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Context Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS. Objective This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI). Methods We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6 years. Results MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 +/- 22 pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007). Conclusions The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.

The relationship between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has gained considerable scientific interest in adults over the past few years. However, this association has recently emerged in children. Several published studies have suggested a role for NAFLD as a risk factor for CKD from the earliest age, with a potential influence of the major NAFLD risk polymorphisms, resulting in an increased risk of both cardiovascular and metabolic diseases. In view of the progressive course and increased cardiometabolic risk closely related to NAFLD and CKD, we focused on the link between these diseases in childhood.

Background and aim: To compare cardiometabolic risk profile and preclinical signs of target organ damage in youth with normal and elevated blood pressure (BP), according to the American Academy of Pediatrics (AAP) guidelines. Methods and results: This cross-sectional multicenter study included 2739 youth (5-17 year-old; 170 normal-weight, 610 overweight and 1959 with obesity) defined non hypertensive by the AAP guidelines. Anthropometric, biochemical and liver ultrasound data were available in the whole population; carotid artery ultrasound and echocardiographic assessments were available respectively in 427 and 264 youth. Elevated BP was defined as BP >= 90th to = 120/80 to

Objective Vitamin D may potentially play a central role in glucose homeostasis and β-cell function (BCF), although studies are not consistent. Aim of our study was to test the hypotheses of a direct relationship between vitamin D, insulin sensitivity (IS) and BCF in overweight and obese non-diabetic children. Design and methods Cross-sectional study carried out at the Childhood Obesity Outpatient Clinic, University Hospital of Verona. One hundred twenty-two Caucasian overweight and obese children (age: 12.8 ± 0.2 years) were enrolled. Exclusion criteria: genetic or endocrine causes of obesity, chronic diseases or therapies. Patients underwent oral glucose tolerance test. HOMA-IR, Matsuda index and insulinogenic index were calculated. BCF was reconstructed by mathematical modeling and described by Derivative and Proportional Control. Total 25-hydroxyvitamin D and vitamin D-binding protein (VDBP) were measured. Two SNPs (rs4588 and rs7041) in the VDBP gene were studied, and bioavailable vitamin D (BVD) was calculated. Results Hypovitaminosis D was documented in 90% of patients. Forty-seven subjects were homozygous for both SNPs. Total vitamin D was positively correlated with Matsuda index (P = 0.002), VDBP (P = 0.045), and negatively with BMI SDS (P = 0.043), HOMA-IR (P = 0.008), HOMA-B (P = 0.001), IGI (P = 0.007), derivative control (P = 0.036) and proportional control (P = 0.018). Total vitamin D, adjusted for age, gender, BMI SDS, puberty and seasonality of vitamin D measurement, was a predictor of Matsuda index, HOMA-IR, HOMA-B, IGI, proportional control (all P P P = 0.041). Conclusions Hypovitaminosis D negatively influences BCF and IS, suggesting that vitamin D levels might be implicated in glucose metabolism impairment in overweight and obese individuals.

The rapid global spread of coronavirus disease 2019 (COVID-19) infection has become a major health issue with higher morbidity and mortality rates. Besides respiratory symptoms, a growing body of evidence indicates a variety of gastrointestinal manifestations including liver involvement. In this regard, several data supported an association between COVID-19 infection and liver injury in adults, while in children there is compelling but currently limited evidence. In particular, patients with COVID-19 have shown a higher risk of liver injury (mainly expressed as increased transaminase levels or hepatic steatosis). Conversely, a greater risk of more severe forms of COVID-19 infection has been observed in subjects with pre-existing chronic liver diseases. The dramatic interplay between COVID-19 and liver damage has been related to the inflammatory pathways chronically active in patients with nonalcoholic fatty liver disease and acutely in those affected by COVID-19, but other different pathogenic mechanisms have also been supposed. Of note, patients with previous metabolic comorbidities also had a higher risk of severe COVID-19 infection. This emphasizes the pathogenic interrelation of the inflammatory pathways with a dysregulated metabolic milieu in COVID-19 patients. Taking into account the prognostic role of fatty liver in COVID-19 patients and its intrinsic relationship with metabolic abnormalities even in childhood, a strict monitoring of this condition is recommended. We aimed to summarize the most recent evidence regarding the potential interplay between pediatric fatty liver and COVID-19.

Background: Vesicoureteral reflux (VUR) may be associated with renal dysplasia and reduced renal length (RL). The diagnosis of VUR in children with congenital solitary functioning kidney (CSFK) identifies patients at risk of kidney injury but exposes to invasive procedures. Objective: We aimed to test the hypothesis that an RL >2 standard deviation score (SDS) in the first months of life – reflecting renal hyperplasia – could identify CSFK patients with lower probability of presenting VUR. Method: We retrospectively selected 207 CSFK patients with prenatal diagnosis of CSFK and having undergone renal ultrasound (RUS) both at 0–3 and 10–13 months of life, renal scintigraphy, and cystourethrography/cysto­scintigraphy. We compared the cumulative proportion of an RL >2 SDS by Kaplan-Meier analysis and evaluated the odds to present VUR of patients with an RL >2 SDS both at the first and second RUS. Results: Overall, 3.3% of patients with VUR and 22.0% of patients without VUR presented an RL >2 SDS at the first RUS (p = 0.02). At the second RUS, 53.3% of patients with VUR and 52.5% of patients without VUR presented an RL >2 SDS (p = 0.93). Patients without VUR presented higher cumulative proportion of an RL >2 SDS at 3 months of life than those with VUR (p = 0.02). This difference however disappeared at 11 and 13 months of age (p = 0.17 and p = 0.54, respectively). An RL >2 SDS within 3 months of life presented an OR for VUR of 0.12 (95% CI: 0.02–0.92; p = 0.005), while an RL >2 SDS at 12 months of life presented an OR for VUR of 0.96 (95% CI: 0.45–2.1; p = 0.93). Conclusion: Only an RUS made in the first months of life could identify CSFK patients at lower risk of presenting an associated VUR.

Background and aim: The relationships between uric acid (UA) and prediabetes is poorly explored in youth. We investigated the association between UA, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), insulin resistance (IR) and low insulin sensitivity (IS) in youth with overweight/obesity (OW/OB). Methods and results: A cross-sectional study was performed in 2248 youths with OW/OB (age 5–17 years). The sample was stratified in sex-specific quintiles (Q1 to Q5) of UA and the associations with fasting (FG), 2-h post-load glucose (2H-PG), IR and low IS were investigated. IR and low IS were estimated by assessment model of insulin resistance (HOMA-IR) and whole-body IS index (WBISI), respectively. IFG was defined as FG ≥ 100 < 126 mg/dL, IGT as 2H-PG ≥140 < 200 mg/dL, IR as HOMA-IR ≥75th percentile and low IS as WBISI ≤25th percentile by sex. Age, body mass index z-score, 2H-PG, HOMA-IR and WBISI, increased across sex-quintiles of UA while FG did not. The prevalence of IFG and IR were significantly increased in Q5 vs Q1 (reference quartile, P < 0.025). The prevalence of IGT increased from Q3 to Q5 vs Q1 (P < 0.025–0.0001) and that of low IS from Q2 to Q5 vs Q1 (P < 0.005–0.0001). Conclusions: In youth with OW/OB, rates of IGT and low IS increased progressively across quintiles of UA. On the contrary, IFG and IR were associated only with the highest quintile of UA. Our data suggest that UA is a biomarker of impaired glucose metabolism prevalently in post–challenge condition rather than in fasting state.

Due its close relationship with obesity, nonalcoholic fatty liver disease (NAFLD) has become a major worldwide health issue even in childhood. The most accepted pathophysiological hypothesis is represented by the "multiple hits" theory, in which both hepatic intracellular lipid accumulation and insulin resistance mainly contribute to liver injury through several factors. Among these, lipotoxicity has gained particular attention. In this view, the pathogenic role of different lipid classes in NAFLD (e.g., sphingolipids, fatty acids, ceramides, etc.) has been highlighted in recent lipidomics studies. Although there is some contrast between plasma and liver findings, lipidomic profile in the NAFLD context provides novel insights by expanding knowledge in the intricate field of NAFLD pathophysiology as well as by suggesting innovative therapeutic approaches in order to improve both NAFLD prevention and treatment strategies. Selective changes of distinct lipid species might be an attractive therapeutic target for treating NAFLD. Herein the most recent evidence in this attractive field has been summarized to provide a comprehensive overview of the lipidomic scenario in paediatric NAFLD.

Bisphenol A (BPA) is a xenobiotic endocrine-disrupting chemical.In vitroandin vivostudies have indicated that BPA alters endocrine-metabolic pathways in adipose tissue, which increases the risk of metabolic disorders and obesity. BPA can affect adipose tissue and increase fat cell numbers or sizes by regulating the expression of the genes that are directly involved in metabolic homeostasis and obesity. Several studies performed in animal models have accounted for an obesogen role of BPA, but its effects on human adipocytes – especially in children – have been poorly investigated. The aim of this study is to understand the molecular mechanisms by which environmentally relevant doses of BPA can interfere with the canonical endocrine function that regulates metabolism in mature human adipocytes from prepubertal, non-obese children. BPA can act as an estrogen agonist or antagonist depending on the physiological context. To identify the molecular signatures associated with metabolism, transcriptional modifications of mature adipocytes from prepubertal children exposed to estrogen were evaluated by means of microarray analysis. The analysis of deregulated genes associated with metabolic disorders allowed us to identify a small group of genes that are expressed in an opposite manner from that of adipocytes treated with BPA. In particular, we found that BPA increases the expression of pro-inflammatory cytokines and the expression ofFABP4andCD36, two genes involved in lipid metabolism. In addition, BPA decreases the expression ofPCSK1, a gene involved in insulin production. These results indicate that exposure to BPA may be an important risk factor for developing metabolic disorders that are involved in childhood metabolism dysregulation.

Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs' group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver. © 2014 Baishideng Publishing Group Inc. All rights reserved.

A selective and highly sensitive liquid chromatography-tandem mass spectrometry method has been developed and validated for determination of Bisphenol A (BPA) in human urine using labeled d6-BPA as internal standard. BPA was purified from human urine by affinity chromatography on solid extraction AFFINIMIP® Bisphenol A cartridges, based on molecularly imprinted polymers. After purification, the samples were analyzed on a Phenomenex Kinetex 100 × 4.6 mm, 2.6 μm particle PFP reversed-phase HPLC column, coupled to a triple quadrupole mass spectrometer by an electrospray ion source. Analyses were performed in the multiple reaction monitoring mode and negative ionization; the product ions at 133.2 and 212.1 m/z for BPA and at 138.2 and 215.0 m/z for d6-BPA were monitored to assess unambiguous identification. The linearity of the detector response was verified in human urine over the concentration range 0.100-200 ng/mL. The detection limit was calculated as 0.03 ng/mL and the limit of quantification of the method is 0.10 ng/mL. This LC/ESI-MS/MS method was in-house validated evaluating specificity, trueness, within-day and between-days precision. The mean recoveries of BPA from spiked urine samples were higher than 94 % and good reproducibility (relative standard deviations ≤ 8.1 %) was observed. The developed method was applied to a pilot study involving 105 children, aged from 6 to 14 years (16 normal weight and 89 obese children), from the Regione Campania (Southern Italy). The aim of this study was to determine the concentrations of BPA in urine of children and possible correlations with childhood obesity. © 2013 Springer-Verlag Berlin Heidelberg.

Ipercaloric diet and reduced physical activity have driven the rise in the prevalence of childhood obesity over a relatively short time interval. Family and twin studies have led to the conclusion that the strong predicitve value of parental body mass index (BMI) mainly stems from genetic rather than environmental factors. Whereas the common polygenic obesity arises when an individual genetic make-up is susceptible to an environment that promotes energy consumption over energy expenditure, monogenic obesity, on the contrary, is the obesity associated with a single gene mutation, which is sufficient by itself to cause weight gain in a food abundant context. Genes involved in the leptin-melanocortin pathway are often mutated in these cases. The cumulative prevalence of monogenic obesity among children with severe obesity is about 5%. Recently, deletions in the region p11.2 of the chromosome 16 encompassing the gene SH2B1, which is involved in the leptin and insulin signaling, have been reported in about 0.5% of children with severe early-onset obesity. These patients show extreme hyperphagia, severe insulin resistance and, in some cases, mild developmental delay.

Aims: The prevalence of obesity is increasing among children in the developed world. The association of obesity and abnormal cardiac function is still debated. The reported changes may reflect the role of comorbidities that contribute to ventricular dysfunction. Obese children, without arterial hypertension, may be a unique clinical opportunity to evaluate the effect of obesity, per se, on myocardial function, excluding the influence of possible comorbidities. We sought to define the preclinical effects of obesity on the cardiovascular system, of healthy children with excess weight who have no other clinically appreciable cause of heart disease, using the more sensitive ultrasonic-derived strain and strain rate (SR) imaging. Methods and results: We studied 300 subjects divided into two groups: (i) obese children (Group O: n=150; age, 12±3 years); (ii) healthy lean children comparable for age, sex, and pubertal stage (Referents: n=150; mean age, 12±3 years). Systolic (SBP) and diastolic blood pressure (DBP), as well as 24 h-SBP and 24 h-DBP were comparable between groups. Left ventricular (LV) mass/height 2.7 was increased (P

In this study we analyzed the effect of the (TA)7 polymorphism of the UGT1A gene associated with Gilbert's syndrome in G6PD-deficient subjects during an acute hemolytic crisis (fabic crisis). DNA from 44 subjects originating from the same geographic area in Sardinia was analyzed for the UGT1A promoter polymorphism. The increase of unconjugated bilirubin level during fabic crisis and its relationship with UGT1A polymorphism was evaluated. The UGT1A (TA)7 TATA box variant was found in 9/44 (21%) of the G6PD deficient subjects examined. The median value for unit of increase of bilirubin (mg/dl)/unit of decrease of hemoglobin (g/dl) was higher in variant homozygous than in heterozygous and normal subjects. These findings imply a contribution of the UGT1A polymorphism associated to Gilbert's syndrome to development of the hyperbilirubinemia in G6PD deficient subjects during acute hemolytic anemia.