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This is a retrospective multicenter nationwide Italian study collecting neonatal anthropometric data of Caucasian subjects with Prader-Willi syndrome (PWS) born from 1988 to 2018. The aim of the study is to provide percentile charts for weight and length of singletons with PWS born between 36 and 42 gestational weeks. We collected the birth weight and birth length of 252 male and 244 female singleton live born infants with both parents of Italian origin and PWS genetically confirmed. Percentile smoothed curves of birth weight and length for gestational age were built through Cole's lambda, mu, sigma method. The data were compared to normal Italian standards. Newborns with PWS showed a lower mean birth weight, by 1/2 kg, and a shorter mean birth length, by 1 cm, than healthy neonates. Females with a 15q11-13 deletion were shorter than those with maternal uniparental maternal disomy of chromosome 15 (p < .0001). The present growth curves may be useful as further traits in supporting a suspicion of PWS in a newborn. Because impaired prenatal growth increases risk of health problems later in life, having neonatal anthropometric standards could be helpful to evaluate possible correlations between the presence or absence of small gestational age and some clinical and metabolic aspects of PWS., (© 2019 Wiley Periodicals, Inc.)

Background . Cervical lymphadenopathy in children is common and its etiologies diverse. No systematic review of the differential diagnosis of pediatric cervical lymphadenopathy has been conducted. Objective . To determine the prevalence rate of specific etiologies of pediatric cervical lymphadenopathy. Data Sources . EMBASE, PubMed, and SCOPUS were searched electronically. Bibliographies of select studies were reviewed as well. Study Selection . (1) Any clinical trial, observational study, or cross-sectional case series with 10 or more subjects that included delineation of etiologies and/or associated conditions with lymphadenopathy; (2) subjects aged 0 to 21 years with enlarged lymphoid tissue on body; (3) lymphadenopathy was confirmed by clinical evaluation; and (4) no specific diagnoses were excluded. Data Extraction . Year and location of publication, definition of lymphadenopathy, percentage of lymphadenopathy that was cervical, total number of subjects, gender distribution of subjects, age range of patients, and specific etiologies. Results . Of the 1790 studies, 7 studies that were combined resulted in 2687 subjects that were selected. Nonspecific benign etiology was the most common diagnosis occurring at a rate of 67.8%. Epstein-Barr virus was the next most prevalent (8.86%), followed by malignancy (4.69%) and granulomatous disease (4.06%). The most common malignancy etiology was non-Hodgkin's lymphoma (46.0%), and the most common granulomatous disease was tuberculosis (73.4%). Conclusions . This systematic review and meta-analysis provides a rate-based differential diagnosis of pediatric cervical lymphadenopathy. Although the most common causes of pediatric cervical lymphadenopathy are nonspecific, the etiologies are diverse. Rates and credible intervals are provided to enable a probability-based diagnostic approach to palpable cervical lymphadenopathy in this age group., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background Prader-Willi syndrome (PWS) is a genetic disorder due to loss of expression of paternally transcribed genes of the imprinted region of chromosome 15q11-13. PWS is characterized by peculiar signs and symptoms and many endocrine abnormalities have been described (growth hormone deficiency, hypogonadotropic hypogonadism). The abnormalities of thyroid function are discussed in literature and published data are discordant. The aim of our study was to report the thyroid function in patients with PWS to identify the prevalence of thyroid dysfunction. Methods Thyroid function tests were carried out in 339 patients with PWS, aged from 0.2 to 50 years. A database was created to collect personal data, anthropometric data, thyroid function data and possible replacement therapy with L-thyroxine. Subjects were classified according to thyroid function as: euthyroidism (EuT), congenital hypothyroidism (C-HT), hypothyroidism (HT - high thyroid-stimulating hormone [TSH] and low free thyroxine [fT4]), central hypothyroidism (CE-H - low/normal TSH and low fT4), subclinical hypothyroidism (SH - high TSH and normal fT4), and hyperthyroidism (HyperT - low TSH and high fT4). Results Two hundred and forty-three out of 339 PWS patients were younger than 18 years (71.7%). The prevalence of thyroid dysfunction was 13.6%. Specifically, C-HT was found in four children (1.18%), HT in six patients (1.77%), CE-H in 23 patients (6.78%), SH in 13 patients (3.83%), and HyperT in none. All other subjects were in EuT (86.4%). Conclusions Hypothyroidism is a frequent feature in subjects with PWS. Thyroid function should be regularly investigated in all PWS patients both at the diagnosis and annually during follow-up.

Context: An etiologic diagnosis of diabetes can affect the therapeutic strategy and prognosis of chronic complications., Objective: The aim of the present study was to establish the relative percentage of different diabetes subtypes in patients attending Italian pediatric diabetes centers and the influence of an etiologic diagnosis on therapy., Design, Setting, and Patients: This was a retrospective study. The clinical records of 3781 consecutive patients (age, 0 to 18 years) referred to 15 pediatric diabetes clinics with a diagnosis of diabetes or impaired fasting glucose from January 1, 2007 to December 31, 2012 were examined. The clinical characteristics of the patients at their first referral to the centers, type 1 diabetes-related autoantibodies, molecular genetics records, and C-peptide measurements, if requested for the etiologic diagnosis, were acquired., Main Outcome Measures: The primary outcome was to assess the percentage of each diabetes subtype in our sample., Results: Type 1 diabetes represented the main cause (92.4%) of diabetes in this group of patients, followed by monogenic diabetes, which accounted for 6.3% of cases [maturity onset diabetes of the young (MODY), 5.5%; neonatal diabetes mellitus, 0.6%, genetic syndromes, 0.2%]. A genetic diagnosis prompted the transfer from insulin to sulphonylureas in 12 patients bearing mutations in the HNF1A or KCNJ11 genes. Type 2 diabetes was diagnosed in 1% of the patients., Conclusions: Monogenic diabetes is highly prevalent in patients referred to Italian pediatric diabetes centers. A genetic diagnosis guided the therapeutic decisions, allowed the formulation of a prognosis regarding chronic diabetic complications for a relevant number of patients (i.e.,GCK/MODY), and helped to provide genetic counseling., (Copyright © 2017 Endocrine Society)

Context: Childhood type 1 diabetes mellitus (T1DM) is associated with decreased bone mass. Sclerostin and dickkopf-1 (DKK-1) are Wnt inhibitors that regulate bone formation., Objective: To evaluate sclerostin and DKK-1 levels in T1DM children and to analyze the influence of glycemic control on bone health., Design and Setting: Cross-sectional study conducted at a clinical research center., Participants: One hundred and six T1DM subjects (12.2 ± 4 years), 66 on multiple daily injections (MDIs) and 40 on continuous subcutaneous infusion of insulin (CSII), and 80 controls., Results: The average bone transmission time (BTT) and amplitude-dependent speed of sound (AD-SoS) z scores were lower in patients with diabetes than in controls. Significantly increased DKK-1 (3593 ± 1172 vs 2652 ± 689 pg/mL; P < 0.006) and sclerostin (29.45 ± 12.32 vs 22.53 ± 8.29; P < 0.001) levels were found in patients with diabetes with respect to controls, particularly in patients on MDI compared with ones on CSII. Glycemic control was improved in CSII patients compared with MDI ones (P < 0.001) and was also associated with significantly higher BMI-SDS (P < 0.002) and BTT z scores (P < 0.02). With adjustment for age, multiple linear regression analysis of DKK-1 and sclerostin as dependent variables showed that levels of glycated hemoglobin, glucose, 25(OH) vitamin D, osteocalcin, and parathyroid hormone; years of diabetes; and BMI-SDS and AD-SoS z score were the most important predictors (P < 0.0001)., Conclusions: Our study highlighted (1) the high serum levels of DKK-1 and sclerostin in T1DM children and their relationship with altered glycemic control and (2) the effect of CSII on improvement of glycemic control and bone health in T1DM children., (Copyright © 2017 Endocrine Society)

Background: Childhood acute lymphoblastic leukemia (ALL) survivors have increased risk of obesity, metabolic alterations and cardiovascular disease (CVD). Vascular endothelial function has been studied in adult cancers. Limited data exist regarding CVD risk factors among childhood ALL survivors. We aimed to assess endothelial function, metabolic and cardiovascular risk factors in young survivors of childhood ALL., Methods: Auxological parameters, blood pressure, glucose, lipid profile, hemostatic markers (total adiponectin and high-molecular-weight subfraction, endothelin-1, von Willebrand factor antigen, thrombin-antithrombin complex, D-dimers, fibrinogen), high sensitive C-reactive protein and ultrasound parameters of endothelial function (flow-mediated dilation-FMD, common carotid intima-media thickness-C-IMT, and antero-posterior diameter of infra-renal abdominal aorta-APAO) were assessed in 52 ALL survivors and 34 sex and age-matched controls., Results: ALL patients and controls were not statistically different as regards body mass index and waist circumference. Blood pressure, glucose, total and LDL-cholesterol, triglycerides, high sensitive C-reactive protein were statistically higher in ALL than in controls, while HDL-cholesterol was lower in ALL than in controls. Patients showed statistically lower high-molecular-weight adiponectin and thrombin-antithrombin complex (p=0.003 and p<0.001, respectively) and higher vonWillebrand factor antigen (p=0.002) than controls. FMD was lower in patients than in controls (p<0.001). Biomarkers of endothelial function, systolic blood pressure and waist circumference were correlated to FMD., Conclusions: ALL survivors showed derangement of endothelial function, which likely occurs during chemotherapy and lasts till follow up. They showed metabolic alterations even though obesity was not documented. Endothelial vascular parameters should be evaluated earlier during follow-up to detect preclinical onset of CVD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Childhood acute lymphoblastic leukaemia (ALL) survivors have an increased risk of metabolic and cardiovascular disease. We aimed to assess the presence of non-alcoholic fatty liver disease (NAFLD) in childhood ALL and if it is associated with early cardiovascular dysfunction., Methods: In total, 53 childhood ALL survivors and 34 controls underwent auxological evaluation, biochemical assay, liver, heart and vascular ultrasound study., Results: NAFLD was more frequent in ALL patients than in controls (39.6% vs 11.7%, P < 0.01). Patients with NAFLD were more obese and insulin resistant than patients without NAFLD. Flow-mediated dilatation and interventricular septum were lower in the ALL group than those in the control group (P < 0.001 for both). The patients with NAFLD showed lower left ventricular ejection fraction than those without NAFLD (P = 0.011). In ALL survivors, BMI-SDS and subcutaneous fat were the strongest predictors of NAFLD, whereas preperitoneal adipose tissue and C-reactive protein were the strongest predictors of left ventricular ejection fraction., Conclusions: Childhood ALL survivors had higher prevalence of NAFLD than healthy controls, which is associated with early left ventricular impairment. In the case of fatty liver, a comprehensive heart evaluation is mandatory. We strongly recommend to prevent visceral adiposity in ALL survivors, to search for metabolic syndrome or its components and to reinforce the need of intervention on diet and lifestyle during the follow-up of these patients., (© 2017 European Society of Endocrinology.)

Background/aims: Gonadotropin-releasing hormone analogues (GnRHa) represent the gold standard treatment for central precocious puberty (CPP). We aimed to assess the effects of GnRHa treatment on metabolic outcomes, bone status, and polycystic ovary syndrome (PCOS) prevalence in young girls with idiopathic CPP (ICPP)., Methods: We enrolled 94 ICPP girls who were at least 2 years after menarche and had already attained adult height at the time of the study: 56 previously treated with depot triptorelin (3.4 ± 0.6 years) and 38 untreated. Auxological parameters, lipid profile, homeostatic model assessment of insulin resistance (HOMA-IR), bone state, and prevalence of PCOS were assessed., Results: The 2 groups were similar for body mass index (BMI) and waist circumference. HOMA-IR, dehydroepi-androsterone sulfate, and Δ4-androstenedione were higher in the treated than in the untreated subjects (p < 0.001). Significant differences were found for amplitude-dependent speed of sound (p < 0.03) and bone transmission time z-scores (p < 0.01). The prevalence of PCOS was higher in the treated than in the untreated subjects (p < 0.04)., Conclusion: GnRHa therapy is associated with hyperandrogenism and an increase in insulin resistance and PCOS prevalence, but not with increased BMI or lipid profile alterations. Long-term evaluations at the time of expected peak bone mass achievement are needed to understand the persistent or transient nature of subtle bone abnormalities., (© 2017 S. Karger AG, Basel.)

OTX2 mutations are reported in patients with eye maldevelopment and in some cases with brain or pituitary abnormalities. We describe a child carrying a novel OTX2 heterozygous mutation. She presented microphthalmia, absence of retinal vascularization, vitreal spots and optic nerve hypoplasia in the right eye and mild macular dystrophy in the left eye. Midline brain structures and cerebral parenchyma were normal, except for the ectopic posterior pituitary gland. OTX2 sequencing showed a heterozygous c.402del mutation. Most of OTX2 mutations are nonsense or frameshift introducing a premature termination codon and resulting in a truncated protein. More rarely missense mutations occur. Our novel OTX2 mutation (c.402del) is a frameshift mutation (p.S135Lfs*43), never reported before, causing a premature codon stop 43 amino-acids downstream, which is predicted to generate a premature truncation. The mutation was associated with microphthalmia and ectopic posterior pituitary.

Background: Small-for-gestational-age (SGA) children have increased cardiovascular risk, but the mediating factors are poorly understood. We hypothesized that birth size could affect the cardiovascular system since childhood in the absence of other risk factors. We investigated endothelial and myocardial function in SGA children with regular catch-up growth., Methods and results: Biochemical markers, blood pressure, flow-mediated vasodilation (FMD), common carotid intima-media thickness (cIMT), anteroposterior diameter of the infrarenal abdominal aorta (APAO) and echocardiographic parameters of left and right ventricular (LV and RV) function were studied in 27 SGA and 25 appropriate-for-gestational-age (AGA) subjects. SGA subjects had a higher homeostasis model assessment index than controls (2.61±1.27 vs. 1.56±0.40, P=0.01), higher cIMT (0.51±0.04 mm vs. 0.45±0.07 mm, P=0.007) and APAO (1.31±1.35 cm vs. 1.30±0.16 cm, P=0.005), and lower FMD (10.11±4.17% vs. 12.34±4.28, P=0.04) than controls. On echocardiography SGA had higher Tei index both at LV and RV than controls (P=0.001). Reduced RV systolic function was also observed in SGA subjects., Conclusions: SGA subjects had vascular morphological and function abnormalities compared with AGA, which increase their cardiovascular risk profile. Furthermore, a subtle cardiac alteration in both RV and LV functions was seen in SGA patients compared with AGA.

The aim of the replacement therapy with levothyroxine in congenital hypothyroidism (CH) is to correct hypothyroidism and ensure normal growth and neuropsychological development. Few data are available about the appropriate dose during childhood and early adolescence; therefore, we performed a multicenter observational study in a large population of patients with CH to assess the required levothyroxine dose to obtain euthyroidism. We recruited 216 patients with permanent CH classified into three groups (agenesia, ectopia, and in situ gland) on the basis of the thyroid imaging. The levothyroxine dose was recorded at 6 and 12 months and then yearly until 12 years of age. The daily levothyroxine requirement progressively decreased during the follow-up, irrespective of etiology. It was significantly lower in patients with in situ gland than in patients with athyreosis during the entire study period and with ectopic gland from the age of 1 year. The levothyroxine requirement at 6 months of age was correlated with the requirement at each later time-point. The daily dose was modified less frequently in patients with in situ thyroid (36 %) than in patients with ectopic gland (41.4 %) or with athyreosis (43.6 %). Patients with in situ gland required a lower dose than the other two subgroups. The dose at 6 months seems predictive of the requirement until 12 years of age. Euthyroidism may be achieved in pre-school and in-school patients by 3-4 and 2-3 µg/kg/day (70-90 and 60-80 µg/m(2)/day) of levothyroxine, respectively.

Background. Acute bronchiolitis infection during infancy is associated with an increased risk of asthma later in life. The objective of this study was to determine if inhaled steroids are effective in preventing the development of recurrent wheeze or asthma following acute bronchiolitis. Methods. Multiple databases and bibliographies of selected references were searched. Inclusion required (a) a randomized controlled trial of inhaled steroids and control group, (b) at least 2 weeks duration of therapy started during the acute phase of disease, and (c) identification of the rate of recurrent wheeze or asthma at least 6 months after therapy. Results. Of 1410 studies reviewed, 8 reports were included in this meta-analysis (748 patients). The overall odds ratio for developing recurrent wheeze or asthma with treatment versus without treatment was 1.02 (95% confidence interval = 0.58-1.81). Conclusions. A course of inhaled steroids after acute bronchiolitis is not effective in preventing recurrent wheeze or asthma.

A significant number of long-term complications have been described in childhood leukemia survivors. In particular, these patients may present features of metabolic syndrome (MetS), and therefore increased risk for cardiovascular diseases. The aim of this meta-analysis is to evaluate the prevalence and the risk of MetS in survivors of childhood leukemia. Two authors independently performed a systematic literature search in PubMed and EMBASE to March 2014, reviewed and selected articles, based on pre-determined selection criteria. Twelve articles, comprising 2,337 participants (1,462 cases and 875 controls), were included in the meta-analysis. Only three of them were case-control studies eligible for the meta-analysis. The childhood leukemia survivors showed an increased risk of MetS as compared to healthy controls (OR = 4.36; 95 % CI 1.19-16.22). The risk was significantly increased only in patients treated with chemotherapy and radiotherapy (OR = 7.79; 95 % CI 1.27-47.77), and not in patients treated with only chemotherapy (OR = 2.35; 95 % CI 0.40-13.78). Childhood leukemia survivors, in particular if treated also with radiotherapy, are prone to develop MetS more than healthy controls. Monitoring of MetS components in these patients is necessary to avoid cardiovascular consequences later in life.

Background: In the latest decades, epidemiological studies on allergic disorders in children, including atopic dermatitis, rhinitis and asthma, demonstrated a continuous increase in prevalence. However, such studies are usually performed by questionnaires and, sometimes, by skin prick test or in vitro IgE tests, while the portion of allergy sustained by the cell-mediated mechanism is neglected, because the essential test, i.e. the atopy patch test is not performed., Methods: This cross-sectional survey studied by a specific questionnaire, skin prick test and atopy patch test, an unselected population, represented by the entire scholastic population attending a Primary school and a Junior Secondary school in the rural town of San Marco in Lamis, 12.000 inhabitants (Puglia, Italy)., Results: Among the 456 subjects included, 78 (17.1 %) had a positive skin prick test and 57 (12.5 %) had a positive atopy patch test. In particular, 13.4 % of subjects were positive only to skin prick test and 8.8 % were positive only to atopy patch test. The allergen most frequently positive was the house dust mite, with 41 positive results to skin prick test and 55 to atopy patch test, while for pollen positive results concerned almost exclusively the skin prick test., Conclusions: This survey on an unselected population of children detected a prevalence of positive results to atopy patch test not so distant from the positive results to skin prick test, and in 8.8 % of subjects the atopy patch test was the only positive test. This would suggest to add the atopy patch test in future epidemiological studies on allergy, in order to avoid to overlook the not negligible portion of patients with T-cell-mediated allergy.

Type 2 and monogenic diabetes are emerging causes of diabetes in youths. Among 1244 Italian patients <18 years of age, 91.9% had type 1, 0.2% type 2, and 4.9% monogenic diabetes. Monogenic diabetes ranks second as a cause of diabetes in Italian youth, while type 2 diabetes appears to be rare., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We provide a detailed clinical and molecular characterization of an 11-year-old female patient presenting with neurodevelopmental delay (NDD), intellectual disability (ID), seizures, stereotypies and dysmorphic features. Chromosomal microarrays analysis (CMA) detected a small, rare de novo deletion on chromosome 12q24.31 encompassing 31 protein-coding RefSeq genes and a microRNA. Phenotypic comparison with molecularly well-defined cases previously reported in the literature harboring an overlapping 12q24.31 microdeletion indicate that these patients shared common clinical features including neurodevelopmental delay, intellectual disability and behavioral problems. Also, seizures and dysmorphic features are frequent and a consistent pattern was recognized. Since there are remarkable resemblance between the patient described here and at least another one previously reported, our report is provides supportive evidence for the existence of an emerging syndrome caused by a microdeletion in 12q24.31. We propose a minimal region shared among patients contributing to the etiology of the common clinical features observed suggesting as candidate, for the first time, the gene SETD1B which is a component of a histone methyltransferase complex. In addition, we speculate on the possible contributive role of the MIR4304 to some clinical features observed in our patient. Evaluation of more patients with well-characterized deletions within 12q24.31, as well as careful clinical assessment of them, is needed to corroborate our hypothesis, to perform a more detailed genotype-phenotype correlation and, finally, to fully delineate this emerging microdeletion syndrome., (© 2014 Wiley Periodicals, Inc.)

Background: This study evaluated the diagnostic performance of the atopy patch test (APT) compared with skin prick testing (SPT) and in vitro IgE measurement in a large group of patients with atopic dermatitis (AD) with or without respiratory symptoms (RS)., Methods: The study included 521 patients (292 males, 229 females; age, 0.5-18 years; median age, 6 years) with AD and RS with different clinical presentations: current AD, 47 patients (Group A); current AD and RS, 72 patients (Group B), past AD and RS, 69 patients (Group C); and RS only, 280 patients (Group D). Fifty-three healthy individuals served as controls. All participants underwent the APT, SPT, and CAP/RAST with the most common inhalant allergens. The presence of a control group allowed calculation of specificity and positive and negative predictive values., Results: A significant difference was found for a positive APT versus both SPT and CAP/RAST (P < .0001) but not for SPT versus CAP/RAST. The differences for APT were significant in all group comparisons except group B vs C and group C vs D. In the control group, the APT was positive in 2% of cases (specificity of 96.2%), SPT was positive in 6% of cases (specificity of 88.4%), and CAP/RAST was positive in 4% of cases (specificity of 92.5%)., Conclusions: In young patients sensitized to inhalant allergens with AD in addition to RS, the APT has a superior diagnostic performance to SPT and in vitro IgE measurement.

Background: Wolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WFS, whose minimal criteria for diagnosis are diabetes mellitus and optic atrophy. The disease gene for WFS2 is CISD2. The clinical phenotype of WFS2 differs from WFS1 for the absence of diabetes insipidus and psychiatric disorders, and for the presence of bleeding upper intestinal ulcers and defective platelet aggregation. After the first report of consanguineous Jordanian patients, no further cases of WFS2 have been reported worldwide. We describe the first Caucasian patient affected by WFS2., Case Presentation: The proband was a 17 year-old girl. She presented diabetes mellitus, optic neuropathy, intestinal ulcers, sensorineural hearing loss, and defective platelet aggregation to ADP. Genetic testing showed a novel homozygous intragenic deletion of CISD2 in the proband. Her brother and parents carried the heterozygous mutation and were apparently healthy, although they showed subclinical defective platelet aggregation. Long runs of homozygosity analysis from SNP-array data did not show any degree of parental relationship, but the microsatellite analysis confirmed the hypothesis of a common ancestor., Conclusion: Our patient does not show optic atrophy, one of the main diagnostic criteria for WFS, but optic neuropathy. Since the "asymptomatic" optic atrophy described in Jordanian patients is not completely supported, we could suppose that the ocular pathology in Jordanian patients was probably optic neuropathy and not optic atrophy. Therefore, as optic atrophy is required as main diagnostic criteria of WFS, it might be that the so-called WFS2 could not be a subtype of WFS. In addition, we found an impaired aggregation to ADP and not to collagen as previously reported, thus it is possible that different experimental conditions or inter-patient variability can explain different results in platelet aggregation. Further clinical reports are necessary to better define the clinical spectrum of this syndrome and to re-evaluate its classification.

Objective: To evaluate clinical and biochemical features of 115 children (98 female, mean age 11.3 ± 3.5 years) with Graves disease to identify possible determinants of remission., Study Design: We defined as positive outcome the improvement of clinical features and restoration of euthyroidism or induction of hypothyroidism after antithyroid drug (ATD) therapy and as negative outcome hyperthyroidism persistent over 2 years of ATD therapy or relapsed after ATD withdrawal., Results: Thirty-eight children (33%) had remission after 2 years of ATD therapy. The absence of goiter at diagnosis was correlated with a better outcome. Median thyroid-stimulating hormone receptor antibody (TRAb) values at diagnosis were significantly lower in patients with a positive outcome (P = .031). We found a significant relationship between the time required for TRAb normalization and the patient outcome; TRAb normalization within 1 year from time of Graves disease diagnosis was significantly more common among patients with a positive outcome (P < .0001), and the mean time for TRAb normalization was significantly shorter in patients with a positive outcome (1.3 ± 0.8 years) compared with that observed in patients with a negative outcome (2.5 ± 2.7 years, P = .026)., Conclusions: Although no clinical variable investigated is constantly associated with a definite outcome, the absence of goiter at the diagnosis may be associated with a better outcome. The most relevant predictor of Graves disease outcome was serum level; TRAb at time of Graves disease diagnosis less than 2.5 times the upper reference limit, TRAb normalization during ATD, and TRAb normalization timing each may predict positive outcomes. These results may have a role in the empiric clinical management of pediatric patients with Graves disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background/aims: Prolactin (PRL) is produced by the anterior pituitary gland. It exerts its role on the breast gland but also plays a modulatory role in autoimmune mechanisms. Celiac disease (CD) is a gluten-sensitive autoimmune enteropathy sometimes associated with autoimmune endocrinopathies. No data on PRL levels in CD patients are available at diagnosis, and no conclusive data are reported., Methods: We aimed to evaluate PRL secretion in newly diagnosed CD pediatric patients and, in the case of hyperprolactinemia, any changes in its levels while the patients were on a gluten-free diet (GFD). We recruited 67 patients and 39 healthy controls., Results: PRL was statistically higher in the CD patients (13.5±9.2 ng/ml) than in the controls (8.5±5.0 ng/ml). In the CD group, PRL was inversely correlated with the age at diagnosis (r=-0.326; p=0.007). In patients with hyperprolactinemia at diagnosis, PRL decreased after 6 months of GFD., Conclusion: This paper confirms that PRL may be increased at diagnosis of CD and shows, for the first time, that it decreases after a short course of GFD. Changes in the levels of inflammatory cytokines in CD may account for changes in PRL levels. Younger patients seem more prone to develop hyperprolactinemia than older ones., (© 2014 S. Karger AG, Basel.)

CBP and p300 are histone acetyltransferases (HATs) that associate with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-Å crystal structure of the catalytic core of human p300 containing its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation.

Childhood obesity and its related comorbidities are increasingly recognised in children, predisposing them to early cardiovascular disease and metabolic syndrome. The objective of the study was to investigate markers of metabolism, inflammation and haemostasis in a group of Italian obese children and adolescents. Fifty-nine obese and 40 non-obese subjects were recruited. Fasting glucose and insulin, total cholesterol, HDL and LDL cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor alpha (TNF-α), and adiponectin were measured. Hypercoagulability was assessed by measuring the circulating levels of thrombin-antithrombin complex (TAT), D: -dimer, fibrinogen, plasminogen activator inhibitor 1 (PAI-1) and von Willebrand Factor (vWF). A significant degree of insulin resistance was present in obese subjects compared with controls (p < 0.0001). The obese showed higher levels of total cholesterol, LDL cholesterol and triglycerides, and lower levels of HDL cholesterol than controls (p < 0.0001). Circulating levels of hsCRP and TNF-α were significantly higher in obese than in controls while serum adiponectin levels were significantly lower in obese than non-obese subjects (p < 0.001; p = 0.031; p < 0.0001, respectively). vWF, TAT, D-dimer, fibrinogen and PAI-1 levels were significant higher in obese subjects compared with control group (p = 0.02; p < 0.0001; p = 0.0037; p < 0.0001; p = 0.017, respectively). In conclusion, our results suggest that childhood obesity per se is associated with a proinflammatory and prothrombotic state.

In a subset of poorly differentiated and highly aggressive carcinoma, a chromosomal translocation, t(15;19)(q13;p13), results in an in-frame fusion of the double bromodomain protein, BRD4, with a testis-specific protein of unknown function, NUT (nuclear protein in testis). In this study, we show that, after binding to acetylated chromatin through BRD4 bromodomains, the NUT moiety of the fusion protein strongly interacts with and recruits p300, stimulates its catalytic activity, initiating cycles of BRD4-NUT/p300 recruitment and creating transcriptionally inactive hyperacetylated chromatin domains. Using a patient-derived cell line, we show that p300 sequestration into the BRD4-NUT foci is the principal oncogenic mechanism leading to p53 inactivation. Knockdown of BRD4-NUT released p300 and restored p53-dependent regulatory mechanisms leading to cell differentiation and apoptosis. This study demonstrates how the off-context activity of a testis-specific factor could markedly alter vital cellular functions and significantly contribute to malignant cell transformation.

Background: The association of obesity with sleep-associated respiratory disturbances, which has traditionally been described as a problem in adults, actually originates in childhood. We sought an association between sleep-disordered breathing (SDB) and overweight and/or obesity in a large cohort of school- and preschool-aged children in Southern Italy., Methods: One thousand two hundred seven children (612 girls and 595 boys; mean age 7.3 years) were screened by self-administered questionnaires. According to answers, subjects were divided into three groups: nonsnorers (NS), occasional snorers (OS), and habitual snorers (HS). All HS, who also failed an oximetry study at home, underwent polysomnographic monitoring for the definition of SDB. BMI was calculated according to Italian growth charts., Results: A total of 809 subjects (67.0%) were eligible for the study. Of them, 44 subjects (5.4%) were classified as HS, 138 (17.0%) as OS, and 627 (77.5%) as NS. Fourteen subjects (1.7%) were given a diagnosis of obstructive sleep apnea syndrome (OSAS). Sixty-four subjects (7.9%) were defined as obese, 121 (14.9%) as overweight, and 624 (77.2%) as normal weight. The frequency of HS was significantly higher in obese subjects than in overweight and normal-weight subjects (12.5% vs 5.8% vs 4.6%, respectively; P = .02), whereas the frequency of OSAS was 1.6% in normal-weight, 1.6% in overweight, and 3.1% in obese subjects (P = not significant)., Conclusions: Our findings in a large sample of Italian children suggest that obesity is associated with snoring.

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.

A girl with celiac disease and KCNJ11 mutation was transferred to glibenclamide when 19.8 years old. When her compliance to the gluten free diet worsened, her metabolic control deteriorated. Since glibenclamide is absorbed in the intestine, its absorption seems to be impaired by chronic malabsorption, increasing the risk of hyperglycaemia.

Craniopharyngioma is a rare, benign, suprasellar brain tumor associated with a significant number of endocrine and metabolic impairments. Growth hormone deficiency, caused by the tumor itself or by its subsequent surgical treatment, is the most common hormone deficiency in these patients and replacement is frequently necessary. Hypothalamic obesity observed after surgery treatment, whether combined with radiotherapy or not, presents with increased abdominal fat and altered lipid profiles and is likely caused by both disruption of the mechanisms controlling satiety, hunger and energy balance and impairment of sensitivity to leptin, insulin and ghrelin axis. It is well known that hyperlipemia is associated with acute pancreatitis, both as a precipitant and as an epiphenomenon. Moreover, the increased incidence of acute pancreatitis during growth hormone therapy is possibly due to increased enzyme production (e.g., amylase, lipase and elastase). We report the case of a 13-year-old girl affected by craniopharyngioma on growth hormone replacement treatment who developed acute pancreatitis. We suggest including routine evaluation of lipid profile during follow-up of all children on growth hormone treatment, especially those affected by hypopituitarism secondary to craniopharyngioma, given pancreatic adverse effects of growth hormone replacement therapy and associated metabolic impairment due to hypothalamic obesity., (2008 S. Karger AG, Basel)

Alditol oxidase (AldO) from Streptomyces coelicolor A3(2) is a soluble monomeric flavin-dependent oxidase that performs selective oxidation of the terminal primary hydroxyl group of several alditols. Here, we report the crystal structure of the recombinant enzyme in its native state and in complex with both six-carbon (mannitol and sorbitol) and five-carbon substrates (xylitol). AldO shares the same folding topology of the members of the vanillyl-alcohol oxidase family of flavoenzymes and exhibits a covalently linked FAD which is located at the bottom of a funnel-shaped pocket that forms the active site. The high resolution of the three-dimensional structures highlights a well-defined hydrogen-bonding network that tightly constrains the substrate in the productive conformation for catalysis. Substrate binding occurs through a lock-and-key mechanism and does not induce conformational changes with respect to the ligand-free protein. A network of charged residues is proposed to favor catalysis through stabilization of the deprotonated form of the substrate. A His side chain acts as back door that "pushes" the substrate-reactive carbon atom toward the N5-C4a locus of the flavin. Analysis of the three-dimensional structure reveals possible pathways for diffusion of molecular oxygen and a small cavity on the re side of the flavin that may host oxygen during FAD reoxidation. These features combined with the tight shape of the catalytic site provide insights into the mechanism of AldO-mediated regioselective oxidation reactions and its substrate specificity.

Aims: To evaluate therapy and dose adjustments in patients with congenital hypothyroidism (CH), longitudinally followed up until 16 years old, according to aetiology, Beclard's nuclei presence, and thyroxine (T4) level at diagnosis., Methods: L-T4/kg/day and dose change ratio (CR) were assessed in 74 CH patients., Results: The dose was statistically larger in athyreosis than in dyshormonogenesis (1-10 and beyond 14 years) and in ectopy (2, 15, 16 years). The ectopic children required statistically larger L-T4/kg than the dyshormonogenetic ones (3-7 years). The L-T4/kg/day was increased, not statistically, in patients or with T4 <30 nmol/l or without Beclard's nuclei at diagnosis. The CR progressively dropped after the 6th month at each attendance, without any difference in terms of aetiology, T4 level at diagnosis, or Beclard's nuclei. The total CR was greater (significantly) in patients without Beclard's nuclei, and (not significantly) in those with T4 <30 nmol/l at diagnosis or with agenesia., Conclusion: The L-T4 dose in CH is highly affected by the aetiology. The CR is higher in patients with delayed bone maturation at diagnosis. We suggest that these latter patients need blood tests more frequently to obtain a proper titration of the therapy., (Copyright 2007 S. Karger AG, Basel.)

Objective: To evaluate pubertal development and final height (FH) in early treated patients with congenital hypothyroidism (CH) and to identify the main factors predicting FH., Design: Retrospective., Patients: Eighty-five patients with early diagnosed and treated CH., Measurements: Evaluation of length/height at diagnosis (mean age 26.6 days), at onset of puberty, and at the end of linear growth., Results: Mean FH was 161.7 cm in females and 173.8 cm in males, within +/- 0.9 cm of the 50th percentile of Italian growth charts, 5 cm higher than the mean target height (TH). Linear growth did not differ according to thyroid imaging findings. In males, height at onset of puberty was 0.16 standard deviation score (SDS), not statistically different from FH (-0.09 SDS). In females, height both at onset of puberty (0.39 SDS) and at menarche (0.57 SDS) was significantly higher (P < 0.001) than FH (-0.10 SDS). Puberty started at a mean chronological age of 10.2 and 11.6 years in females and males, respectively, with a corresponding bone age. FH correlated with TH and height at diagnosis, at onset of puberty, and at menarche. Multiple regression analysis showed that height at onset of puberty and TH are the most important factors explaining FH variability, although height at onset of puberty is slightly more important., Conclusions: Our results, obtained in the largest reported available group of congenital hypothyroid patients, show that final height is higher than target height in both sexes and that height at onset of puberty is the main factor affecting final height.

Aim: Congenital or acquired hearing loss in infanthood has been associated with lifelong deficits in speech and language acquisition, poor school performances and emotional and social maladjustments. The identification of hearing loss through neonatal and infant life can prevent or reduce many of these adverse consequences, permitting early intervention., Methods: We performed the screening of hearing loss with a technical device, echo-screen Madsen, based on transient evoked otoacoustic emissions (TEOAE). The screening was carried out in 50 newborns during the 1st day of life and in 80 newborns during the 2nd day of life., Results: The 2nd day of life showed a significant better stability of the test and a better symmetry (P<0.001), and less incidence of artefacts (P<0.001)., Conclusions: The results obtained confirm that the 2nd day of life is the most appropriate time for the neonatal hearing assessment with TEOAE.

Purpose: We verify the sodium fraction excretion rate (FE Na) and potassium fraction excretion (FE K) rates in monosymptomatic nocturnal enuresis. We also correlate FE Na and FE K to urinary osmolality, nocturnal polyuria and vasopressin in the same population., Materials and Methods: A total of 438 children 6 to 15 years old (mean age 9.7) presenting with monosymptomatic nocturnal enuresis were recruited from different centers. Inclusion criteria were 3 or greater wet nights a week, no daytime incontinence and no treatment in the previous 2 months. Exclusion criteria were cardiopathy, endocrinopathy, psychiatric problems and urinary tract abnormalities. Micturition chart, diurnal (8 am to 8 pm) and nocturnal (8 pm to 8 am) urine collection, including separate diuresis volumes, (Na, K and Ca) electrolytes and osmolality were evaluated, as well as serum electrolytes, creatinine and nocturnal (4 am) vasopressin. Diurnal and nocturnal FE K and FE Na were calculated. ANOVA test, chi-square test, Student's t test and Pearson correlation test were used for statistical analysis., Results: : Nocturnal polyuria (diurnal to nocturnal diuresis ratio less than 1) was found in 273 children (62.3%, group 1 and nocturnal urine volumes were normal in 165 with enuresis (37.7%, group 2). Nocturnal FE Na was abnormal in 179 children (40.8%), including 118 in group 1 (43.2%) and 61 in group 2 (36.9%) (chi-square not significant). FE Na was also increased in nocturnal versus daytime diuresis (Student's t test p <0.001). In group 1 nocturnal FE Na correlated with nocturnal diuresis (Pearson correlation p = 0.003, r = +0.175), while daytime FE Na and nocturnal FE Na correlated with diurnal diuresis (Pearson correlation p = 0.001, r = +0.225 and Pearson correlation p = 0.001, r = +0.209, respectively). In group 2 nocturnal FE Na did not correlate with diuresis (Pearson correlation p = 0.103, r = +0.128) but correlated with vasopressin values (Pearson correlation p = 0.042, r = -0.205). Urine osmolality was reduced in 140 children (31.9%) and correlated with nocturnal diuresis (Pearson correlation p = 0.003, r = -0.321). Vasopressin was decreased in 332 children (75.8%, 62.6% in group 1 and 13.2% in group 2). No significant difference was found between sexes and age of enuretic subgroups., Conclusions: Nocturnal FE Na correlates with nocturnal diuresis, whereas daytime FE Na does not. FE K in daytime and nighttime diuresis does not statistically differ in nocturnal polyuric and nonpolyuric enuretic groups. Osmolality correlates with nocturnal diuresis, and vasopressin at 4 am was lower in the nocturnal polyuric group. The hypothesis of a subset of enuretic patients presenting with nocturnal polyuria associated with high nocturnal natriuria and low vasopressin values has been confirmed.

nalyot (nal) is a novel olfactory memory mutant of Drosophila, encoding Adf1, a myb-related transcription factor. Following extended training sessions, Adf1 mutants show normal early memory but defective longterm memory. Adf1 shows widespread spatiotemporal expression, yet mutant alleles reveal no discernible disruptions in gross morphology of the nervous system. Studies at the larval neuromuscular junction, however, reveal a role for Adf1 in the modulation of synaptic growth-in contrast to the role established for dCREB2 in the control of synaptic function (Davis et al., 1996). These findings suggest that Adf1 and dCREB2 regulate distinct transcriptional cascades involved in terminal stages of synapse maturation. More generally, Adf1 provides a novel link between molecular mechanisms of developmental and behavioral plasticity.

The aim of this study was to evaluate the toxicity and efficacy of a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with metastatic melanoma. Consecutive patients with metastatic melanoma were enrolled in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon 3 MU subcutaneously three times a week and tamoxifen 20 mg orally were given throughout. Ninety-two patients were included in this study. Patient characteristics in the three groups were well balanced. The three regimens were delivered on an outpatient basis without major toxicity. The toxicities that did occur consisted primarily of flu-like symptoms in the IL-2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No grade IV toxicities were encountered and no treatment-related deaths occurred. The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The median duration of response was 6 months and the median survival was 11 months. According to this phase II randomized trial polychemoimmunotherapy with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has a response rate of 13%.