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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]

Despite the implementation of preventive measures to counteract the obesity epidemics, the prevalence of childhood obesity is still alarming all over the world. Childhood obesity is the most common risk factor for both cardiovascular and metabolic diseases. In fact, an earlier onset of obesity can cause a greater risk of adiposity tracking across the lifespan and consequently a longer exposure to cardiometabolic risk factors. Accumulating evidence provided by prospective and intervention studies demonstrated the link between pediatric obesity and selected subclinical signs of cardiovascular damage (atherosclerosis and left ventricular hypertrophy), or fatal and not fatal cardiovascular events as early as 40 years of age. The numerous guidelines and scientific documents published in the last years demonstrate the relevance of assessing cardiometabolic risk factors in children and adolescents with OB. This Position paper, released by experts of the "Childhood Obesity study group" within the Italian Society for Pediatric Endocrinology and Diabetology, aims to review the assessment of cardiometabolic risk factors and comorbidities in children and adolescents with OW/OB on the light of the most recent scientific evidence. The main recommendations are: (a) early detection of comorbidities, including hypertension, dyslipidemia, prediabetes/type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, polycystic ovary syndrome, inactivity, obstructive sleep apnea and decline in kidney function; (b) weight loss treatment, which is associated with a reduction of all cardiometabolic risk factors; (c) specific treatment of comorbidities, through lifestyle modifications or pharmacological treatment added to lifestyle for suitable individuals; d). monitoring comorbidities for mitigating future morbidity and mortality. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has had a huge impact on children's lifestyle and eating behaviour, resulting in an increase of obesity prevalence. The CEBQ (Children's Eating Behaviour Questionnaire) is a validate questionnaire that investigates children's eating behaviour. Knowing the psychological consequences of daily routine disruption during lockdown, we evaluated the changes in eating behaviours in a paediatric cohort before and during the lockdown period through the evaluation of the Italian version of the CEBQ. We prospectively enrolled children attending the pediatric clinic of the University of Campania 'Luigi Vanvitelli'. All parents answered the parent-report version of the CEBQ before lockdown containment. During lockdown, the second survey was carried out by telephone call. The study sample included 69 children. Food responsiveness and emotional overeating subscales showed higher scores during lockdown compared to data before lockdown (p = 0.009 and p = 0.001, respectively). Conversely, desire to drink and satiety responsiveness showed lower scores at follow-up (p = 0.04 and p = 0.0001, respectively). No differences were observed for slowness in eating and enjoyment of food. Delta changes were higher in normal-weight children compared to children with obesity (p = 0.02). Our results confirm that containment measures during the COVID-19 pandemic have acted as triggers on certain eating behaviors that mostly predispose to an obesogenic manner. [ABSTRACT FROM AUTHOR]

We hypothesized that—as in other common pediatric conditions—acute appendicitis (AA) could be complicated by acute kidney injury (AKI). We aimed to investigate the prevalence of, and the factors associated with AKI in a cohort of patients with AA. We retrospectively collected data of 122 children (63.9% of male gender; mean age 8.6 ± 2.9 years; range: 2.2–13.9 years) hospitalized for AA. AKI was defined according to the Kidney Disease/Improving Global Outcomes creatinine criteria. We considered a basal serum creatinine value as the value of creatinine estimated with the Hoste (age) equation, assuming that the basal estimated glomerular filtration rate (eGFR) was 120 mL/min/1.73 m2. Explorative univariate logistic regression analysis was used to explore the associations with AKI. Out of 122 patients, nine (7.4%) presented with AKI. One patient had stage two AKI and the remaining had stage one AKI. The maximum AKI stage was found at admission. The patients with AKI showed a higher prevalence of fever ≥ 38.5 °C (p = 0.02), vomiting (p = 0.03), ≥5% dehydration (p = 0.03), and higher levels of both C-reactive protein (CRP) (p = 0.002) and neutrophils (p = 0.03) compared with patients without AKI. Because all patients with AKI also presented with vomiting, an Odds Ratio (OR) for the vomiting was not calculable. The exploratory univariate logistic regression analysis confirmed that fever ≥ 38.5 °C (OR = 5.0; 95% CI: 1.2/21.5; p = 0.03), ≥5% dehydration (OR = 8.4; 95% CI: 1.1/69.6; p = 0.04), CRP (OR = 1.1; 95% CI: 1.05/1.2; p = 0.01), and neutrophil levels (OR = 1.1; 95% CI: 1.01/1.3; p = 0.04) were all predictive factors of AKI. AKI can occur in 7.4% of patients with AA. Particular attention should be paid to the kidney health of patients with AA especially in the presence of vomiting, ≥5% dehydration, fever ≥ 38.5 °C, and high CRP and neutrophils levels. [ABSTRACT FROM AUTHOR]

Context: Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies. Objective: This work aims to identify the genetic cause of growth failure in 3 "classical" GHI individuals. Methods: A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6O pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function. Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6 GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6O pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6O pseudoexon not identified in wild-type constructs. Inclusion of the 6O pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6O pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation. Conclusion: Novel GHR 6O pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders. [ABSTRACT FROM AUTHOR]

The severe impact of global crises, such as COVID-19 and climate change, is plausibly reshaping the way in which people perceive risks. In this paper, we examine and compare how global crises and local disasters influence public perceptions of multiple hazards in Italy and Sweden. To this end, we integrate information about the occurrence of hazardous events with the results of two nationwide surveys. These included more than 4000 participants and were conducted in two different phases of the COVID-19 pandemic corresponding to low (August 2020) and high (November 2020) levels of infection rates. We found that, in both countries, people are more worried about risks related to experienced events. This is in line with the cognitive process known as the availability heuristic: individuals assess the risk associated with a given hazard based on how easily it comes to their mind. Epidemics, for example, are perceived as less likely and more impactful in Italy compared to Sweden. This outcome can be explained by cross-country differences in the impact of, as well as governmental responses to, COVID-19. Notwithstanding the ongoing pandemic, people in both Italy and Sweden are highly concerned about climate change, and they rank it as the most likely threat. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate prevalence of acute kidney injury (AKI) and its risk factors in children hospitalized for acute gastroenteritis (AGE) to identify early predictors of AKI. Methods: We retrospectively collected clinical and biochemical data of 114 children (57.9% male; mean age 2.9 ± 2.8 years) hospitalized for AGE. AKI was defined according to Kidney Disease/Improving Global Outcomes creatinine criteria. We considered basal serum creatinine as value of creatinine estimated with Hoste (age) equation assuming basal eGFRs were median age-based eGFR normative values for children ≤ 2 years of age, and eGFR 120 mL/min/1.73m2 for children > 2 years. Univariate and multivariate logistic regression models were used to explore associations with AKI. We included in multivariate analyses only variables with significant p after Bonferroni correction. Results: AKI was found in 28/114 (24.6%) patients. No patients required hemodialysis, 2 (1.8%) reached AKI stage 3, 2 (1.8%) AKI stage 2, and 24 (21.0%) AKI stage 1. Mean length of stay was 3.6 ± 1.2, 5.0 ± 1.8, and 10.5 ± 5.8 days, for patients with no, mild, and severe AKI (p < 0.001), respectively. Duration of symptoms before hospitalization (OR = 2.5; 95% CI = 1.3–5.0; p = 0.006), dehydration > 5% (OR = 43.1; 95% CI = 5.4–344.1; p = < 0.001), and serum bicarbonate levels (OR = 1.6; 95% CI = 1.2–2.1; p = 0.001) were independent predictors of AKI. Conclusions: About one quarter of patients hospitalized for AGE may suffer from AKI with a longer stay for patients with more severe AKI. Particular attention, however, should be paid to volemia and kidney health of patients with AGE especially in the presence of increased duration of symptoms before hospitalization, dehydration, and lower serum bicarbonate levels. [ABSTRACT FROM AUTHOR]

Objective: To examine body image problems and their associations with disordered eating behavior in adolescents with type 1 diabetes and well-matched healthy peers. Methods: Using a cross-sectional design, 183 adolescents with type 1 diabetes (13.02–18.05 years) were recruited from diabetes centers in southern Italy and compared to healthy peers matched for age and gender. Participants completed self-report measures of disordered eating behaviors (DEPS-r and EDI-3RF) and a gender-specific body image problem questionnaire (SATAQ-4R). Socio-demographic and clinical data (zBMI, HbA1c, and disease duration) were also collected. Hierarchical multiple linear regression analyses were computed to determine the relative importance of diabetes variables and body image problems on participants' disordered eating behaviors after controlling for demographic variables. Results: Adolescents with type 1 diabetes showed diabetes-specific eating problems in 37.7% of cases and had more eating problem symptoms (assessed as drive for thinness and bulimia) than healthy peers. Male adolescents with type 1 diabetes did not display more body image problems (p > 0.05); females with type 1 diabetes compared to females in the control group were found to be more pressured by family (p = 0.025) but less by media (p = 0.022) to improve their appearance and attain a thin body. zBMI and body image problems contributed to a significant increase in disordered eating behavior risk both in male and female adolescents with diabetes and in healthy peers (zBMI 0.213 < β < 0.426, p < 0.05; body image 0.243 < β < 0.572, p < 0.05). None of the variables analyzed were found to significantly predict male bulimic symptoms (all β < 0.296, p > 0.05). Conclusion: Since in adolescence type 1 diabetes and insulin therapy may increase the risk of weight gain and promote focus and attention on the body and thus contribute to the development of body image problems and disordered eating behaviors, continuity of medical, nutritional, and psychological care is needed. [ABSTRACT FROM AUTHOR]

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: Body Mass Index Italian reference data are available for clinical and/or epidemiological use, but no study compared the ability of this system to classify overweight and obesity and detect subjects with clustered cardiometabolic risk factors with international standards. Therefore our aim was to assess 1) the agreement among the Italian Society for Pediatric Endocrinology and Diabetology (ISPED), the World Health Organisation (WHO) and the International Obesity Task Force (IOTF) Body Mass Index cut-offs in estimating overweight or obesity in children and adolescents; 2) the ability of each above-mentioned set of cut-points to detect subjects with cardiometabolic risk factors. Methods: Data of 6070 Italian subjects aged 5-17 years were collected. Prevalence of normal-weight, overweight and obesity was determined using three classification systems: ISPED, WHO and IOTF. High blood pressure, hypertriglyceridemia, low high density lipoprotein-cholesterol and impaired fasting glucose were considered as cardiometabolic risk factors. Results: ISPED and IOTF classified more subjects as normal-weight or overweight and less subjects as obese as compared to WHO (p <0.0001) in the whole sample and in groups divided by gender and age. The strength of agreement between the three methods compared to each other was excellent for overweight (including obesity) definition (k > 0.900), while it differed for obesity definition, ranging from the highest agreement between ISPED and IOTF (k 0.875) to the lowest between ISPED and WHO (k 0.664). WHO had the highest sensitivity, while ISPED and IOTF systems had the highest specificity, in identifying obese subjects with clustered cardiometabolic risk factors. Analogous results were found in subjects stratified by gender or age. Conclusions: ISPED and IOTF systems performed similarly in assessing overweight and obesity, and were more specific in identifying obese children/adolescents with clustered cardiometabolic risk factors; on the contrary, the WHO system was more sensitive. Given the seriousness of the obesity epidemic, we wonder whether the WHO system should be preferable to the national standards for clinical practice and/or obesity screening. [ABSTRACT FROM AUTHOR]

Background: In recent years, there has been an increasing attention to thyroid function in paediatric obese patients. In the present study we aimed 1) to determine the prevalence of abnormally elevated thyroid-stimulating hormone (TSH) levels in Italian obese children and adolescents 2) to investigate whether hyperthyrotropinemia in obese children cardiovascular and metabolic risk factors 3) to verify if TSH elevation is reversible after weight loss. Methods: We examined 938 obese children and adolescents (450 females). Anthropometric, metabolic and hormonal variables were determined at baseline and, in a subgroup of children with hyperthyrotropinemia, after a six month weight loss program. Results: Hyperthyrotropinemia (TSH ≥4.2 μUI/ml) was diagnosed in 120 patients (12,8%). Body mass index (BMI) z-score (p = 0.02) and free T3 (fT3) levels (p = 0.03) were higher in patients with elevated TSH compared to the group with normal TSH. There were not significant differences in other metabolic parameters between the two groups. A positive correlation between baseline TSH and BMI z-score (p = 0.0045) and between Ft3 and BMI z-score (p = 0.0034) was observed, while there was no correlation between TSH and lipids. Twenty-three patients among those with hyperthyrotropinemia who participated to weight reduction intervention (64 patients), presented substantial weight loss and concomitantly a significant decrease in TSH and in fT3. Conclusions: These results suggest that: (1) a moderate elevation of TSH concentrations, is frequently found in obese children; (2) in obese children increase of TSH is not associated to metabolic risk factors, (3) hyperthyrotropinemia is reversible after weight loss and these data suggest that it should not be treated. [ABSTRACT FROM AUTHOR]

Vitamin D plays a pivotal role in the regulation of calcium-phosphorus metabolism, particularly during pediatric age when nutritional rickets and impaired bone mass acquisition may occur. Besides its historical skeletal functions, in the last years it has been demonstrated that vitamin D directly or indirectly regulates up to 1250 genes, playing so-called extraskeletal actions. Indeed, recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious, allergic and autoimmune diseases. Thus, vitamin D deficiency may affect not only musculoskeletal health but also a potentially wide range of acute and chronic conditions. At present, the prevalence of vitamin D deficiency is high in Italian children and adolescents, and national recommendations on vitamin D supplementation during pediatric age are lacking. An expert panel of the Italian Society of Preventive and Social Pediatrics reviewed available literature focusing on randomized controlled trials of vitamin D supplementation to provide a practical approach to vitamin D supplementation for infants, children and adolescents. [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., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

This Position Statement updates the different components of the therapy of obesity (lifestyle intervention, drugs, and surgery) in children and adolescents, previously reported in the consensus position statement on pediatric obesity of the Italian Society of Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Lifestyle intervention is the first step of treatment. In children older than 12 years, pharmacotherapy is the second step, and bariatric surgery is the third one, in selected cases. Novelties are available in the field of the medical treatment of obesity. In particular, new drugs demonstrated their efficacy and safety and have been approved in adolescents. Moreover, several randomized control trials with other drugs are in process and it is likely that some of them will become available in the future. The increase of the portfolio of treatment options for obesity in children and adolescents is promising for a more effective treatment of this disorder., (© 2023. The Author(s).)

Adequate and balanced nutrition is essential to promote optimal child growth and a long and healthy life. After breastfeeding, the second step is the introduction of complementary feeding (CF), a process that typically covers the period from 6 to 24 months of age. This process is, however, still highly controversial, as it is heavily influenced by socio-cultural choices, as well as by the availability of specific local foods, by family traditions, and pediatrician beliefs. The Società Italiana di Pediatria Preventiva e Sociale (SIPPS) together with the Federazione Italiana Medici Pediatri (FIMP), the Società Italiana per lo Sviluppo e le Origine della Salute e delle Malattie (SIDOHaD), and the Società Italiana di Nutrizione Pediatrica (SINUPE) have developed evidence-based recommendations for CF, given the importance of nutrition in the first 1000 days of life in influencing even long-term health outcomes. This paper includes 38 recommendations, all of them strictly evidence-based and overall addressed to developed countries. The recommendations in question cover several topics such as the appropriate age for the introduction of CF, the most appropriate quantitative and qualitative modalities to be chosen, and the relationship between CF and the development of Non-Communicable Diseases (NCDs) later in life.

Background and Aims: Birth weight (BW) has been associated with the risk of obesity and metabolic derangements in children and adults. The aims of this study were: i. to evaluate the distribution of BW in a sample of overweight and obese children and adolescents compared with the general reference population; ii. to explore the relationship between the BW and insulin resistance and other cardiometabolic derangements in a population of children and adolescents with overweight and obesity., Methods and Results: 710 overweight and obese children and adolescents were recruited and categorized into small (SGA), appropriate (AGA), and large (LGA) for gestational age, according to the BW percentile. Arterial blood pressure, lipid profile, glucose metabolism and hepatic steatosis were evaluated to assess cardiometabolic obesity-related derangements. The distribution of BW categories in our population was significantly different compared with the general population (SGA 6.9% vs. 8.6%, AGA 74.6% vs. 81.4%, LGA 18.5% vs. 10%; p < 0.0001). We found a higher frequency of prediabetes conditions (21.7% vs 8.9%, OR 2.97, 95% CI 1.38-6.38, p = 0.005) and borderline/high low-density lipoprotein cholesterol (31.8% vs 18.6%, OR 2.13, 95% CI 1.09-4.18, p = 0.033) in overweight and obese children born SGA compared to those born non-SGA, independently of age, sex, and BMI., Conclusions: BW is a risk factor of cardiometabolic derangements in a population of children and adolescents with overweight and obesity. Therefore, adequate obesity prevention strategies should be planned for children born SGA to minimize their risk to become obese and to reduce their short- and long-term cardiometabolic risks., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objectives: Recent evidence linked early menarche to a higher risk of insulin-resistance (IR) and nonalcoholic fatty liver disease (NAFLD) in adulthood. We aimed to evaluate the impact of early menarche on glucose derangements and NAFLD in a sample of Italian adolescents with obesity., Methods: Anthropometric and biochemical evaluations were conducted in all the enrolled 318 obese patients (mean age 12.31 ± 2.95 years). NAFLD was defined by the presence of ultrasound detected liver steatosis and/or alanine transaminase (ALT) levels >40 IU/L., Results: Patients with early menarche showed both higher homeostasis model assessment of insulin-resistance (HOMA-IR) (p=0.008) and ALT (p=0.02) values, an increased prevalence of NAFLD (p=0.001), and lower Matsuda and Insulinogenic Index (IGI) values than the other obese patients. The association between early menarche and both ALT and Matsuda Index remained significant in General Linear Models (GLMs) in which respectively body mass index standard deviation score (BMI-SDS) and Matsuda Index, and BMI-SDS were included as covariates. Patients with early menarche also showed a higher risk of both HOMA-IR>3 (OR 1.69, CI 1.05-2.70, p=0.02) and NAFLD (OR 1.10, CI 1.01-1.21, p=0.03)., Conclusions: Girls with obesity presenting early menarche showed higher HOMA-IR levels, lower Matsuda Index and IGI values, and higher risk of NAFLD compared to girls without early menarche., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2., Methods: We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD)., Results: No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD)., Conclusions: As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

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 <95th percentile for age, gender and height in children or BP ≥ 120/80 to <130/80 in adolescents. The overall prevalence of elevated BP was 18.3%, and significantly increased from normal-weight to obese youth. Young people with elevated BP showed higher levels of body mass index (BMI), insulin resistance and a higher prevalence of liver steatosis (45% vs 36%, p < 0.0001) than normotensive youth, whilst they did not differ for the other cardiometabolic risk factors, neither for carotid intima media thickness or left ventricular mass. Compared with normotensive youth, individuals with elevated BP had an odds ratio (95%Cl) of 3.60 (2.00-6.46) for overweight/obesity, 1.46 (1.19-1.78) for insulin-resistance and 1.45 (1.19-1.77) for liver steatosis, controlling for centers, age and prepubertal stage. The odds for insulin resistance and liver steatosis persisted elevated after correction for BMI-SDS., Conclusion: Compared to normotensive youth, elevated BP is associated with increased BMI, insulin resistance and liver steatosis, without significant target organ damage., Competing Interests: Declaration of Competing Interest Nothing to disclose., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Context: Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce., Objectives: The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment., Design: Multicenter retrospective study., Settings and Patients: Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers., Main Outcome Measures: We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification., Results: Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency in 3 (9.4%), diencephalic syndrome in 4 (12.5%), and growth hormone hypersecretion in 2 (6.2%). In a multivariate cox regression analysis, hypothalamic involvement was the only independent predictor of endocrine dysfunctions (hazard ratio 5.02 [1.802-13.983]; P = .002)., Conclusions: Endocrine disorders were found in approximately one-third of patients with Neurofibromatosis type 1 and OPGs before any oncological treatment, central precocious puberty being the most prevalent. Sign of diencephalic syndrome and growth hormone hypersecretion, although rare, could be predictive of optic pathway gliomas in NF1. Tumor location was the most important predictor of endocrine disorders, particularly hypothalamic involvement., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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/h 2.16 ) 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.

Background: Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD., Aims: We examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors., Methods: We recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ± 2.8 years, z-BMI 3.3 ± 0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system., Results: The overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75-0.88] vs. 0.77 [0.70-0.84] without SNPs; p = 0.047)., Conclusions: NAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

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. CONCLUSION: Exercise is part of the strategy to obtain the best control of asthma in childhood, but we have to optimise the asthma control therapy before starting exercise programming. Furthermore, it is crucial to give best attention on the effects of obesity and insulin resistance, because they could in turn influence patients' symptoms., (Copyright © 2018 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

PNPLA3 and MTP genes have been associated with liver steatosis and chronic hepatitis C. We studied the influence of MTP and PNPLA3 polymorphisms in 114 Italian patients with chronic hepatitis C, evaluating the histological and clinical presentation of liver disease. The study confirmed the association of PNPLA3 polymorphisms with liver steatosis (p=0.041), but did not show any additive effect of MTP polymorphisms in the development of steatosis. MTP polymorphisms do not seem to influence PNPLA3 in the development of liver steatosis. Further studies with a larger number of patients are required.

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention.The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase.

Introduction: Since standardization of the ICCS terminology, only two small case series of children with extraordinary daytime only urinary frequency (EDOUF) have been published. The aims of the present study were i) to describe a large cohort of children affected by EDOUF, to evaluate its rate among the main micturition pediatric disturbances, and to determine if there is different EDOUF onset among seasons; ii) to investigate possible associations with urodynamic abnormalities by non-invasive techniques; iii) to evaluate whether postponing micturition exercise (PME) can objectively verify the anamnestic data hinting at the EDOUF diagnosis; and iv) to determine the effect of postponing micturition at home., Material and Methods: We reviewed the records of all patients with EDOUF, nocturnal enuresis, and/or overactive bladder firstly examined from March 2012 to February 2016. We evaluated post-void residual and bladder wall thickness by urinary ultrasound and uroflowmetry and recorded the season in which the EDOUF started. Through the PME, the EDOUF diagnosis was confirmed if patients were able to postpone micturition reaching at least 80% of the expected bladder capacity without showing urinary incontinence. At home, we recommended postponing micturition for a maximum of 3 h if EDOUF affected the normal daily activities of both children and parents. We set a telephone interview for 3 months later., Results: The clinical characteristics of the EDOUF population are shown in the Table. The EDOUF rate was 12.1%. The rate of EDOUF onset was significantly lower during the summer than in other seasons (p = 0.02) and the OR for onset of EDOUF in the summer - compared with the other seasons - was 0.37 (95% CI 0.18-0.74; p = 0.005). Eighty-five (80.2%) patients reported an intermittent trend of the EDOUF with variable periods of improvement and worsening. All the EDOUF patients had normal uroflowmetry, 1/106 had post-micturition bladder wall thickness >5 mm and one post-void residual. At the PME, 106 out of 106 (100%) patients with EDOUF were able to reach at least 80% of the EBC without showing urinary incontinence or urgency incontinence. After 3 months, in 98.1% of the patients the symptoms had disappeared or improved., Discussion and Conclusions: Childhood EDOUF is rather common and is generally associated with normal non-invasive urodynamic patterns. The PME allows verification of anamnestic data of EDOUF. The sole recommendation to postpone micturition for a maximum of 3 h or until the micturition postponement became stressful could be considered as a possible approach., (Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

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.

Background: The patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been associated with liver steatosis and disease progression in nonalcoholic steatohepatitis and chronic hepatitis C., Aims: The aim of the present study was to evaluate the influence of the PNPLA3 I148M polymorphisms on the clinical, histological, viral, and host parameters in Italian patients with chronic hepatitis B (CHB)., Methods: Ninety-nine patients with CHB entered the study and underwent a clinical, histological, virological, and biochemical evaluation. PNPLA3 (p.I148M) variants were genotyped., Results: PNPLA3 rare variant (148M) was significantly associated with liver steatosis (p = 0.0019) and cholesterol (p = 0.04) levels, but not with fibrosis or histological activity index. The 13 patients with severe liver steatosis (score > 3) (38%) were more frequently homozygous for PNPLA3 148M variant than the 86 without (6%, p = 0.003). At logistic regression analysis, severe steatosis was independently associated with the rare allele (p = 0.001) and waist circumference, but not with body mass index (BMI)., Conclusions: In our CHB patients, the PNPLA3 polymorphisms influenced the development of liver steatosis, but not fibrosis status. The association of PNPLA3 p.I148M with liver steatosis increased with the greater amount of abdominal fat, irrespective of BMI.

Background & Aims: A common non-synonymous polymorphism, E167K, in transmembrane six superfamily member 2 (TM6SF2) gene has been recently associated with an increased hepatic triglyceride content, dyslipidemia and liver fibrosis in NAFLD patients. We investigated possible associations between the TM6SF2 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 TM6SF2 E167K and PNPLA3 I148M variants., Results: The score of liver steatosis was higher in the 18 patients with TM6SF2 E167K variant (mean 1.9 ± 1.3) than in the 130 homozygotes for TM6SF2 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 TM6SF2 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 TM6SF2 E167K variant is an independent predictor of liver steatosis in chronic hepatitis C., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Celiac disease (CD) is a chronic inflammatory disease of the small bowel that occurs with the ingestion of gluten, found in several grains products. Although HLA-DQ2 variant is required for the gluten-derived peptide gliadin presentation by antigen-presenting cells to T-cells, non-HLA genetic factors account for the majority of heritable risk. Several genome-wide association studies have identified susceptibility loci for CD on chromosome 1. Cells of the immune system express the cannabinoid receptor type 2 (CB2), a plasma-membrane receptor activated by both endogenous and exogenous cannabinoids. Consistent data evidence that CB2 is linked to a variety of immune functional events and that, in the course of an inflammatory process, an increased number of receptors becomes available for activation. The cannabinoid receptor type 2 gene (CNR2; GeneID1269) maps on 1p36.11. In order to investigate the possible involvement of CB2 in CD establishment, immunohistochemistry toward CB2 receptor and CD4+ cells in small bowel biopsies from celiac children and association analysis, through TaqMan assay, of a CNR2 common missense variant, rs35761398 (CAA/CGG), resulting in the aminoacidic substitution of Glutamine at codon 63 with Arginine (Q63R), in a cohort of 327 South Italian children have been performed. We observed in this study that CB2 is up-regulated in CD small bowel biopsies and CNR2 rs35761398 is significantly associated with CD (χ(2) = 37.064; d.f. 1; p = 1.14 × 10(-9)). Our findings suggest a role of CB2 in CD. The Q63R variant, increasing more than six-fold the risk for CD susceptibility, might eventually represent a novel molecular biomarker for CD risk stratification. Indeed, we provide here further evidence that CB2 receptor plays a critical role in autoimmunity susceptibility and indicates that it represents a molecular target to pharmacologically modulate the immune components in CD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Obese children have a great risk of hypertension and cardiovascular morbidity in adults. The insulin-like growth factor type II (IGF-II) regulates glucose homeostasis, cardiovascular functions, and lipid metabolism. IGF2 gene variants have shown a strong association with weight, body mass index (BMI), and metabolic profile in adults. We performed the molecular screening of two IGF2 polymorphisms (6815 A/T, 820 G/A), in 227 obese children to evaluate the potential association between IGF2 variants with either obesity or high blood pressure (assessed with a 24-h holter system) or both. A second cohort of age-, sex-, and BMI-matched children were enrolled to confirm any eventual association. We observed a significant association between the 6815 A/T IGF2 gene variant and high systolic blood pressure in obese children. Homozygote subjects for the T6815 allele showed, even in 24-h measurements, a higher risk to develop hypertension than those carrying the A6815 allele (OR = 3.7, 95% CI: 1.59-8.66). This result was confirmed in the second cohort (OR = 4.1, 95% CI: 1.41-6.50). Any statistically significant difference in terms of BMI between the genotype groups was observed. Our results suggest that IGF2 gene variants are involved in the blood pressure regulation in obese children.

Context: Obesity and iron deficiency are two of the most common nutritional disorders worldwide. Several studies found higher rates of iron deficiency in obese than in normal-weight children. Hepcidin represents the main inhibitor of intestinal iron absorption, and its expression is increased in adipose tissue of obese patients. Leptin is able, in vitro, to raise hepcidin expression., Objectives: Aims of this work were 1) to assess the association between poor iron status and obesity, 2) to investigate whether iron homeostasis of obese children may be modulated by serum hepcidin variations, and 3) to assess the potential correlation between leptin and serum hepcidin variations., Methods: Iron status and absorption as well as hepcidin, leptin, and IL-6 levels were studied in 60 obese children and in 50 controls., Results: Obese children showed lower iron and transferrin saturation (both P < 0.05) and higher hepcidin levels (P = 0.004) compared with controls. A direct correlation between hepcidin and obesity degree (P = 0.0015), and inverse correlations between hepcidin and iron (P = 0.04), hepcidin and transferrin saturation (P = 0.005), and hepcidin and iron absorption (P = 0.003) were observed. A correlation between leptin and hepcidin (P = 0.006) has been found. The correlation remained significant when adjusted for body mass index, sex, pubertal stage, and IL-6 values., Conclusions: We propose that in obese patients, increased hepcidin production, at least partly leptin mediated, represents the missing link between obesity and disrupted iron metabolism.

Background: Melanocortin-4-receptor (MC4R) mutations represent the most frequent genetic cause of non-syndromic early onset obesity. Children carrying MC4R mutations seem to show a particular phenotype characterized by early onset, severe obesity and high stature. To verify whether MC4R mutations are associated with this particular phenotype in the Italian pediatric population, we decided to screen the MC4R gene in a group of obese children selected on the basis of their phenotype., Methods: To perform this study, a multicentric approach was designed. Particularly, to be enrolled in the study subjects needed to meet the following criteria: Body mass index > or = 3 deviation scores according to age and sex, familiar history of obesity (at least one parent obese), obesity onset before the 10 years old, height > or = 2 deviation scores. The coding region of MC4R gene was screened in 240 obese children (mean age 8.3 +/- 3.1, mean BMI 30.8 +/- 5.4) and in 200 controls (mean age 8.1 +/- 2.8; mean BMI 14.2 +/- 2.5)., Results: Three mutations have been found in five obese children. The S127L (C380T), found in three unrelated children, had been described and functionally characterized previously. The Q307X (C919T) and the Y332H (T994C) mutations were found in two patients. Functional studies showed that only Q307X impaired protein function., Conclusion: The low prevalence of MC4R mutations (1.6%) in this group of obese children selected according to the obesity degree, the tall stature and the family history of obesity was similar to the prevalence observed in previous screenings performed in obese adults and in not phenotypically selected obese children.

Recently, DYX1C1, a candidate gene for developmental dyslexia, encoding a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain, has been characterized through a translocation breakpoint in a Finnish family. Two putatively functional variants, -3G/A and 1249G/T, have been reported to be significantly associated with dyslexia in this population. Further studies, conducted on different ethnic groups (English and Canadian), have not confirmed a role for DYX1C1 variants in increasing the risk for dyslexia. We investigated the role of these variants in dyslexic children and adolescents from Southern Italy. No significant evidence for association between dyslexia and these DYX1C1 putative functional variants has been shown. We argue that the different DYX1C1 allele frequencies shown among Italian and Finnish subjects with dyslexia could be attributable to the different linkage disequilibrium structure of these populations.

The muscarinic-regulated potassium current (M-current), formed by the heteromeric assembly of subunits encoded by the KCNQ2 and KCNQ3 genes, is a primary regulator of neuronal excitability; this regulation is accomplished by impeding repetitive firing and causing spike-frequency adaptation. Mutations in KCNQ2 or KCNQ3 cause benign familial neonatal convulsions (BFNC), a rare autosomal-dominant generalized epilepsy of newborns, by reducing the maximal current carried by the M-channels without affecting ion selectivity or gating properties. Here we show that KCNQ2/KCNQ3 channels carrying a novel BFNC-causing mutation leading to an arginine to tryptophan substitution in the voltage-sensing S4 domain of KCNQ2 subunits (R214W) displayed slower opening and faster closing kinetics and a decreased voltage sensitivity with no concomitant changes in maximal current or plasma membrane expression. These results suggest that mutation-induced gating alterations of the M-current may cause epilepsy in neonates.