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ImportanceAlthough hypoglycaemia and hyperglycaemia represent the most common metabolic problem in neonates, there is still uncertainty regarding the effects of glucose homoeostasis on the neurological outcomes of infants with neonatal encephalopathy (NE).ObjectiveTo systematically investigate the association between neonatal hypoglycaemia and hyperglycaemia with adverse outcome in children who suffered from NE.Study selectionWe searched Pubmed, Embase and Web of Science databases to identify studies which reported prespecified outcomes and compared infants with NE who had been exposed to neonatal hypoglycaemia or hyperglycaemia with infants not exposed.Data analysisWe assessed the risk of bias (ROBINS-I), quality of evidence (Grading of Recommendations, Assessment, Development and Evaluation (GRADE)) for each of the studies. RevMan was used for meta-analysis (inverse variance, fixed effects).Main outcomeDeath or neurodevelopmental outcomes at 18 months of age or later.Results82 studies were screened, 28 reviewed in full and 12 included. Children who were exposed to neonatal hypoglycaemia had higher odds of neurodevelopmental impairment or death (6 studies, 685 infants; 40.6% vs 25.4%; OR=2.17, 95% CI 1.46 to 3.25; p=0.0001). Neonatal exposure to hyperglycaemia was associated with death or neurodisability at 18 months or later (7 studies, 807 infants; 46.1% vs 28.0%; OR=3.07, 95% CI 2.17 to 4.35; p<0.00001). These findings were confirmed in the subgroup analysis, which included only the infants who underwent therapeutic hypothermia.ConclusionsThese data suggest that neonatal hypoglycaemia and hyperglycaemia may be associated with the neurodevelopmental outcome later on in infants with NE. Further studies with long-term follow-up are needed to optimise the metabolic management of these high-risk infants.PROSPERO registration numberCRD42022368870.

To compare the prevalence of mildly reduced estimated glomerular filtration rate (MRGFR) (eGFR >60 and < 90 mL/min/1.73 m2), calculated by two creatinine-based equations, and its association with cardiometabolic risk factors (CMRF) in youth with overweight (OW)/obesity (OB).

Dehydration is a significant cause of morbidity and mortality in children worldwide. Infants and young children are vulnerable to dehydration, and clinical assessment plays a pivotal role in their care. In addition, laboratory investigations can, in some children, be helpful when assessing the severity of dehydration and for guiding rehydration treatment. In this interpretation, we review the current literature and provide an evidence-based approach to recognising and managing dehydration in children.

Background: Several studies identified genetic variants in FADSand ELOVL2genes associated with obesity-related conditions, such as alterations in blood lipid parameters and insulin homeostasis. The aim of this cross-sectional study was to determine whether FADSand ELOVL2genetic variants were associated with obesity and adiposity, besides dyslipidaemia and insulin resistance, in a large sample of obese children and adolescents. Materials and methods: One thousand six hundred and forty-nine obese children underwent physical examination, anthropometry, fasting blood tests measuring plasma glucose, lipid and liver profile. Two genetic variants were genotyped: rs2236212 in ELOVL2gene and rs1535 in FADS2, for the gene cluster FADS. In a subgroup of obese children (n?=?105), erythrocyte fatty acid composition was measured. Generalized linear models were used to assess association between genotypes and variables. Results: A positive association between zBMI and the minor allele of rs2236212 (p?=?0.028), the major allele of rs1535 (p?=?0.046) and the genetic score (p?=?0.008), created by summing up both risk alleles, were found. The estimation of enzymatic activity revealed that minor alleles were associated significantly with a reduction of the enzymatic activity of elongase and desaturase (p?=?0.048 and p?=?0.0001, respectively). Discussion and conclusions: Common variants in the FADS2and ELOVL2genes were associated with BMI in a large population of obese Italian children. These SNPs were associated with alterations in LC-PUFAs homeostasis, not accompanied by modifications of plasma lipids or HOMA-IR. These findings provide additional support to the genetics accounting for BMI interindividual variability and the molecular basis of obesity.

The objective of this study is to evaluate the effect of body mass index (BMI) on estimated glomerular filtration rate (eGFR) levels in children with congenital solitary kidney (CSK). Moreover, we evaluated if other factors could influence this relationship.

We first investigated in obese children the protective role of the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)rs72613567:TA variant in liver damage. Six hundred eighty-five obese children were genotyped for HSD17B13, patatin-like phospholipase domain containing 3(PNPLA3), transmembrane 6 superfamily member 2(TM6SF2), and membrane bound O-acyltransferase domain containing 7(MBOAT7) polymorphisms and underwent anthropometrical, ultrasonographic, and biochemical evaluation. Indirect measurement of liver fibrosis (Pediatric NAFLD Fibrosis Index [PNFI]) was calculated. The population was clustered in 2 genetic risk groups based on the numbers of steatogenic alleles (low: carriers up to 3 risk alleles, high: 4–6 risk alleles). Carriers of the HSD17B13rare A allele showed lower percentage of hepatic steatosis and both lower serum transaminase and PNFI levels than noncarriers, even after adjustments for confounders. These findings were also confirmed in both risk groups. We demonstrated the protective effect of the rs72613567:TA HSD17B13 variant in reducing liver damage in obese children regardless of genetic predisposition.

Background Two different systems for the screening and diagnosis of hypertension (HTN) in children currently coexist, namely, the guidelines of the 2017 American Academy of Pediatrics (AAP) and the 2016 European Society for Hypertension (ESH). The two systems differ in the lowered cut-offs proposed by the AAP versus ESH.Objectives We evaluated whether the reclassification of hypertension by the AAP guidelines in young people who were defined non-hypertensive by the ESH criteria would classify differently overweight/obese youth in relation to their cardiovascular risk profile.Methods A sample of 2929 overweight/obese young people (6–16 years) defined non-hypertensive by ESH (ESH–) was analysed. Echocardiographic data were available in 438 youth.Results Using the AAP criteria, 327/2929 (11%) young people were categorized as hypertensive (ESH–/AAP+). These youth were older, exhibited higher body mass index, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), triglycerides, total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, blood pressure, left ventricular mass index and lower HDL-C (p<0.025–0.0001) compared with ESH–/AAP–. The ESH–/AAP+group showed a higher proportion of insulin resistance (i.e. HOMA-IR ≥3.9 in boys and 4.2 in girls) 35% vs. 25% (p<0.0001), high TC/HDL-C ratio (≥3.8 mg/dl) 35% vs. 26% (p= 0.001) and left ventricular hypertrophy (left ventricular mass index ≥45 g/h2.16) 67% vs. 45% (p= 0.008) as compared with ESH–/AAP–.Conclusions The reclassification of hypertension by the AAP guidelines in young people overweight/obese defined non-hypertensive by the ESH criteria identified a significant number of individuals with high blood pressure and abnormal cardiovascular risk. Our data support the need of a revision of the ESH criteria.

Asthma is the most frequent chronic disease in childhood. Chest tightness, cough, wheezing and dyspnoea during or after exercise may be unique manifestations of asthma in up to 90% of subjects. Physical activity may be reduced by uncontrolled asthma symptoms and parental beliefs, impairing physical fitness of asthmatic children. Clinicians working in the field of allergy are aware of evidence supporting the benefits of physical activity for patients with asthma. Treatment of asthma is required in order to obtain its control and to avoid any limitation in sports and active play participation. As exercise performance in children with controlled asthma is not different from that of healthy controls, any exercise limitation cannot be accepted. Overweight and obesity may interfere with asthma and exercise, leading to dyspnoea symptoms. Evidences on the effect of insulin resistance on airway smooth muscle and on bronchial hyperactivity are presented.

Frequently, general pediatricians could face a patient with syncope, which represents approximately 1% to 3% of emergency visits. Micturition syncope is a transient loss of consciousness with onset immediately before, during, or after micturition. Literature evidence indicates that healthy young men are a population with major risk for presenting micturition syncope, with a peak of incidence around 40 to 50 years of age. Usually, this syncope occurs in the morning, after wake-up, or, more generally, when the male patients assume the orthostatic position after a period of supine position in a warm bed. No information on micturition syncope clinical presentation and prevalence in childhood is available in the literature, and probably, this kind of syncope is unrecognized in childhood. We describe 4 unreported pediatric patients with a diagnosis of micturition syncope and well-defined clinical presentation. In all patients, the syncope has been presented in the same conditions: in the morning; after wake-up; in an orthostatic position; just before, after, or during urinary bladder voiding; and with spontaneous recovery in few minutes. Interestingly, 1 patient presented with the syncope during urinary bladder voiding by autocatheterization. In our patients, all investigations made as the first approach in the pediatric emergency department did not show any abnormal results, possibly underlying the syncope episodes. By describing our experience, we want to underline the clinical presentation of micturition syncope and give to the clinicians the elements to recognize and manage it easily in children.

Existing studies usually do not measure the free vitamin D in pediatric patients with inflammatory bowel disease (IBD) and not consider the effect of inflammation on vitamin D levels. The aim of our study was to evaluate the concentrations of vitamin D–binding protein (VDBP), total and free 25-hydroxyvitamin-D (25(OH)D), and to correlate these values with the disease activity markers. Newly diagnosed children with IBD and a group of healthy controls (HCs) were enrolled. VDBP and total and free 25(OH)D levels were measured by enzyme-linked immunosorbent assay and compared using the Student ttest. In each patient with IBD, the activity scores of disease and the main inflammation markers were correlated to total and free 25(OH)D levels. C-reactive protein was also measured in the control group, and it was related to VDBP by a linear regression test for all the groups. Fifty-one consecutive children were enrolled: IBD = 33, HC = 18. Levels of total 25(OH)D were higher in HC than in patients with IBD (P= 0.01). The free/total 25(OH)D ratio was, however, higher in patients with IBD compared to HC (P< 0.001). Finally, levels of VDBP were lower in patients with IBD than in HC (P= 0.001). A significant direct correlation was found between the free/total 25(OH)D ratio and the activity index of disease (r2: 0.17; P= 0.01). Moreover, in patients with IBD and controls we found a significant indirect correlation between VDBP and C-reactive protein (r2: 0.12; P= 0.01). Inflammation inversely correlates to VDBP concentrations and patients with IBD, despite their deficiency in total 25(OH)D, have normal or even higher levels of free 25(OH)D.

We aimed to investigate which clinical and metabolic factors could influence the estimated glomerular filtration rate (eGFR) levels, evaluating a large population of obese children without suspect of primary kidney disease.

The aims of this retrospective study were to describe ulcerative colitis (UC) phenotype at diagnosis and follow-up and to identify possible predictors of severe disease course. This was a retrospective, single-center study. We reviewed the charts of patients with UC diagnosed between 2 and 18 years at our referral center from January 2007 to January 2016. Laboratory and clinical features at diagnosis, such as disease extent, atypical phenotypes, extraintestinal manifestations, and therapies, and pattern changes during the follow-up, including relapse rate, disease extension, and the cumulative risk for colectomy were collected. One hundred eleven patients were enrolled. Atypical phenotypes were identified at diagnosis in 55 out of 111 patients (49.5%). Extraintestinal manifestations were detected in 16 out of 111 (14.4%) at the diagnosis. During the follow-up 60 out of 111 (54%) patients needed to start azathioprine, 9 out of 111 (8.1%) patients started biologic therapy and 10 out of 111 (patients underwent surgery, resulting in a cumulative risk of 8% at 5 years and 16% at 10 years. Steroid refractoriness (hazard ratio: 13.9) and starting of biologic therapy (hazard ratio: 25.3) represented the best predictors for surgery. The cumulative probability of first relapse was 47% at 6 months and 63% at 1 year. Disease extension was reported in 21 out of 70 patients (30%). Pediatric UC is associated with a severe phenotype and a high percentage of atypical features. Surgery rate seems to be decreased from early reports.

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Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty. We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2–8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2–8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9–14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients. No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:−0.35; p:0.02), Luteinizing Hormone (r:−0.35; p:0.03), FSH (r:−0.37; p:0.02), and (17)estradiol (r: −0.36; p:0.02). We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small. In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

Context:Young-onset obesity is strongly associated with the early development of type 2 diabetes (T2D). Genetic risk scores (GRSs) related to T2D might help predicting the early impairment of glucose homeostasis in obese youths.Objective:Our objective was to investigate the contributions of four GRSs (associated with: T2D [GRS-T2D], beta-cell function [GRS-β], insulin resistance [GRS-IR], and body mass index) to the variation of traits derived from oral glucose tolerance test (OGTT) in obese and normal-weight children and young adults.Design:This was a cross-sectional association study.Patients:A total of 1076 obese children/adolescents (age = 11.4 ± 2.8 years) and 1265 normal-weight young volunteers (age = 21.1 ± 4.4 years) of European ancestry were recruited from pediatric obesity clinics and general population, respectively.Intervention:Standard OGTT was the intervention in this study.Main Outcome Measures:Associations between GRSs and OGTT-derived traits including fasting glucose and insulin, insulinogenic index, insulin sensitivity index, disposition index (DI) and associations between GRSs and pre-diabetic conditions were measured.Results:GRS-β significantly associated with fasting glucose (β = 0.019; P= 3.5 × 10−4) and DI (β = −0.031; P= 8.9 × 10−4, last quartile 18% lower than first) in obese children, and nominally associated with fasting glucose (β = 0.009; P= 0.017) and DI (β = −0.030; P= 1.1 × 10−3, last quartile 11% lower than first) in normal-weight youths. GRS-T2D showed weaker contribution to fasting glucose and DI compared to GRS-β, in both obese and normal-weight youths. GRS associated with insulin resistance and GRS associated with body mass index did not associate with any traits. None of the GRSs associated with prediabetes, which affected only 4% of participants overall.Conclusion:Single nucleotide polymorphisms identified by genome-wide association studies to influence beta-cell function were associated with fasting glucose and indices of insulin secretion in youths, especially in obese children.

Context:Studies examining vitamin D levels in association with childhood obesity usually do not consider the effect of insulin on vitamin D–binding protein and do not calculate the unbound, bioavailable vitamin D.Objective:This study aimed to evaluate in a group of children 1) the concentrations of both total 25-hydroxyvitamin D and bioavailable fraction, and 2) the potential role of insulin resistance in modulating the concentrations of bioavailable vitamin D.Design, Setting, and Patients or Other Participants:This was a cross-sectional study at a University Pediatric Department in which 63 obese children and 21 lean controls were enrolled.Main Outcome Measures:Total 25-hydroxyvitamin D and vitamin D–binding protein were measured, two single-nucleotide polymorphisms in the coding region of the vitamin D–binding protein (rs4588 and rs7041) were studied, and the vitamin D bioavailable fraction was calculated.Results:Obese children showed total 25-hydroxyvitamin D levels lower compared with nonobese children (21.3 ± 6.7 ng/mL vs 29.6 ± 11.7 ng/mL; P= .0004). Bioavailable 25-hydroxyvitamin D levels were not different among the two groups (3.1 ± 1.6 ng/mL vs 2.6 ± 1.2 ng/mL; P> .05). Insulin-resistant children showed higher bioavailable levels of 25-hydroxyvitamin D compared with noninsulin-resistant children (3.4 ± 1.4 ng/mL vs 2.0 ± 0.9 ng/mL; P= .013) and an inverse correlation between insulin resistance and vitamin D–binding protein was found (r:= −0.40; P= .024).Conclusions:Obese children present levels of bioavailable 25-hydroxyvitamin D similar to those of normal-weight children due to reduced concentration of vitamin D–binding protein. The insulin resistance could play a role in this reduced concentration.

Studies of adults and children with celiac disease have reported an increased risk of overweight during gluten‐free diet (GFD). The fat mass and obesity‐associated gene (FTO) variant rs9939609 has been associated with increased risk of developing obesity in children and adults. In our study, we analyzed the effect of this variant on weight gain in a cohort of 280 children with celiac disease on GFD. We found that after a mean follow‐up time of 3.0 years on GFD, FTO polymorphism influenced significantly the mean change in body mass index zscore (P= 0.01). We conclude that the FTO gene contributes to determine weight changes in children with celiac disease on GFD.

The G-protein–coupled receptor 120 (GPR120) is a receptor for polyunsaturated fatty acids with anti-inflammatory activity. The R270H variant of GPR120enhances inflammation in adipose and hepatic tissues. We investigated whether the R270H variant could play a role in determining liver injury in children and adolescents with obesity. Five hundred eighty-one children with obesity were studied. No homozygotes and 20 heterozygotes for the 270H allele were found. Heterozygotes showed higher alanine transaminase (ALT) levels (P=0.01) than wild-type subjects, and also showed an odds ratio to have pathologic ALT of 3.2 (95 confidence interval CI 1.2–8.0, P<0.05). Moreover, we genotyped the same patients for the patatin-like phospholipase-containing domain 3 (PNPLA3) I148M polymorphism, which is implicated in the development of liver steatosis. Stratifying the patients with the GPR120 270H variant on the basis of their PNPLA3polymorphism, we demonstrated a significant interaction effect on ALT levels (P=0.00001), suggesting a driving effect of the PNPLA3148M allele on liver injury in children with obesity carrying this variant.

The G-protein–coupled receptor 120 (GPR120) is a receptor for polyunsaturated fatty acids with anti-inflammatory activity. The R270H variant of GPR120enhances inflammation in adipose and hepatic tissues. We investigated whether the R270H variant could play a role in determining liver injury in children and adolescents with obesity. Five hundred eighty-one children with obesity were studied. No homozygotes and 20 heterozygotes for the 270H allele were found. Heterozygotes showed higher alanine transaminase (ALT) levels (P= 0.01) than wild-type subjects, and also showed an odds ratio to have pathologic ALT of 3.2 (95% confidence interval [CI] 1.2–8.0, P< 0.05). Moreover, we genotyped the same patients for the patatin-like phospholipase-containing domain 3 (PNPLA3) I148M polymorphism, which is implicated in the development of liver steatosis. Stratifying the patients with the GPR120 270H variant on the basis of their PNPLA3polymorphism, we demonstrated a significant interaction effect on ALT levels (P= 0.00001), suggesting a driving effect of the PNPLA3148M allele on liver injury in children with obesity carrying this variant.

Nonalcoholic fatty liver disease negatively impacts on renal function with the contribution of the I148 M variant in the patatin-like phospholipase-containing domain 3(PNPLA3) gene. We hypothesized that children with prediabetes present with a lower estimated glomerular filtration rate (eGFR) than those with normal glucose tolerance (NGT) and that the 148M PNPLA3allele could play a worsening role. We aimed evaluating the influence of the I148 M PNPLA3polymorphism on the relationship between the eGFR and prediabetes in children with obesity.

The 911 amino acid band 3 (SLC4A1) is the major intrinsic membrane protein of red cells and is the principal CL-/HCO3-exchanger. The N-terminal cytoplasmic domain of band 3 anchors the spectrin-based membrane skeleton to the lipid bilayer through its interaction with ankyrin and also binds glycolytic enzymes and hemoglobin. We identified a son of a consanguineous marriage with severe anemia in association with marked deficiency of band 3 (12% ± 4% of normal). Direct nucleotide sequencing of SLC4A1gene demonstrated a single base substitution (T → C) at position + 2 in the donor splice site of intron 2, resulting in the generation of a novel mutant protein. Biochemical characterization of the mutant protein showed that it lacked the first 11 N-terminal amino acids (band 3 Neapolis). The expression of the mutant protein resulted in the complete absence of membrane-bound aldolase, and the mutant band 3 could not be tyrosine phosphorylated. The ability of the malarial parasite P falciparumto invade these red cells was significantly decreased. The identification of a novel band 3 mutant and its structural and functional characterization enabled us to identify pivotal roles for the 11 N-terminal amino acids in several protein functions and, in turn, in red-cell physiology.

The 911 amino acid band 3 (SLC4A1) is the major intrinsic membrane protein of red cells and is the principal \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{CL}^{-}{/}\mathrm{HCO}_{3}^{-}\) \end{document} exchanger. The N-terminal cytoplasmic domain of band 3 anchors the spectrin-based membrane skeleton to the lipid bilayer through its interaction with ankyrin and also binds glycolytic enzymes and hemoglobin. We identified a son of a consanguineous marriage with severe anemia in association with marked deficiency of band 3 (12% ± 4% of normal). Direct nucleotide sequencing of SLC4A1 gene demonstrated a single base substitution (T → C) at position + 2 in the donor splice site of intron 2, resulting in the generation of a novel mutant protein. Biochemical characterization of the mutant protein showed that it lacked the first 11 N-terminal amino acids (band 3 Neapolis). The expression of the mutant protein resulted in the complete absence of membrane-bound aldolase, and the mutant band 3 could not be tyrosine phosphorylated. The ability of the malarial parasite P falciparum to invade these red cells was significantly decreased. The identification of a novel band 3 mutant and its structural and functional characterization enabled us to identify pivotal roles for the 11 N-terminal amino acids in several protein functions and, in turn, in red-cell physiology.

Congenital dyserythropoietic anemia type II (CDA-II) is the most common form of inherited dyserythropoiesis. Previous studies have shown that the anion transporter (band 3) is narrower and it migrates faster on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE); this aspect was related to insufficient glycosylation. Biochemical data support the hypothesis that this disease is due to a deficiency of N-acetylglucosaminyltransferase II (GnT II) or α-Mannosidase II (α-Man II), which represent the key to glycosylation. In addition, a third candidate gene is α-Man IIx, which shows a strong homology with α-Man II. The knowledge of the chromosomal localization of these putative genes allowed us to perform a linkage study using three sets of microsatellite markers flanking the candidate genes. Six families with two or more affected children were enrolled in this study. The data obtained exclude linkage to all three candidate genes. In consideration of the biochemical data (reduction of enzymatic activity) of the same enzymes, our results suggest the hypothesis that a defect in an unknown transcriptional factor is involved in CDA-II.

Congenital dyserythropoietic anemia type II (CDA-II) is the most common form of inherited dyserythropoiesis. Previous studies have shown that the anion transporter (band 3) is narrower and it migrates faster on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE); this aspect was related to insufficient glycosylation. Biochemical data support the hypothesis that this disease is due to a deficiency of N-acetylglucosaminyltransferase II (GnT II) or α-Mannosidase II (α-Man II), which represent the key to glycosylation. In addition, a third candidate gene is α-Man IIx, which shows a strong homology with α-Man II. The knowledge of the chromosomal localization of these putative genes allowed us to perform a linkage study using three sets of microsatellite markers flanking the candidate genes. Six families with two or more affected children were enrolled in this study. The data obtained exclude linkage to all three candidate genes. In consideration of the biochemical data (reduction of enzymatic activity) of the same enzymes, our results suggest the hypothesis that a defect in an unknown transcriptional factor is involved in CDA-II.