Publications by authors named "Anna Grandone"

64 Publications

Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty.

Ital J Pediatr 2021 Jan 7;47(1). Epub 2021 Jan 7.

Department of Child, Woman, General and Specialized Surgery, University of Campania "L. Vanvitelli", Naples, Italy.

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.
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http://dx.doi.org/10.1186/s13052-020-00951-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792053PMC
January 2021

Pediatric obesity-related non-alcoholic fatty liver disease: waist-to-height ratio best anthropometrical predictor.

Pediatr Res 2020 Oct 10. Epub 2020 Oct 10.

Department of the Woman, the Child, of General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in pediatric obesity. Our study aims to identify a predictive anthropometrical measure for NAFLD in obese children.

Methods: We retrospectively enrolled children and adolescents with obesity. Physical, biochemical, and ultrasound assessments were available. ROC curve tests were performed to identify the best predictor of NAFLD among waist-to-height ratio (WHR), BMI z-score, and triponderal mass index (TMI, an anthropometric index recently associated with increased adiposity in children). Subsequently, a cut-off value was identified.

Results: In total, 1900 children and adolescents (1011 with NAFLD) were included. WHR (AUC 0.62, 95% CI 0.59-0.64) was the best predictor of NAFLD compared to BMI z-score (AUC 0.58, 95% CI 0.55-0.60) and TMI (AUC 0.58, 95% CI 0.55-0.61). WHR ≥ 0.53 in boys and 0.63 in girls displayed the best sensitivity and specificity for NAFLD presence. In addition, children with high WHR showed a significantly higher risk of NAFLD (boys: OR 2.43, 95% CI 1.61-3.68, p < 0.0001; girls: OR 1.92, 95% CI 1.58-2.34, p < 0.0001) and elevated ALT (OR 5.71, 95% CI 2.09-15.56, p = 0.0007; girls: OR 2.16, 95% CI 1.70-2.74, p < 0.0001) independent of covariates.

Conclusions: WHR might represent a good anthropometric tool to candidate children and adolescents to NAFLD screening. WHR cut-off differs according to sex, being lower in boys than girls.

Impact: Waist-to-height ratio is a better predictor of non-alcoholic fatty liver disease risk compared to other anthropometric measures in obese children and adolescents. The predictive cut-off of waist-to-height ratio differs between boys and girls, being lower in boys than girls. The use of waist-to-height ratio measurement and its cut-off in clinical practice might help clinician in identifying obese children and adolescents at risk of non-alcoholic fatty liver disease.
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http://dx.doi.org/10.1038/s41390-020-01192-wDOI Listing
October 2020

Growth Trajectory and Adult Height in Children with Nonclassical Congenital Adrenal Hyperplasia.

Horm Res Paediatr 2020 18;93(3):173-181. Epub 2020 Aug 18.

Department of Biomedical Sciences and Human Oncology, Pediatric Section, University of Bari "A. Moro", Bari, Italy.

Background: Children with nonclassical congenital adrenal hyperplasia (NCCAH) often present increased growth velocity secondary to elevation of adrenal androgens that accelerates bone maturation and might compromise adult height (AH).

Objective: The aim of the study was to analyze prognostic factors affecting growth trajectory (GT) and AH in children with NCCAH.

Methods: The study was a retrospective, multicentric study. The study population consisted of 192 children with a confirmed molecular diagnosis of NCCAH, followed by pediatric endocrinology centers from diagnosis up to AH. Clinical records were collected and analyzed. AH (standard deviation score; SDS), pubertal growth (PG) (cm), GT from diagnosis to AH (SDS), and AH adjusted to target height (TH) (AH-TH SDS) were evaluated as outcome indicators using stepwise linear regression models.

Results: The stepwise linear regression analysis showed that AH and AH-TH were significantly related to chronological age (CA) (p = 0.008 and 0.016), bone age (BA)/CA ratio (p = 0.004 and 0.001), height (H) (p < 0.001 for both parameters) at NCCAH diagnosis, and TH (p = 0.013 and <0.001). PG was higher in males than in females (22.59 ± 5.74 vs. 20.72 ± 17.4 cm, p = 0.002), as physiologically observed, and was positively related to height (p = 0.027), negatively to BMI (p = 0.001) and BA/CA ratio (p = 0.001) at NCCAH diagnosis. Gender, genotype, biochemical data, and hydrocortisone treatment did not significantly impair height outcomes of these NCCAH children.

Conclusions: The results of this study suggest that AH and GT of NCCAH patients are mainly affected by the severity of phenotype (CA, BA/CA ratio, and H) at the time of diagnosis.
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http://dx.doi.org/10.1159/000509548DOI Listing
August 2020

Variants in the 5'UTR reduce SHOX expression and contribute to SHOX haploinsufficiency.

Eur J Hum Genet 2021 Jan 9;29(1):110-121. Epub 2020 Jul 9.

Laboratorio di Genetica Umana, Dipartimento di Scienze della Salute, Università del Piemonte Orientale, Novara, Italy.

SHOX haploinsufficiency causes 70-90% of Léri-Weill dyschondrosteosis (LWD) and 2-10% of idiopathic short stature (ISS). Deletions removing the entire gene or enhancers and point mutations in the coding region represent a well-established cause of haploinsufficiency. During diagnostic genetic testing on ISS/LWD patients, in addition to classic SHOX defects, five 5'UTR variants (c.-58G > T, c.-55C > T, c.-51G > A, c.-19G > A, and c.-9del), were detected whose pathogenetic role was unclear and were thus classified as VUS (Variants of Uncertain Significance). The purpose of the present study was to investigate the role of these noncoding variations in SHOX haploinsufficiency. The variants were tested for their ability to interfere with correct gene expression of a regulated reporter gene (luciferase assay). The negative effect on the mRNA splicing predicted in silico for c.-19G > A was assayed in vitro through a minigene splicing assay. The luciferase assay showed that c.-51G > A, c.-19G > A, and c.-9del significantly reduce luciferase activity by 60, 35, and 40% at the homozygous state. Quantification of the luciferase mRNA showed that c.-51G > A and c.-9del might interfere with the correct SHOX expression mainly at the post-transcriptional level. The exon trapping assay demonstrated that c.-19G > A determines the creation of a new branch site causing an aberrant mRNA splicing. In conclusion, this study allowed us to reclassify two of the 5'UTR variants identified during SHOX diagnostic screening as likely pathogenic, one remains as a VUS, and two as likely benign variants. This analysis for the first time expands the spectrum of the genetic causes of SHOX haploinsufficiency to noncoding variations in the 5'UTR.
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http://dx.doi.org/10.1038/s41431-020-0676-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852508PMC
January 2021

Genetic Evaluation of Patients With Delayed Puberty and Congenital Hypogonadotropic Hypogonadism: Is it Worthy of Consideration?

Front Endocrinol (Lausanne) 2020 19;11:253. Epub 2020 May 19.

Department of Woman, Child, General and Specialized Surgery, University of Campania L. Vanvitelli, Naples, Italy.

Delayed puberty is a common reason of pediatric endocrinological consultation. It is often a self-limited (or constitutional) condition with a strong familial basis. The type of inheritance is variable but most commonly autosomal dominant. Despite this strong genetic determinant, mutations in genes implicated in the regulation of hypothalamic-pituitary-gonadal axis have rarely been identified in cases of self-limited delayed puberty and often in relatives of patients with congenital hypogonadotropic hypogonadism (i.e., and genes). However, recently, next-generation sequencing analysis has led to the discovery of new genes (i.e., , and ) that are implicated in determining isolated self-limited delayed puberty in some families. Despite the heterogeneity of genetic defects resulting in delayed puberty, genetic testing may become a useful diagnostic tool for the correct classification and management of patients with delayed puberty. This article will discuss the benefits and the limitations of genetic testing execution in cases of delayed puberty.
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http://dx.doi.org/10.3389/fendo.2020.00253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248176PMC
May 2020

Pretreatment Endocrine Disorders Due to Optic Pathway Gliomas in Pediatric Neurofibromatosis Type 1: Multicenter Study.

J Clin Endocrinol Metab 2020 06;105(6)

Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Università degli studi della Campania "Luigi Vanvitelli", Naples, Italy.

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.
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http://dx.doi.org/10.1210/clinem/dgaa138DOI Listing
June 2020

Changing the diagnostic approach to diabetes insipidus: role of copeptin.

Ann Transl Med 2019 Dec;7(Suppl 8):S285

Department of Pediatrics, IRCCS Istituto Giannina Gaslini, University of Genova, Genova, Italy.

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http://dx.doi.org/10.21037/atm.2019.11.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976509PMC
December 2019

Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders.

Genes (Basel) 2019 07 31;10(8). Epub 2019 Jul 31.

Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Napoli, Italy.

Pigmentary manifestations can represent an early clinical sign in children affected by Neurofibromatosis type 1 (NF1), Legius syndrome, and other neurocutaneous disorders. The differential molecular diagnosis of these pathologies is a challenge that can now be met by combining next generation sequencing of target genes with concurrent second-level tests, such as multiplex ligation-dependent probe amplification and RNA analysis. We clinically and genetically investigated 281 patients, almost all pediatric cases, presenting with either NF1 ( = 150), only pigmentary features (café au lait macules with or without freckling; ( = 95), or clinical suspicion of other RASopathies or neurocutaneous disorders ( = 36). The causative variant was identified in 239 out of the 281 patients analyzed (85.1%), while 42 patients remained undiagnosed (14.9%). The and genes were mutated in 73.3% and 2.8% of cases, respectively. The remaining 8.9% carried mutations in different genes associated with other disorders. We achieved a molecular diagnosis in 69.5% of cases with only pigmentary manifestations, allowing a more appropriate clinical management of these patients. Our findings, together with the increasing availability and sharing of clinical and genetic data, will help to identify further novel genotype-phenotype associations that may have a positive impact on patient follow-up.
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http://dx.doi.org/10.3390/genes10080580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722641PMC
July 2019

Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics.

Brain 2019 04;142(4):867-884

Department of Clinical Genetics, Erasmus University Medical Center (Erasmus MC), CA Rotterdam, The Netherlands.

Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.
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http://dx.doi.org/10.1093/brain/awz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439326PMC
April 2019

Congenital solitary kidney size at birth could predict reduced eGFR levels later in life.

J Perinatol 2019 01 19;39(1):129-134. Epub 2018 Oct 19.

Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Via Luigi De Crecchio 2, 80138, Napoli, Italy.

Objectives: To evaluate the impact of congenital solitary functioning kidney (CSFK) length, measured early in life, on the eGFR levels during the follow-up.

Study Design: We retrospectively selected 162 CSFK patients undergoing, within 60 days of life, renal length (RL) measurement by ultrasound. We divided the population in: Group 1 = RL ≥ 2 standard deviation score (SDS). Group 2 = RL < 2 SDS and showing RL ≥ 2 SDS during the follow-up. Group 3 = RL < 2 SDS and showing RL < 2 SDS during the follow-up.

Primary Outcome: development of eGFR below the range of normality.

Results: The median follow-up period of the overall population was 6.2 years (range 2-21.5 years). The cumulative proportion of patients free of primary outcome at 15 years of age was 96.4% in group 1, 64.6% in group 2, and 45.6% in group 3 (p = 0.03). The RL > 2 SDS within 60 days of life was a significant protective factor (hazard ratio = 0.13; 95% C.I. 0.02-0.97) against development of primary outcome.

Conclusion: RL ≥ 2 SDS within 60 days of life could identify a population of CSFK with reduced risk of presenting reduced eGFR levels later in life.
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http://dx.doi.org/10.1038/s41372-018-0260-2DOI Listing
January 2019

MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study.

Horm Res Paediatr 2018 28;90(3):190-195. Epub 2018 Sep 28.

Department of Woman, Child, General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.

Background: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment.

Methods: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2-8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17β-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed.

Results: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001).

Conclusions: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.
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http://dx.doi.org/10.1159/000493134DOI Listing
February 2019

Basal levels of 17-hydroxyprogesterone can distinguish children with isolated precocious pubarche.

Pediatr Res 2018 10 6;84(4):533-536. Epub 2018 Jul 6.

Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Via Luigi De Crecchio 2, 80138, Napoli, Italy.

Background: Basal levels of androgens, in particular 17-hydroxyprogesterone (17OHP), are widely debated as predictors of non-classical congenital adrenal hyperplasia (NCCAH) among patients with precocious pubarche (PP). Many authors have recommended the use of adrenocorticotropic hormone (ACTH) stimulation test in children with PP. The aim of our study was to identify clinical and biochemical predictors of NCCAH in children with PP.

Methods: We conducted a prospective study of 92 patients with PP undergoing an ACTH stimulation test. We tested the association of basal clinical and biochemical parameters with NCCAH diagnosis. Patients were suspected to have NCCAH if their stimulated 17OHP plasma levels were >10 ng/mL. In these patients, the diagnosis was confirmed by genetic test.

Results: Seven (7.6%) patients resulted having NCCAH. The best basal biochemical predictor for NCCAH was 17OHP level >2 ng/mL. In fact, a basal 17OHP level >2 ng/mL had 100% (95% confidence interval (CI), 59.04-100) sensitivity and 93% (95% CI, 85.3-97.37) specificity. The area under the receiver-operating characteristic curve for 17OHP was 0.99 (95% CI, 0.98-1.007).

Conclusions: Basal 17OHP cut-off of 2 ng/mL was very effective in predicting NCCAH among our patients with PP. Assay-specific cut-off would probably be the best strategy to avoid unnecessary ACTH test.
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http://dx.doi.org/10.1038/s41390-018-0096-7DOI Listing
October 2018

A 23-month-old girl with chronic 'seborrhoeic' dermatitis, dehydration and failure to thrive.

Arch Dis Child Educ Pract Ed 2019 06 27;104(3):154-156. Epub 2018 Apr 27.

Department of Woman, Child and General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Campania, Italy.

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http://dx.doi.org/10.1136/archdischild-2018-314828DOI Listing
June 2019

Anthropometric and Biochemical Determinants of Estimated Glomerular Filtration Rate in a Large Cohort of Obese Children.

J Ren Nutr 2018 09 13;28(5):359-362. Epub 2018 Feb 13.

Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy.

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

Design: Retrospective, cross-sectional study.

Setting: Pediatric university department.

Subjects: We enrolled 2,957 obese children and adolescents consecutively attending our department between January 2000 and 2017. Inclusion criteria were body mass index (BMI) > 95th percentile and eGFR > 90 mL/min/1.73 m. Exclusion criteria were secondary forms of obesity, eGFR < 90 mL/min/1.73 m, proteinuria/hematuria at urine dipstick, or consumption of any medication.

Interventions: Weight, waist circumference, height, waist to height ratio (W/Hr), BMI-standard deviation score (SDS), pubertal stage, systolic blood pressure (SBP) and diastolic blood pressure (DBP), duration of obesity, insulin, eGFR, and homeostasis model assessment (HOMA-IR) were obtained. A general linear model was performed for a multiple variable analysis.

Main Outcome Measure: The population was divided in tertiles for BMI-SDS, W/Hr, SBP- and DBP-SDS, HOMA-IR, and duration of obesity. We compared eGFR levels among these tertiles.

Results: The eGFR levels significantly increased across both BMI-SDS and W/Hr tertiles. Conversely the eGFR levels significantly decreased across SBP-SDS, HOMA-IR, and duration of obesity tertiles. No significant differences in eGFR levels across DBP-SDS tertiles were detected. Pubertal patients presented significantly lower eGFR values compared with prepubertal patients. A general linear model for eGFR variance including as covariates W/Hr, HOMA-IR, duration of obesity, pubertal stage, BMI-SDS, and SBP-SDS (model R 39.7%; model P < .00001) was performed. It confirmed a direct association of eGFR values with BMI-SDS and an indirect association with HOMA-IR, duration of obesity, pubertal stage, and SBP-SDS.

Conclusions: We showed a positive correlation of eGFR with both BMI-SDS and a negative one with SBP-SDS, HOMA-IR, pubertal stage, and duration of obesity. The duration of obesity was the variable most significantly associated to eGFR levels.
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http://dx.doi.org/10.1053/j.jrn.2018.01.001DOI Listing
September 2018

The use of nonselective beta blockers is a risk factor for portal vein thrombosis in cirrhotic patients.

Saudi J Gastroenterol 2018 Jan-Feb;24(1):25-29

Department of Clinical and Experimental Medicine and Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background/aim: A reduction in portal vein inflow velocity seems to predispose to the emergence of portal vein thrombosis (PVT). Nonselective β-blockers (NSBBs), used to prevent variceal bleeding, may increase the development of PVT by reducing portal vein inflow velocity. In this retrospective case-control study, we evaluated the risk factors and clinical features of a first event of PVT in 130 cirrhotics, 19 (15%) with (PVT group) and 111 (85%) without PVT (non-PVT group).

Patients And Methods: Patient evaluation and NNBB treatment were carried out according to the AASLD guidelines.

Results: PVT was prevalently partial (84%) and asymptomatic (84%). Patients with PVT were treated with different regimens, and resolution of thrombosis was observed in about 50% of the cases. In both groups, HCV was the most frequent cause of cirrhosis and Child-Pugh score A was prevalent. Ascites and esophageal varices were more frequent in the PVT group (P = 0.05 and <0.000, respectively). Treatment with NSBBs was significantly more frequent in the PVT group than in the non-PVT group (P < 0.000). PVT was associated with higher prevalence of chronic renal disease (P = 0.002), higher PT impairment (P = 0.003) and lower AST and ALT (P = 0.000). At multivariate logistic regression analysis, history of esophageal varices (P = 0.007) and NSBB treatment (P = 0.0003) were independent risk factors significantly associated with PVT.

Conclusions: Esophageal varices and NSBB treatment were independent risk factors of PVT. Larger studies should evaluate the risk between variceal bleeding and portal vein thrombosis of using NSBBs, particularly in the prevention of first bleeding in nonadvanced liver cirrhosis.
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http://dx.doi.org/10.4103/sjg.SJG_100_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848320PMC
November 2018

Micturition Syncope in Childhood: How to Recognize and Manage It.

Pediatr Emerg Care 2019 May;35(5):e86-e89

Pediatric Emergency Department, Azienda Ospedaliera di Rilievo Nazionale Santobono-Pausilipon di Napoli, Napoli, Italy.

Frequently, general pediatricians could face a patient with syncope, which represents approximately 1% to 3% of emergency visits. Micturition syncope is a transient loss of consciousness with onset immediately before, during, or after micturition. Literature evidence indicates that healthy young men are a population with major risk for presenting micturition syncope, with a peak of incidence around 40 to 50 years of age. Usually, this syncope occurs in the morning, after wake-up, or, more generally, when the male patients assume the orthostatic position after a period of supine position in a warm bed. No information on micturition syncope clinical presentation and prevalence in childhood is available in the literature, and probably, this kind of syncope is unrecognized in childhood. We describe 4 unreported pediatric patients with a diagnosis of micturition syncope and well-defined clinical presentation. In all patients, the syncope has been presented in the same conditions: in the morning; after wake-up; in an orthostatic position; just before, after, or during urinary bladder voiding; and with spontaneous recovery in few minutes. Interestingly, 1 patient presented with the syncope during urinary bladder voiding by autocatheterization. In our patients, all investigations made as the first approach in the pediatric emergency department did not show any abnormal results, possibly underlying the syncope episodes. By describing our experience, we want to underline the clinical presentation of micturition syncope and give to the clinicians the elements to recognize and manage it easily in children.
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http://dx.doi.org/10.1097/PEC.0000000000001345DOI Listing
May 2019

Molecular Screening of MKRN3, DLK1, and KCNK9 Genes in Girls with Idiopathic Central Precocious Puberty.

Horm Res Paediatr 2017 3;88(3-4):194-200. Epub 2017 Jul 3.

Background: Mutations in the imprinted gene MKRN3 have been described as a common genetic cause of idiopathic central precocious puberty (CPP), in particular in familial cases. However, the exact prevalence of mutations is unknown. Single nucleotide polymorphisms in 2 other imprinted genes, DLK1 and KCNK9, have been associated with age at menarche. We investigated the prevalence of mutations in MKRN3, DLK1, and KCNK9 genes in a cohort of girls with idiopathic CPP.

Methods: MKRN3, DLK1, and KCNK9 coding regions were sequenced in 60 girls with idiopathic CPP (familial in 23 cases).

Results: Three mutations, including a new one, in MKRN3 were found in 2 familial cases (c.1229G>A; p.Cys410Ter and c.477_485del; p.Pro160Cysfs*14) (8.7%) and in 1 sporadic case (c.982C>T; p.Arg328Cys) (2.8%). We did not find rare variants in DLK1 and KCNK9 genes.

Conclusions: (1) The prevalence of MKRN3 mutations in our cohort was similar to that reported in the literature in sporadic cases but lower than previously described in familial ones. This could be due to different inheritance patterns of families studied; (2) we expanded the phenotype of MKRN3 defects describing 3 more patients with MKRN3 mutations; and (3) point mutations in DLK1 and KCNK9 at least do not seem to be a common cause of CPP in girls.
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http://dx.doi.org/10.1159/000477441DOI Listing
June 2018

Outcomes of a Cohort of Prenatally Diagnosed and Early Enrolled Patients with Congenital Solitary Functioning Kidney.

J Urol 2017 11 26;198(5):1153-1158. Epub 2017 May 26.

Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli," Naples, Italy.

Purpose: We evaluated the clinical course of patients prenatally diagnosed and enrolled early with congenital solitary functioning kidney, and identified the risk factors for renal injury.

Materials And Methods: We retrospectively evaluated 322 patients with congenital solitary functioning kidney according to the inclusion criteria of 1) prenatal diagnosis of solitary kidney; 2) first evaluation at 1 to 3 months of life with confirmation of congenital solitary functioning kidney, and evaluation of possible associated congenital anomalies of the kidney and urinary tract by abdominal ultrasound, renal scintigraphy and cystography; and 3) absence of any condition potentially affecting renal function in the neonatal period as well as absence of renal injury at enrollment (1 to 3 months of life) confirmed by a normal estimated glomerular filtration rate, lack of proteinuria and hypertension. Followup of 306 patients was evaluated.

Results: Median followup was 7.2 years (range 1 to 23) and 1 or more signs of renal injury were found in 12 of 306 patients (3.9%). Considering the entire population the cumulative proportion of patients free from renal injury at 17 years old was 93.7%, vs 81.3% and 95.9% for subjects with and those without congenital anomalies of the kidney and urinary tract of congenital solitary functioning kidney (p <0.001), respectively. Of congenital anomalies of the kidney and urinary tract, congenital solitary functioning kidney resulted in significant risk factors for renal injury (HR 8.75, 95% CI 2.77-27.65).

Conclusions: In an evaluation of a large cohort of patients enrolled early with congenital solitary functioning kidney with a prenatal diagnosis, excluding those with neonatal onset of renal damage, the prevalence of renal damage was 3.9%. Among congenital anomalies of the kidney and urinary tract, congenital solitary functioning kidney represented the major risk factor.
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http://dx.doi.org/10.1016/j.juro.2017.05.076DOI Listing
November 2017

Adiponectin profile and Irisin expression in Italian obese children: Association with insulin-resistance.

Cytokine 2017 06 3;94:8-13. Epub 2017 Apr 3.

CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, 80145 Napoli, Italy; Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Seconda Università degli Studi di Napoli, Via A. Vivaldi 42, 81100 Caserta, Italy. Electronic address:

Adiponectin (Acrp30), its high molecular weight (HMW) oligomers, and Irisin are molecules involved in several metabolic processes. To investigate if these cytokines could represent new metabolic markers, we evaluated the expression of Acrp30 and Irisin in serum of obese children from South Italy affected by different degrees of insulin resistance (IR). The anthropometric and metabolic features were evaluated in 27 obese children versus 13 age-matched controls. The expression of Acrp30, its pattern and Irisin were investigated by ELISA, western blotting and fast protein liquid chromatography. The HOMA index was significantly higher in obese children versus controls, and metabolic syndrome was more prevalent in obese children with elevated IR versus those with normal HOMA (38% vs 16%). Total Acrp30 and HMW oligomers were significantly lower in obese than in control children, and the difference was more pronounced in children with HOMA >3.4. In control and obese children, total Acrp30 and HMW oligomers were inversely related to HOMA (r-0.38, p 0.02; r-0.35, p 0.03). Irisin was significantly higher in obese than in control children, and was inversely correlated with Acrp30 and HMW (r-0.32, p 0.04; r-0.39, p 0.01). The inverse correlation of Acpr30 and HMW oligomers with HOMA indicates that Acpr30 is directly involved in IR status. Moreover, the inverse correlation between Irisin and Acrp30 and, more significantly, between Irisin and HMW oligomers suggests that the two cytokines are closely connected. The use of Acrp30, HMW oligomers and Irisin as predictive factors of IR in obese children remains to be further elucidated.
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http://dx.doi.org/10.1016/j.cyto.2016.12.018DOI Listing
June 2017

MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study.

Endocrine 2018 01 15;59(1):203-208. Epub 2017 Mar 15.

Department of Woman, Child, General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.

Purpose: Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty.

Methods: We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2-8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2-8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9-14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients.

Results: No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:-0.35; p:0.02), Luteinizing Hormone (r:-0.35; p:0.03), FSH (r:-0.37; p:0.02), and (17)estradiol (r: -0.36; p:0.02).

Conclusions: We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small. In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.
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http://dx.doi.org/10.1007/s12020-017-1281-xDOI Listing
January 2018

Associations Between Type 2 Diabetes-Related Genetic Scores and Metabolic Traits, in Obese and Normal-Weight Youths.

J Clin Endocrinol Metab 2016 11 2;101(11):4244-4250. Epub 2016 Sep 2.

Pediatric Diabetes and Metabolic Disorders Unit (A.M. C.M.), University Hospital of Verona, Verona, Italy; University of Lille (A.B., S.L., L.Y., P.F.), CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France; Department of Woman, Child and General and Specialized Surgery (E.M.d.G., A.G.), Second University of Naples, Naples, Italy; Inserm CIE 05 - Department of Clinical Epidemiology (C.L.-M.), Robert Debré Hospital, Paris, France; Pediatric Endocrine Unit (J.W.), Lille University Hospital, Lille, France; Department of Genomics of Common Disease (P.F.), School of Public Health, Imperial College London, Hammersmith Hospital, London, United Kingdom.

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) and DI (β = -0.031; P = 8.9 × 10, 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, 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.
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http://dx.doi.org/10.1210/jc.2016-2432DOI Listing
November 2016

TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype.

World J Gastroenterol 2016 Oct;22(38):8509-8518

Caterina Sagnelli, Department of Clinical and Experimental Medicine and Surgery, F. Magrassi e A. Lanzara, Second University of Naples, 80131 Naples, Italy.

Aim: To evaluate the impact of the Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients.

Methods: The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system. Patients were genotyped for TM6SF2 E167K (rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males (73.6%), the median age was 40.7 years and the immunological condition good (median CD4 cells/mm = 505.5).

Results: The 17 patients with the TM6SF2 E167K variant, compared with the 150 with TM6SF2-E/E, showed higher AST ( = 0.02) and alanine aminotransferase ( = 0.02) and higher fibrosis score (3.1 ± 2.0 2.3 ± 1.5, = 0.05). In a multivariate analysis, TM6SF2 E167K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCV-genotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167K in non-3 HCV genotypes. No association between the TM6SF2 E167K variant and severe liver necroinflammation was observed.

Conclusion: In HIV/HCV coinfection the TM6SF2 E167K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.
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http://dx.doi.org/10.3748/wjg.v22.i38.8509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064032PMC
October 2016

Multiplex Ligation-Dependent Probe Amplification Accurately Detects Turner Syndrome in Girls with Short Stature.

Horm Res Paediatr 2016 27;86(5):330-336. Epub 2016 Oct 27.

Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.

Aims: We aimed at evaluating a standard multiplex ligation-dependent probe amplification (MLPA) probe set for the detection of aneuploidy to diagnose Turner syndrome (TS). We first fixed an MLPA ratio cutoff able to detect all cases of TS in a pilot TS group. We then tested this value on a second group of TS patients and a short-stature population to measure specificity and sensitivity.

Methods: 15 TS patients with X mosaicism or X structural abnormalities (Pilot TS Group), 45 TS karyotype-assessed patients (TS Group), and 74 prepubertal female patients with apparent idiopathic short stature (Short-Stature Group) were enrolled. All subjects underwent MLPA and karyotype analysis. In the TS and Short-Stature Groups, MLPA testing was performed in blind.

Results: The choice of an MLPA threshold ratio of 0.76 for at least 1 probe allowed us to detect all TS cases, including mosaicisms. Sensitivity and specificity were 100% (CI 95%, 0.92-1) and 88.89% (CI 95%, 0.79-0.94), respectively. The positive predictive value was 88.5%, and the negative predictive value was 100%. MLPA detected the presence of Y chromosome material in 2 patients.

Conclusion: MLPA is an accurate and inexpensive tool to screen for TS in girls with short stature. A customized MLPA kit may be useful for the screening of an even larger population.
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http://dx.doi.org/10.1159/000452219DOI Listing
April 2017

Subclinical hypothyroidism in atopic South Italian children.

World J Clin Pediatr 2016 Aug 8;5(3):306-10. Epub 2016 Aug 8.

Marcella Pedullà, Vincenzo Fierro, Pierluigi Marzuillo, Ester Del Tufo, Anna Grandone, Laura Perrone, Emanuele Miraglia del Giudice, Department of Woman, Child and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Napoli, Italy.

Aim: To verify if subclinical hypothyroidism (SCH) could be associated to atopy in children.

Methods: Seven hundred and thirty-two Caucasian children from South Italy presenting symptoms of allergic disease were enrolled and submitted to atopy, obesity, chronic low grade inflammation, and SCH work up.

Results: Four hundred and forty-five out of 705 (63.12%) children affected by allergic disease were diagnosed as atopic and 260 (36.88%) as not atopic. The SCH prevalence was 6.3%. Significant higher prevalence of SCH among atopic children with average (group 2) and high (group 3) low grade chronic inflammation compared to atopic children with mild (group 1) low grade chronic inflammation was present. Moreover, group 1 and group 2 presented an OR to show SCH of 2.57 (95%CI: 1.55-6.26) and 2.96 (95%CI: 1.01-8.65), respectively. Both in atopic and not atopic children we found C3 serum levels significantly higher in group 3 respect to group 2 and group 1. Noteworthy, among atopic patients, also total immunoglobulin E (IgE) serum levels, were significantly higher in group 3 compared to group 2 and group 1 children. In atopic children, C3 and total IgE serum values increased in parallel with the increase of C-reactive protein values, while in not atopic children this phenomenon was not evident.

Conclusion: The possibility exists that an increasing atopic inflammation contributes to SCH occurrence. So far this is the first report in literature showing an association between SCH and atopy but further studies are needed to confirm our data.
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http://dx.doi.org/10.5409/wjcp.v5.i3.306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978624PMC
August 2016

Novel association between the nonsynonymous A803G polymorphism of the N-acetyltransferase 2 gene and impaired glucose homeostasis in obese children and adolescents.

Pediatr Diabetes 2017 Sep 2;18(6):478-484. Epub 2016 Aug 2.

Department of Woman, Child and General and Specialized Surgery, Seconda Università degli Studi di Napoli, Napoli, Italy.

Background: The N-acetyltransferase 2 ( NAT2 ) A803G polymorphism has been associated with decreased insulin sensitivity in a large adult population with the A allele associated with insulin-resistance-related traits.

Objective: Evaluate the association of this polymorphism with anthropometric and metabolic parameters in obese children and adolescents.

Subjects: A total of 748 obese children and adolescents were enrolled.

Methods: Anthropometric and laboratory data were collected. During oral glucose tolerance test, the presence of a possible exaggerated plasma glucose excursion at 1 h (1HPG) or impaired glucose tolerance (IGT) was considered. Homeostasis model assessment, oral disposition index (oDI) and insulinogenic index (IDI) were calculated. Patients were genotyped for the NAT2 A803G polymorphism.

Results: The prevalence of both IGT and elevated-1HPG was higher in children carrying the A803 allele (P = .02 and P = .03). Moreover, this allele was associated with both oDI and IGI reduction (P = .01). No differences among the NAT2 A803G genotypes for the other parameters were shown. Children homozygous for the A allele presented an odds ratio (OR), to show IGT of 4.9 (P = .01). Children both homozygous and heterozygous for the A allele had higher risk to show elevated-1HPG (OR of 2.7, P = .005; and OR = 2.3, P = .005) compared with patients homozygous for the NAT2 803G allele.

Conclusions: NAT2 A803 allele seems to play a role in worsening the destiny of obese children carrying it, predisposing them to elevated-1HPG and IGT and then to a possible future type 2 diabetes mellitus throughout an impairment of pancreatic β-cellular insulin secretion as suggested by oDI and IGI reduction.
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http://dx.doi.org/10.1111/pedi.12417DOI Listing
September 2017

An abdominal and unexpected cause of persistent fever in a 3-year old boy.

Turk J Gastroenterol 2016 07;27(4):389-90

Department of Woman, Child and General and Specialized Surgery, Seconda Universita degli Studi di Napoli, Napoli, Italy.

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http://dx.doi.org/10.5152/tjg.2016.16172DOI Listing
July 2016

Very early onset of autoimmune thyroiditis in a toddler with severe hypothyroidism presentation: a case report.

Ital J Pediatr 2016 Jun 18;42(1):61. Epub 2016 Jun 18.

Department of Woman, Child and General and Specialized Surgery, Seconda Università degli Studi di Napoli, Via L. De Crecchio n° 2, 80138, Naples, Italy.

Background: In infants under 3 years of age acquired primary hypothyroidism caused by autoimmune thyroiditis is very rare. Hypothyroidism can manifest with different signs and symptoms and has a wide range of presentations from subclinical hypothyroidism to overt form. We describe a child with acquired autoimmune thyroiditis during a very early period of life and with a severe hypothyroidism presentation.

Case Presentation: A 22-month-old white male patient with normal neonatal screening presented with a six-month history of asthenia and cutaneous pallor. At general clinical and biochemical exams he showed weight gain, statural growth deceleration, poor movements, sleepy expression, instability while walking, myxoedema, bradycardia, open anterior fontanelle, changes in the face habitus, macrocytic anaemia, ascites, and high CPK, creatinine and cholesterol levels. Acquired autoimmune thyroiditis was the final diagnosis. The thyroxine replacement therapy normalized all the clinical and biochemical abnormalities but at the age of 30 months his mental age showed a delay of 6 months.

Conclusions: Our case could give useful learning points: i) although the screening for congenital hypothyroidism is routinely performed, a severe hypothyroidism (for example due to autoimmune thyroiditis) can anyway occur early in life and the clinicians should consider this possibility; ii) hypothyroidism can have a misleading and multi-face clinical presentation; iii) anemia, rhabdomyolysis and high creatinine levels should always include the hypothyroidism in the differential diagnosis; iv) thyroxine replacement therapy is able to revert all the clinical manifestations related to the hypothyroidism; v) evaluating the patient's previous pictures could play an important role in resolving a diagnostic conundrum.
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http://dx.doi.org/10.1186/s13052-016-0270-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912771PMC
June 2016

Cannabinoid Receptor 2 as Antiobesity Target: Inflammation, Fat Storage, and Browning Modulation.

J Clin Endocrinol Metab 2016 09 13;101(9):3469-78. Epub 2016 Jun 13.

Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.

Context: Obesity is associated with a low-grade inflammatory state and adipocyte (ADP) hyperplasia/hypertrophy. Obesity inhibits the "browning" of white adipose tissue. Cannabinoid receptor 2 (CB2) agonists reduce food intake and induce antiobesity effect in mice. A common missense CB2 variant, Q63R, causes CB2-reduced function.

Objective: To evaluate the influence of CB2 receptor on the modulation of childhood obesity and of ADP activity and morphology.

Design: CB2-Q63R variant was analyzed in obese Italian children. The effects of an inflammatory stimulus and those of drugs selectively acting on CB2 were investigated on in vitro ADPs obtained from mesenchymal stem cells of adult healthy donors or from sc adipose biopsies of adult nonobese and obese subjects.

Setting: Department of Women, Child and General and Specialist Surgery of the Second University of Naples.

Patients Or Other Participants: A total of 501 obese Italian children (age 11 ± 2.75). Twelve healthy bone marrow donors (age 36.5 ± 15); and 17 subjects, 7 lean (age 42 ± 10) and 10 obese (age 37.8 ± 12) underwent sc adipose tissue biopsies.

Main Outcome Measures: Effects of CB2 stimulation on adipokine, perilipin, and uncoupling protein-1 expression.

Results: The less-functional CB2-R63 variant was significantly associated with a high z-score body mass index. CB2 blockade with AM630 reverse agonist increased inflammatory adipokine release and fat storage and reduced browning. CB2 stimulation with JWH-133 agonist reversed all of the obesity-related effects.

Conclusion: CB2 receptor is a novel pharmacological target that should be considered for obesity.
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http://dx.doi.org/10.1210/jc.2015-4381DOI Listing
September 2016

Bisphenol A is associated with insulin resistance and modulates adiponectin and resistin gene expression in obese children.

Pediatr Obes 2017 10 17;12(5):380-387. Epub 2016 May 17.

National Laboratory on Endocrine Disruptors of the National Institute of Biostructures and Biosystems, c/o Institute of Genetics and Biophysics - CNR, Naples, Italy.

Background: Bisphenol A (BPA) exposure has been associated with increased incidence of diabetes and obesity in adults.

Objectives: To evaluate whether an association between BPA urinary levels and insulin resistance as well as adiponectin and resistin production and serum concentrations may occur in obese children.

Methods: Clinical and biochemical features of 141 obese children were collected. Serum resistin and adiponectin were evaluated. Insulin resistance and urinary BPA levels were assessed. Moreover, the effect of BPA on adiponectin and resistin gene expression in adipocytes from eight normal weight prepubertal children was investigated by quantitative real-time RT-PCR (qPCR).

Results: Direct association between BPA and homeostasis model assessment (r = 0.23; p: 0.0069) and a strong inverse association between BPA and adiponectin have been found (r = -0.48; p < 0.0001). In adipocytes, resistin expression was detected only after BPA treatment, while adiponectin expression resulted down-regulated after BPA exposure (p < 0.05 at both 10 and 100 nM BPA concentrations).

Conclusions: We suggest the involvement of BPA in the development of insulin resistance in childhood obesity highlighting that urinary BPA levels are directly associated with insulin resistance regardless of BMI. This association may be explained, at least partly, by the findings that BPA affects resistin and adiponectin production in adipose tissue cultures.
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http://dx.doi.org/10.1111/ijpo.12154DOI Listing
October 2017

Iron Metabolism Dysregulation and Cognitive Dysfunction in Pediatric Obesity: Is There a Connection?

Nutrients 2015 Nov 6;7(11):9163-70. Epub 2015 Nov 6.

Department of Woman, Child, General and Specialized Surgery, Second University of Naples Via De Crecchio 2-4, Naples 80138, Italy.

Obesity and iron deficiency (ID) are two of the most common nutritional disorders in the world. In children both conditions deserve particular attention. Several studies revealed an association between obesity and iron deficiency in children and, in some cases, a reduced response to oral supplementation. The connecting mechanism, however, is not completely known. This review is focused on: (1) iron deficiency in obese children and the role of hepcidin in the connection between body fat and poor iron status; (2) iron status and consequences on health, in particular on cognitive function; (3) cognitive function and obesity; (4) suggestion of a possible link between cognitive dysfunction and ID in pediatric obesity; and implications for therapy and future research.
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http://dx.doi.org/10.3390/nu7115458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663586PMC
November 2015