patients have the autosomal dominant form of the disease, whereas both parents of the remaining HS patients are clinically and haematologically normal. These patients could have either the autosomal recessive form of the disease or a de novo mutation. We studied 80 randomly chosen, Italian HS children with normal parents. They had different clinical phenotypes (16 mild, 40 moderate, 16 moderately severe and eight severe). These patients were screened for the occurrence of ankyrin or β-spectrin de novo mutations. To search for ankyrin de novo mutations affecting mRNA accumulation, we studied a (AC)n microsatellite located in the non-coding sequence of the last exon of the ankyrin gene, and four different exonic polymorphisms in the β-spectrin gene were utilized for the detection of de novo mutations influencing β-spectrin mRNA stability. They were also screened for the presence of α-spectrinLEPRA as well as for the mutation -108T→C in the ankyrin promoter, two variants previously found in some cases of genuinely recessive HS. Twenty-five patients showed ankyrin de novo mutations and 10 HS subjects had β-spectrin de novo mutations. Furthermore, we found five patients to be heterozygous for α-spectrinLEPRA and one heterozygous for the mutation in the ankyrin promoter. Therefore, a molecular diagnosis was achieved in about 50% of the cases. Our data demonstrate that, among HS patients with normal parents, de novo dominant mutants are six times more common than recessive mutations. These results should be considered in view of the genetic counselling of a normal couple with a HS child. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on rubinstein-Taybi syndrome associated with growth hormone deficiency in childhood.

Paediatric obesity rates are increasing, and finding simple and feasible screening tools to identify children and adolescents with a higher risk of obesity-related comorbidities are challenging. WHR was the best predictor for glucose and lipid metabolism parameters followed by the TMI, waist I z i -score and finally BMI I z i -score. WHR outperformed the waist I z i -score, the TMI and BMI I z i -score in the association with metabolic parameters in overweight and obese subjects. [Extracted from the article]

Summary: Background: PNPLA3 I148M polymorphism has an effect on modulation of estimated glomerular filtration rate (eGFR) in nonobese nondiabetic adults and in children with histologically confirmed nonalcoholic fatty liver disease (NAFLD). Objectives: The objective of the study is to explore the impact of PNPLA3 I148M polymorphism on eGFR in children with obesity with and without NAFLD. Methods: We genotyped 591 patients with obesity for PNPLA3 I148M polymorphism. Anthropometrical, biochemical, and instrumental data were collected. NAFLD was defined by the presence of ultrasound‐detected liver steatosis and/or ALT levels greater than 40 IU/L. Results: Patients with NAFLD showed significantly lower eGFR levels compared with subjects without NAFLD. Children with PNPLA3 MM genotype showed lower eGFR levels compared with those with either PNPLA3 IM or II genotypes both in the presence and absence of NAFLD. A general linear model for eGFR variance, including gender, duration of obesity, PNPLA3 genotypes, HOMA, BMI‐SDS, LDL‐C, and triglycerides as covariates, confirmed an inverse association between eGFR and PNPLA3 genotype only in the presence of NAFLD. Conclusions: Children with obesity and PNPLA3 MM genotype show lower eGFR levels compared with other genotypes, with a major effect of this polymorphism in the presence of NAFLD. [ABSTRACT FROM AUTHOR]

The article explores the presence of insulin resistance and glucose metabolism abnormalities in children with juvenile idiopathic arthritis (JIA), a common chronic rheumatic disease in childhood. The study conducted on 139 children with JIA in Italy revealed an increased risk of insulin resistance and prediabetes in children with higher body mass index standard deviation scores. The findings suggest the importance of long-term monitoring of glucose metabolism in children with JIA who are overweight or obese to mitigate cardiometabolic risks. [Extracted from the article]

A letter to the editor is presented highlighting a study which proposed that hyperinsulinemia may play a role in influencing height velocity in obese children.

Evaluates the leptin levels in thalassaemic patients. Endocrine disorders related to toxic effects of iron overload; Mechanism of action of leptin; Leptin concentration in thalassaemic males and females.