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We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the

Background: Toxoplasma gondii is an obligate intracellular parasite that migrates through macrophages or dendritic cells to neurons and nerve cells. Glia Maturation Factor (GMF) is a pre-inflammatory protein that is expressed in the central nervous system (CNS). GMFβ expression is related to IL33 and CCL2 and SDF1 in some neurodegenerative diseases. According to the importance of GMFβ in neurodegenerative diseases and its association with IL33, CCL2 and SDF1 genes, this study was designed to determine the level of expression of these genes in the brains of mice with acute toxoplasmosis. Methods: Tachyzoites of T. gondii RH strains were injected to 5 Swiss Albino mice. At the same time, healthy mice were inoculated with the Phosphate-buffered saline (PBS). Their brains were removed and kept at -70 oC in order to RNA extraction, cDNA syntheses and Real Time PCR performance. The level of gene expression was investigated with SYBR Green Quantitative Real-Time PCR. Results: GMFβ gene expression increased significantly (P=0.003) 3.26 fold in Toxoplasma infected mice in comparison to the control. GMFβ gene expression was associated with increased expression level of IL33, CCL2, and SDF1 genes. Conclusion: Considering the prominent role of GMFβ in CNS as well as the immune system, the elevation of GMFβ, IL33, CCL2 and SDF1 genes expression in the early stage of toxoplasmosis is associated with the occurrence of neuropathological alterations. Detection of these genes as an indication of brain damage in the early stages of Toxoplasma infection can prevent neurodegenerative disorders following acquired toxoplasmosis.

Background: Severe congenital neutropenia (SCN4) caused by mutations in glucose-6- phosphatase catalytic subunit 3 (G6PC3) is characterized by recurrent infections due to severe neutropenia, may be accompanied by other extra-hematopoietic manifestations; including structural heart defects, urogenital abnormalities, prominent superficial venous markings, growth retention, and inflammatory bowel diseases with rare incidence. The homozygous or compound heterozygous mutations of G6PC3 are responsible for most cases of autosomal recessive SCN4. Herein, we present two cases of SCN4 affected by novel mutations in the G6PC3, in addition to a summarized list of variants in G6PC3 gene that are reported as pathogenic and related to the SCN4 phenotype. Case presentation: Herein, we present two cases of SCN4; the first case was a three-months old boy with severe neutropenia and prior history of hospitalization due to umbilical separation, umbilical herniation, omphalitis, and pyelonephritis; and the second case was an eight-year-old with a history of neutropenia, recurrent and severe episodes of intractable diarrhea, refractory rectovaginal and rectoperineal fistula, congenital inguinal hernia, and ASD type 2. Whole exome sequencing was performed for both cases, which revealed two novel homozygous missense mutations in G6PC3 that were predicted to be deleterious; c.337G>A, p. Gly113Arg in the first case and c.479C>T; P. Ser160Leu in the second case. To our knowledge, both of these two mutations have not been reported in the G6PDC3 gene. Conclusions: In patients with severe neutropenia with varying extra hematopoietic syndrome, mutation of G6PC3 should be suspected after ruling out other mutations related to neutropenia. This study pointed toward novel G6PC3 mutations that should be considered in order to diagnose patients with severe congenital neutropenia.

Background: Celiac disease is an immune-mediated systemic disease, in which gluten ingestion causes different symptoms. HLA-DQ2 is positive in 90% - 95% of celiac patients. HLA has been considered to inhibit antibody production against the hepatitis B virus vaccine. Considering that celiac disease affects about 1% of the population, this phenomenon could be a significant factor in immunization programs. On the other hand, HLA-DQ2 positive patients not only are at the risk of HBV infection themselves but also have the potential to be an important source of HBV dissemination in the world. Objectives: This study was carried out to evaluate the responsiveness of celiac-affected children to HBV vaccination in Iran. Methods: This case-control prospective study was performed on 62 Iranian children (31 children with confirmed celiac disease before introducing a gluten-free diet and 31 healthy children). HBS Ab (antibody against hepatitis B virus surface antigen) titer was checked in the patients and compared between the two groups. Results: It was shown that 67.7% of cases and 64.5% of controls had HBS Ab titer above 10 mIU/mL, but the difference was not significant statistically. After matching for the time interval from the last HBV vaccination, it was observed that although non-significantly, celiac disease can decrease the chance for anti-HBS production up to 30%. Conclusions: This study did not confirm non-responsiveness against the HBV vaccine in celiac disease in children. This may be due to genetic factors or type of vaccine. Moreover, in our study, responsiveness was assessed qualitatively in the two groups (HBS Ab > 10 mIU/mL was considered as a responder).

Background: Benign esophageal strictures are not rare. Over the past two decades, endoscopic balloon dilatation (EBD) has been used to treat them. Objectives: The purpose of this study was to identify the most common causes of benign esophageal stricture in children determine the success rate of endoscopic balloon dilatation. Methods: Children younger than 16 years with benign esophageal strictures referred to the endoscopy department during one year (2016 - 2017) were enrolled. After obtaining written consent from parents, endoscopy balloon dilatation was performed with two types of balloon catheters. Response to treatment was evaluated based on clinical symptoms and was classified according to the Vantrappen table score. Results: In this study, thirty-one (31) children participated including 19 (61%) boys and 12 (39%) girls. The mean age was 5.1 ± 3.9 years. The most common causes of esophageal stricture were: achalasia (45%), esophageal atresia (19%), stenosis due to the caustic ingestion (19%), another congenital stenosis (16%). Overall, 27 children (87.1%) had a good response to treatment. In children with stenosis due to caustic ingestion, the inappropriate response was higher than the rest (33%). However, only in 4 (12.9%) patients, balloon dilatation failed. No complications were observed. Conclusions: Achalasia, esophageal atresia, and caustic ingestion are the most common cause of benign esophageal stricture in the children. EBD is an effective and safe treatment in these children, even in cases of previous surgery and recurrence. If this procedure is performed by an expert using appropriate balloon catheters, no complications will be created.

Aim of the study Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease which could be associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). The aim of this study was to compare GGT and IgG4 levels among children with UC with PSC and without PSC. Material and methods In this cross sectional study children with UC with PSC and UC without PSC were included. Serum immunoglobulin G4 (IgG4) and gamma-glutamyl transpeptidase (GGT) levels of the 90 UC patients with and without concomitant PSC were measured. Children with serum IgG4 concentration > 175 mg/dl were considered to have elevated IgG4. Results Elevated serum IgG4 was found in 8 of 30 (26.6%) patients with PSC vs. 3 of 60 (5.0%) patients without PSC. Compared with the group without symptoms of PSC, the group with PSC showed significantly higher levels of aspartate aminotransferases (AST; 22.5 U/l vs. 70.0 U/l, p < 0.001), alkaline phosphatase (ALP; 359.0 U/l vs. 602.0 U/l, p < 0.001), and IgG4 (56.0 vs. 73.0, p = 0.02). The odd ratio of the elevated IgG4 and GGT in predicting PSC was 6.9 (95% CI: 1.6-28.4) and 18 (95% CI: 5.7-55.9), respectively. Conclusions AST, alanine aminotransferase (ALT), GGT, ALP, and serum IgG4 were significantly higher in UC patients with sclerosing cholangitis (SC) compared to UC patients without SC. GGT and IgG-4 measurements are recommended for evaluation of UC.

Introduction and aim. Autoimmune hepatitis (AIH) is an immune-mediated destruction of liver cells, in recognition of interface hepatitis, seropositivity for autoantibodies, and interface hepatitis in histology sections. Hepatocyte destruction in AIH is the direct result of CD4+ T-cell destruction. Yet, Th17 mediated immune attach and a diversity of cytokine networks, including pro-inflammatory cytokines such as Interleukin 1 (IL-1) and Interleukin 6 (IL-6), set the stage for the destructive liver damage. Material and method. Peripheral blood samples from 57 patients, with AIH, recruited from referrals to the main pediatric hospital in Tehran. Single nucleotide polymorphisms for the following cytokines genes, were evaluated through, polymerase chain reaction with sequence-specific primers (PCR-SSP) assay: IL-1a (C/T -889), IL-Ια (C/T -511), IL-1 β (C/T +3962), IL-1 receptor (IL-1R; C/T Pst-I 1970), IL-1RA (C/T Mspa-I 11100), and IL-6 (C/G -174 and A/G nt565). Results. Significant higher frequency of genotype AA was detected in patients in IL-6 at position nt565 (15.8% in AIH patients vs. 2.9% in controls, p = 0.003). The haplotype GA of IL-6 at -174 and nt565, was significantly overrepresented in the AIH group, compared to (20.9% of AIH vs. 1.4% in controls p Conclusion. Results of our study, indicate significant deviation toward high yield IL-6 polymorphisms, in AIH patients. These data could bring new insights in pathophysiology of disease, which could contribute to developing novel treatments for AIH.

Autoimmune hepatitis (AIH) is a chronic inflammation in hepatocellular tissues associated with circulating autoantibodies. Imbalance in T-cells population and dysregulation in several cytokine profiles has been implicated in pathogenesis of AIH. This study was performed to assess potential association of AIH with interleukin-2 (IL-2) and interferon-gamma (IFN-γ) genes single nucleotide polymorphisms (SNPs).Fifty-six patients with AIH and 139 healthy individuals were enrolled in this study. IL-2 and IFN-γ typing was performed, using polymerase chain reaction with sequence-specific primers (PCR-SSP) assay. The frequencies of alleles, genotypes and haplotypes in AIH patients were compared to healthy controls.IL-2 T allele at position +166 (rs2069763) showed significant higher frequency in AIH group (36%), compared to the controls (21%) (OR=2.06; 95% CI, 1.24-3.43, P-value0.01). The frequency of IL-2 TT genotype at +166 position was also associated with AIH (OR=18.68, 95% CI 3.74-126.04, P-value0.01). G/T alleles of IL-2 at -330 (rs2069762) and A/T alleles on UTR +5644 position at IFN-γ and their subsequent haplotypes, did not show significant association with AIH.This study identified IL-2T allele at +166 position and TT genotype as susceptibility gene in AIH which would provide better understandings into the mechanisms of AIH and potential immune modulation therapies.

Background: Gastroesophageal reflux disease (GERD) is associated with a number of comorbidities in pediatrics. However, its association with attention deficit hyperactivity disorder (ADHD) has not been reported. The aim of the present study was to investigate the prevalence of ADHD in pediatric patients newly diagnosed with GERD. Materials and Methods: Sixty newly-diagnosed treatment naive GERD patients and sixty healthy controls aging between 5 to 12 years referring to the Children and Adolescent’s medical center, Tehran, Iran were recruited in a case-control study during the year 2015. Then patients were evaluated for ADHD by a psychiatrist according to the DSM-IV criteria. The revised Conners' Parent Rating Scale (CPRS-R) was used for assessment of the symptoms of ADHD. To screen for psychiatry disorders other than ADHD, the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL) questionnaire was used. Logistic regression analysis was used for modeling the association between GERD and ADHD in the study sample. Results: The mean age of GERD patients was 5.77±2.27 and for non-GERD controls was 6.03±2.52 (P= 0.543). Thirty-three out of 60 (55%) GERD patients and 37 out of 60(61.66%) non-GERD controls were male (P: 0.579). Prevalence of ADHD was 33.60 (55%) in GERD patients and 10.60 (16.66%) in non-GERD (P

Background Glycogen storage disease (GSD) is a rare inborn error of the synthesis or degradation of glycogen metabolism. GSD1, the most common type of GSD, is categorized into GSD1a and GSD1b which caused by the deficiency of glucose-6-phosphatase (G6PC) and glucose-6-phosphate transporter (SLC37A4), respectively. The high rates of consanguineous marriages in Iran provide a desirable context to facilitate finding the homozygous pathogenic mutations. This study designates to evaluate the clinical and genetic characteristics of patients with GSD1b to assess the possible genotype-phenotype correlation. Results Autozygosity mapping was performed on nineteen GSD suspected families to suggest the causative loci. The mapping was done using two panels of short tandem repeat (STR) markers linked to the corresponding genes. The patients with autozygous haplotype block for the markers flanking the genes were selected for direct sequencing. Six patients showed autozygosity in the candidate markers for SLC37A4. Three causative variants were detected. The recurrent mutation of c.1042_1043delCT (p.Leu348Valfs*53) and a novel missense mutation of c.365G > A (p.G122E) in the homozygous state were identified in the SLC37A4. In silico analysis was performed to predict the pathogenicity of the variants. A novel whole SLC37A4 gene deletion using long-range PCR and sequencing was confirmed as well. Severe and moderate neutropenia was observed in patients with frameshift and missense variants, respectively. The sibling with the whole gene deletion has shown both severe neutropenia and leukopenia. Conclusions The results showed that the hematological findings may have an appropriate correlation with the genotype findings. However, for a definite genotype-phenotype correlation, specifically for the clinical and biochemical phenotype, further studies with larger sample sizes are needed.

Background: Constipation is a frequent complication in pediatrics, most of which is habitual, comprising 25% of visits in pediatric gastroenterology clinics. Objectives: The main object of this study was to investigate clustering of habitual constipation among families of pediatric patients. Methods: This case-control study was conducted on families of 150 children < 18 years old with chronic habitual constipation alongside families of 150 healthy children as controls. The cases were enrolled in the study according to the Rome IV criteria for constipation. The parents and siblings were evaluated regarding constipation. Data were analyzed using SPSS-16, χ2 and t-test were used for comparison. Results: A total of 300 children and their families participated in the study. No significant differences were found between the study and the control groups in age, sex, or BMI. However, the siblings or parents from the study group had significantly higher rates of constipation compared with the control group. Conclusions: Considering different survey findings, a correlation between “habitual constipation” and “familial background” seems to exist in children. A clear pathophysiological explanation for this phenomenon is not yet available.

Ascites is not a usual finding in prehepatic portal hypertension, including portal vein thrombosis, but when portal vein thrombosis is acute and massive, ascites can be a presenting feature. We report a 9-year-old boy with tense ascites and portal and superior mesenteric vein thrombosis. A 9-year-old boy was evaluated for tense ascites which led to umbilical hernia since one month before admission. He did not have any clinical or laboratory stigmata of parenchymal liver disease. Imaging studies showed superior mesenteric and portal vein thrombosis. In laboratory tests for pre-thrombotic states, he suffered from significant protein S deficiency. Thrombophilic states like protein S deficiency predispose patient to vascular thrombosis. This vascular thrombosis can be present with signs and symptoms related to their territories. Prevention of thrombosis and rethrombosis with anticoagulant therapy is recommended.

Summary Background Allergic colitis (AC) is one of the most common etiologies of rectal bleeding in infants aged one to six months. Aim The aim of this study is to apply step-by-step dietary restrictions in the mother's diet or change of infant formula fed thereby, to evaluate the subsequent clinical response. Methods Sixty healthy infants whose clinical and evaluation results indicated proctocolitis in our outpatient gastroenterology clinic were included in this. They were divided into three groups according to the type of feeding; group 1 were exclusively breast fed, group 2 were exclusively formula fed and group 3 were fed with combination of both. In breast feeding women, discontinuation was allergenic food was studied in four stages; cow-related dairy products, soy, sesame and fast food (stage A), egg (stage B), corn, nuts and fish (stage C) and wheat (stage D). Results Sixty newborns with age at symptom onset 3 days–20 days participated in the study. Up to the time of our initial evaluation, the mean age and weight of infants was 73.34 ± 1.00 day and 3292.71 ± 367.93 g, respectively. There was no significant difference in sex and the type of labor between the groups. Thirty-three infants had a history of eczema and the parents of 47 infants had a history of allergy, with the greatest prevalence in group one. Rectal bleeding in 50% of infants was halted after the elimination of allergenic feed in mother (15 in stage A, 8 in stage B and 7 in stage C). Ten infants needed extensive hydrolyzed formula and 20 needed amino acid-based formulas. Conclusions There is no need for immediate use of amino acid or extensive hydrolyzed formulas in the first stage of blood in stool, perhaps discontinuing allergenic food in mothers could be the primary measure.

Background & aim: Comparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as an important cause of infantile (Very Early Onset) IBD to find any possible variants. Method: With the next generation sequencing technique we screened IL-10, IL-10RA and IL10RB genes of 15 children affected by very early onset-GI (gastrointestinal) disorders. Additionally, we analyzed them based on Thermo Fisher immune deficiency panel for genes either having a known role in IBD pathogenesis or cause the disorders with overlapping manifestations. We performed multiple functional analyses only for the cases showing variants in IL-10-related genes. Result: In 3 out of 15 patients we identified variants including a homozygous and heterozygote mutations in IL-10RA and a novel homozygous mutation in IL-12RB1. Our functional studies reveal that in contrast to the IL-10RA heterozygote mutation that does not have deleterious effects, the homozygous mutation abrogates the IL-10 signaling pathway. Conclusion: Our study suggests we need to modify the classical diagnostic approach from functional assays followed by candidate-gene or genes sequencing to the firstly parallel genomic screening followed by functional studies. (C) 2017 Elsevier Masson SAS. All rights reserved

Background: Autoimmune hepatitis (AIH) is a chronic long-lasting hepatocellular inflammation associated with circulating auto antibodies. In addition to the genetic component, several cytokines have been implicated to be involved in AIH. This study was performed to investigate potential associations of AIH with IL4 gene variants.Method: The studied alleles and genotypes included: IL4G/T allele polymorphisms at position -1098 and C/T allele polymorphisms at two positions (-33 and -590) on the IL4 gene, in addition to the A/G allele polymorphisms at position +1902 on the IL4RA gene.Result: The IL4 C allele and CC genotype at position -590 and TT genotype at position -33 had a significantly higher frequency in AIH patients.Conclusion: This study identified the IL4 C allele and CC genotype susceptibility gene in AIH, which will provide better insights into the mechanisms of AIH and potential therapeutic interventions.

Background: Effective and safe procedural sedation is necessary for percutaneous liver biopsy in children. There are a number of different protocols for this purpose. The current study investigated ketamine and DPT cocktail (meperidine (Demerol®) + promethazine (Phenergan®) + chlorpromazine (Thorazine®)). Methods: The current cohort of 80 Iranian children aimed at investigating percutaneous liver biopsy. Each of the 2 study groups (ketamine and DPT) included 40 patients. Both groups were matched by age (number of participants under and above 7 years old). The current study evaluated the efficacy of 2 protocols by CHEOPS (children’s hospital of Eastern Ontario pain scale) and visual analogue scale (VAS) pain scoring system and sedation scoring A,B,C, and D. Results: Ketamine group was sedated and recovered much more rapidly than the DPT receiving patients. Also, they had significantly less pain during the biopsy. The most common side effect of ketamine was vomiting (27%); in the other group, transient hypotension and tachycardia were more common. Conclusions: Ketamine is a safe and effective choice for procedural sedation in percutaneous liver biopsy in children.

Proper colon preparation in children has been a challenge for many years. Different regimens have been used for this purpose, but the best regimen is not determined. The aim of this study was to evaluate successful colon preparation before colonoscopy in children who were treated with one- or two-day regimen with polyethylene glycol (PEG) plus bisacodyl and clear liquids.In this randomized clinical trial, 100 children (2-14 years old) who were candidates for colonoscopy were enrolled and divided into two groups. The children in group one were started on 2 g/kg PEG powder (17 g in 240 mL water or another beverage) and 5 mg bisacodyl suppository (BD) the day before colonoscopy, whereas those in the other group were started on 1.5 g/kg PEG with fruit juices for two days and 5 mg bisacodyl suppository (BD) for two days before colonoscopy.Compliance rates, regimens, adverse effects, and complete colonoscopy were not significantly different between the two groups. The Boston score was excellent and good in 70% of group one and 72% of group two children, respectively. Compliance rate, adverse effects, and need for enema were similar in both groups. The rate of compliance and non-requirement of enema were significantly higher in children with satisfactory colon preparation.The one-day PEG plus bisacodyl regimen for bowel preparation is as effective as the two-day regimen in children; furthermore, it is well tolerated and has low adverse effects.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Summary Background and aims Autoimmune hepatitis is a chronic immune-mediated liver injury caused by dysregulated immune response to liver antigens. Genetic susceptibility is affected by multiple single nucleotide polymorphisms in immune-related genes. There are few reports on the association of TGF-β and IL-10 genetic variants with autoimmune hepatitis. Methods Allele frequency and genotype status of IL-10 −1082, −819, −592 and TGF-β +869 and +915 polymorphisms were investigated in 57 unrelated patients with autoimmune hepatitis and 140 healthy controls by polymerase chain reaction with sequence-specific primers. Results IL-10 −592 and −819 allele frequencies and genotypes were not associated with autoimmune hepatitis in our population, while IL-10 −1082 genotypes were. IL-10 −1082/−819/−592 “high-producing” haplotype GCC was significantly less frequent in patients. TGF-β +869 “high-producing” allele C and genotype CC were significantly more in autoimmune hepatitis, compared to controls; whereas, TGF-β +915 “low-producing” allele C and genotype CC were significantly more in autoimmune hepatitis compared to control. TGF-β +869/+915 haplotype TG was significantly less frequent in patients while CC haplotype was significantly more frequently observed in patients. Conclusion We identified a significant association between IL-10 −1082/−819 and TGF-β +869/+915 genotypes and haplotypes with autoimmune hepatitis in Iranians.

Celiac disease is a chronic autoimmune disease in which gene-environment interactions cause the immune system to unfavorably react to naturally gluten-containing foods. PTPN22 plays a crucial role in regulating the function of various cells of the immune system, particularly T cells. Polymorphisms of the PTPN22 gene have been associated with many autoimmune diseases. The present genetic association study was conducted to investigate the possible associations between PTPNTT single nucleotide polymorphisms (SNPs) and celiac disease in an Iranian population.The study population consisted of 45 patients with celiac disease and 93 healthy controls. The study genotyped five SNPs of the PTPN22 gene: rs12760457, rs1310182, rs1217414, rs33996649, and rs2476601.Control and patient groups did not differ on the genotype distribution of four of five investigated SNPs in the PTPN22 gene, for example, rs12760457, rs2476601, rs1217414, and rs33996649. The only investigated PTPN22 variant, which could be associated with CD, was rs1310182. A significant increase in the carriage of the T allele of rs1310182 in CD patients was observed (OR (95% CI) = 11.42 (5.41, 24.1), p value0.0001). The TT genotype of this SNP was significantly associated with celiac disease. Our study suggests that the rs1310182 SNP of PTPN22 gene may be a predisposing factor of celiac disease in the Iranian population. Further studies are required to investigate the issue in other racial and ethnic subgroups.

Background: Chronic abdominal pain in children is a common disorder. For an accurate diagnosis of its cause, sometimes invasive diagnostic procedures such as endoscopy should be performed. Objectives: The purpose of the study was to evaluate the fecal calprotectin in children with upper gastrointestinal signs and symptoms and to compare it with endoscopic findings. Methods: A total of 131 children aged 1-14 years with upper gastrointestinal symptoms were enrolled during 2012 - 2013 at two centers. One hundred and twenty patients underwent endoscopy and biopsy. Before endoscopy, the level of calprotectin was measured by the enzyme-linked immunosorbent assay test in stool samples and the results were compared with the endoscopic and pathology findings. Results: Of the 120 children included in this study, 71 (59.2%) were males and 49 (40.8%) females with a mean age of 93.6 months. Of the 112 patients in whom biopsies were taken, 16 had esophagitis, 89 chronic gastritis (79.5%) and 57 colonization with Helicobacter pylori. Conclusions: There was a statistically significant correlation between fecal calprotectin and gastritis and severity of H. pylori infection. Fecal calprotectin level measurement can avoid unnecessary endoscopies and is also useful for evaluation of therapy response.

Introduction: The Wilson disease is an autosomal recessive disease in which the liver, central nervous system, eyes, blood and other parts of the body involved. Timely diagnosis and appropriate treatment of the disease requires awareness of the clinical presentations of this disease in children.Methods: This case series study included 62 patients with Wilson disease who admitted to children's Medical Center in the years 2012-2003.Results: 56% of patients were male. The average age of diagnosis was 9.73 years old (5-17 years) and this was higher in patients with early neurologic symptoms (P = 0.85.( 64.5% of the patients had the hepatic symptoms at the time of diagnosis and the most common type of hepatic involvement was cirrhosis (39.3%) and hepatitis (17.5%) respectively. 17.7% of the patients also had early neurological symptoms. A positive family history for the Wilson Disease were found in 27.4% of patients. 74.2% of patients had KF ring and the frequency of these symptom was higher in patients with early neurological involvement. 83.9% of patients were treated successfully with D-penicillamine and In 30% of patients, adverse drug reactions were seen.Conclusion: Children with unknown liver disease should be evaluated for Wilson disease and the first-degree relatives of patients should be screened. . D-penicillamine have important side effects, but due to the low cost and the availability is an appropriate drug to treat the Wilson disease..Key words: Wilson Disease, Hepatic Involvement, Neurologic Involvement , KF ring ,D-Penicillamine.

Background: Helicobacter pylori (H.pylori) infection has an important role in promoting gastrointestinal disease in human. It may be acquired early in life, particularly in developing countries. The aim of this study is to evaluate the association between H.pylori infection and clinical manifestations in Iranian children.Materials and Methods: In this retrospective, cross-sectional study, H. pylori status was assessed by pathological examination of gastric biopsy in symptomatic children. A total of 266 patients were diagnosed as infected by H. pylori, compared with 268 uninfected patients matched by age and sex. Reported symptoms, endoscopic and pathological findings in the two groups were analyzed using chi square test. The limit of statistical significance was set at P

Background/Aims: Cystic fibrosis (CF), the most common hereditary, life-threatening disease, is caused by a mutation in the CFTR gene. Because different mutations can affect clinical manifestations of patients, this study was conducted to investigate the possible genotype-phenotype relationship in a group of Iranian patients with CF. Materials and Methods: This case-series study was conducted in 30 patients with CF who were referred to a tertiary pediatric hospital in Tehran. In this study, the DNA of the patients was evaluated for delta F508 mutation, whereas some parameters such as the age at diagnosis, the sweat chloride level, and clinical manifestations related to pancreatic insufficiency and pulmonary involvement were also assessed. Results: Among all the studied patients, 16.6% had a delta F508 mutation, either homozygote or heterozygote. The mean age at diagnosis was lower in patients with the delta F508 mutation, but the sweat chloride level tended to be higher in these patients. All the patients with the delta F508 mutation had exocrine pancreatic insufficiency, which tended to be higher than 84% in those without this mutation. In addition, all of these patients had pulmonary involvement, which tended to be higher than 64% in those with negative delta F508 mutation. Conclusion: According to the results of this study, the frequency of delta F508 mutations in Iranian patients appears to be much lower than what is seen in American and the European patients. In those with the delta F508 mutation, pulmonary involvement and pancreatic insufficiency are more common; the sweat chloride level tended to be higher, but the age at diagnosis was lower, all of which resemble a more severe form of disease.

Background/Aims Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract, whose etiologies are still unknown. This study was performed to evaluate the humoral immune response in terms of B cell functions in selected IBD patients. Methods Eighteen pediatric patients with IBD, including 12 cases of ulcerative colitis (UC) and six with Crohn disease (CD), were enrolled in this study. The pneumococcal vaccine was injected in all patients, and the IgG antibody level to the polysaccharide antigen was measured before and 4 weeks after injection. The B cell switch-recombination process was evaluated. Results Five patients with IBD (three CD and two UC) had defects in B cell switching, which was significantly higher than in controls (p=0.05). Ten patients had a specific antibody deficiency and exhibited a higher frequency of bacterial infection than the healthy group. The mean increased level of IgG after vaccination was lower in IBD patients (82.9±32.5 µg/mL vs 219.8±59.0 µg/mL; p=0.001). Among the patients who had an insufficient response, no significant difference in the number of switched memory B-cell was observed. Conclusions A defect in B lymphocyte switching was observed in pediatric IBD patients, and especially in those patients with CD. Owing to an increased risk of bacterial infections in those patients with antibody production defects, pneumococcal vaccination could be recommended. However, not all patients can benefit from the vaccination, and several may require other prophylactic methods.

Introduction To define the clinical features, biochemical and histological findings and outcome of three forms of autoimmune hepatitis. Materials and Methods In a cross sectional study between November 2001 to January 2008 in Tehran and Mashhad university of medical sciences, 61 children who diagnosed as AIH (40 girls and 21 boys) have been analyzed for their clinical, serological, and histological data. Variables analyzed included age, sex, clinical presentation, hepatic function, immunoglobulins, autoimmunity markers, histology and clinical evolution. According to the auto-antibodies profile, AIH patients were classified as type I AIH (ANA or smooth-muscle antibodies or both positive), type II (anti-LKM-1 positive) and type III (antibody negative). Results We analyzed data of 61 children with AIH. 51 patients (median age: 10 (0.7-14) years had anti-nuclear and/or smooth muscle antibody (ANA/ASMA or both), 5 (median age: 7 (2-8) years) had liver/kidney microsomal antibody (LKM-1). 5 patients had no detectable autoantibody. At presentation: 60% had jaundice or symptoms of acute hepatitis; LKM-1 positive were younger. Interface hepatitis was seen in 100% and fibrosis+/- cirrhosis were found in 70%. Frequency of AIH was 2:1 in girls. Type 1 was the most frequent diagnosis (83%) and was more frequent in older children. Relapse and treatment failure were common in type II. Conclusion AIH may have different clinical presentation in children. Althout most of cases may have high inflammatory activity or cirrhosis, good response to treatment and remission may accur.

Girifl ve Amac: Kistik fibrozis en s›k karfl›lafl›lan kal›t›msal olumcul hastal›kt›r ve yenidoan taramas›n›n yap›lmad›¤› bolgeler- de hastalar gec tespit edilebilir. Erken tan› konulan kistik fibrozis hastalar›n›n sonuclar› dramatik olarak daha iyidir. Bu cal›fl- mada kistik fibrozis hastalar›nda ilk baflvuruda tespit edilen tan›ya goturen bulgular›n›n incelenmesi amaclanm›flt›r. Gerec ve Yontem: Bu cal›flma ‹ran'da birden cok pediatrik referans merkezinde gerceklefltirildi, hastalar›n tan› an›ndaki demografik, kli- nik ve labaratuvar verileri kontrol listesi ile kay›t alt›na al›nd›. Tum hastalar›n 2 adet ter klor testi mevcuttu. Bulgular: Kistik fibrozis tan›s› olan 197 hasta cal›flmaya dahil edildi. Bu hastalardan, 119'unun (%74) yafl› 6 aydan kucuktu ve 34 hastan›n (%21) yafl› 6-12 ay aras›ndayd›. En s›k karfl›lafl›lan klinik bulgular buyume gerilii (n=178; %90) , tekrarlayan akcier enfeksiyonlar› (n=139; %71) ve steatore (n=135; %69) olarak tespit edildi. En s›k karfl›lafl›lan radyolojik anormallik akcierlerde afl›r› havalan- mayd›. Terde tuz tad›, steatore, metabolik alkaloz, radyolojik anormallikler ve karacier testlerinde anormallik olan hastalar›n or- talama tan› yafl› dierlerine gore dufluk bulundu. Sonuc: Bu cal›flma sonuclar›na gore buyume gerilii, tekrarlayan solunum sis- temi enfeksiyonu, steatore, metabolik alkaloz ve tuzlu cilt tad› kistik fibrozis ile s›k karfl›lafl›lan bolgelerde klinikte uyar›c› olmal›- d›r. Bu bolgelerde, dikkat ve klinik fluphe ile hastalar›n erken tespit edilmesi mumkun olabilir. Anahtar kelimeler: Kistik fibrozis, tan›, klinik bulgular, tarama Background/aims: Cystic fibrosis is the most common inherited lethal disease, which could be frequently identified late in regi- ons without newborn screening. There are dramatically better outcomes in the early diagnosis of cystic fibrosis patients. This study aimed to evaluate the spectrum of manifestations of cystic fibrosis at first admission leading to diagnosis. Materials and Methods: This study was performed in a multi-referral pediatrics center in Iran. Data of patients with cystic fibrosis at the time of diagnosis were recorded based on a checklist denoting demographic characteristics, clinical and laboratory features. All of the patients had two documented sweat chloride tests. Results: One hundred and ninety seven patients with cystic fibrosis were enrolled in this study. Among them, 119 patients (74%) were less than six months and 34 patients (21%) were between 6 and 12 months of age. The most common clinical findings were failure to thrive, recurrent pulmonary infections, and steatorrhea in 178 (90%), 139 (71%), and 135 (69%) patients, respectively. The most common radiologic abnormality was hyperaeration. In patients with salty tasting skin, steatorrhea, metabolic alkalosis, radiologic findings, and liver function abnormalities, the mean age at the time of diagnosis was significantly low than in the subjects without these findings. Conclusion: This study suggests that some conditions such as failu- re to thrive, recurrent respiratory infections, steatorrhea, metabolic alkalosis, and salty tasting skin should be considered as clini- cal screening tools for cystic fibrosis, especially in regions with high rate of cystic fibrosis. In these regions, awareness and clinical suspicion of medical professionals are crucial for early diagnosis of cystic fibrosis patients in the pre-diagnostic period.

Introduction Poor weight gain is one of the most important mortality hazards in cystic fibrosis (CF) patients. The mechanisms that may hinder body weight regulation are not completely understood. Leptin and its role in fat mass could be related to control of weight gain in CF patients. As the previous data are conflicting, we aimed to investigate serum leptin level in Iranian CF children compared to a control group. Material and methods Forty-three CF patients aged from 3 to 120 months and 43 age-matched controls were enrolled. Patients were recruited from the outpatient clinic of the Children's Medical Center Hospital. Controls were visited in the general outpatient clinic for an annual check-up. Both groups were divided into three subgroups based on age: 3 to 12 months, 13 to 48 months, and 49 to 120 months. Body mass index (BMI) was calculated for all the participants. Serum leptin levels were measured applying a solid phase enzyme-linked immunosorbent assay (ELISA). Results Leptin levels and BMI values were significantly different between patients and controls (p = 0.02, p < 0.001, respectively) but only patients aged 13–48 months had significantly higher levels of leptin than age-matched controls (p = 0.016). Overall male patients’ mean leptin level was significantly higher than in female patients (p = 0.032) and male controls (p < 0.001). Conclusions Leptin level in our patients was significantly higher than controls. It seems that leptin levels during infancy are higher than in adult patients. Further studies are required on specific genotypes, gender and age to reveal the probable correlation with BMI and leptin levels in CF patients from different ethnic groups.

Although several invasive and noninvasive tests have been developed for the diagnosis of Helicobacter pylori infection, all of the tests have their limitations. We conducted a study to investigate and compare the suitability of rapid urease test (RUT), serology, histopathology and stool antigen tests with polymerase chain reaction (PCR) for detection of H. pylori, and correlate the diagnostic methods with PCR. Eighty nine patients (61 adults, 28 children) referred to the Firoozgar Hospital and Children Medical Center Hospital for diagnostic upper gastrointestinal endoscopy entered to the study and noninvasive tests such as immunoassay for serological antibodies against H. pylori and detection of its antigen in feces were measured. The biopsies were utilized for histological examination, RUT and PCR. The H. pylori statuses were evaluated by the positivity of ureC PCR in biopsy specimens and 53 subjects had H. pylori positive result. Histopathology showed high overall performance in adults and children with sensitivity and specificity 100% and 90%, respectively. Sensitivity, specificity, and accuracy for stool antigen test were 87.8%, 75% and 82%, respectively. Correlation of RUT, serology (IgG), histopathology and stool antigen tests with PCR were 0.82, 0.32, 0.91 and 0.63, respectively. In conclusion, the RUT and histopathology are as accurate as the PCR of biopsy and stool antigen test can consider as appropriate noninvasive test for detection of H. pylori infection.

Background: Liver disease is increasingly common in pediatric cystic fibrosis (CF). Liver dysfunction in CF patients is an early complication and relatively common which may progress silently. Objectives: The purpose of this study was to determine the prevalence of abnormal liver architecture by Ultrasonography (US) and their associations to abnormal liver function tests particularly abnormal Gamma Glutamyl Transpeptidase (GGT), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) level for its early detection before the complications occur. Patients and Methods: This study as a cross-sectional study was performed at the Children's Medical Center Hospital, Pediatrics Center of Excellence in Tehran, Iran. In all, 114 patients with cystic fibrosis (70 boys, 44 girls) were enrolled. Sample blood test including AST, ALT, GGT and abdominal Sonography was obtained from all patients. Abnormal liver function test was defined by two consecutive occasions; ALT and/or AST levels were ≥ 2 times the upper limit of normal values. GGT normal values were defined by patient age. Data were analyzed using χ2 test and independent T test. Statistical significance was defined as P values of < 0.05 by SPSS ver.19 software. Results: Abnormal liver function test was detected in CF patients. As well, liver sonogram was abnormal in approximately one-third of the patients. This study showed a higher prevalence of biochemical abnormality in patients with abnormal livers ultrasonography. Conclusions: Noninvasive paraclinical evaluation methods could be recommended in the patients with CF for early detection of silent liver abnormalities before progression to end stage liver disease.

Background. Eosinophilic esophagitis is an inflammatory condition where there is a dense infiltration of eosinophils typically exceeding fifteen cells per high power field. Familial Mediterranean fever is an autosomal recessive disorder characterized by brief, acute, and self-limited episodes of fever and polyserositis that recur at irregular intervals. Case Presentation. A three-year-and-nine-month-old Iranian girl was admitted to our center. The patient’s parents complained of a history of abdominal pain, poor appetite, and poor weight gain from 1.5 years ago and episodes of food impaction after starting solid foods. Eosinophilic esophagitis was diagnosed based on histology. Because of continuing abdominal pain after treatment of eosinophilic esophagitis, the episodic nature of disease, and the presence of fever with pain, screening for familial Mediterranean fever mutation was performed and the patient was found to be heterozygote for Mediterranean fever. Conclusion. We have reported a case of eosinophilic esophagitis coexisting with familial Mediterranean fever which has not been described previously.

INTRODUCTION: Cystic fibrosis (CF) is a common genetic disorder as a result of mutation in the CF transmembrane conductance regulator gene. Weight loss in CF patients seems to be multifactorial and metabolic factors, inflammation, recurrent infections and poor appetite are possible candidates. Ghrelin affects energy hemostasis by stimulating growth hormone secretion, glucose and lipid metabolism alteration and inhibition of the inflammatory system. Data on the role of ghrelin in energy deficiency in CF patients are sparse and controversial. The study was done to compare the plasma levels of the acylated form of ghrelin in CF patients with healthy participants. MATERIAL AND METHODS: Thirty cystic fibrosis patients (aged 1-168 months) and thirty healthy matched participants were enrolled in the study. Plasma ghrelin and albumin levels were measured and body mass index (BMI) was calculated as well. RESULTS: Plasma levels of acylated ghrelin in CF patients were significantly higher than the control group (mean 25-75%: 14.5 vs. 2.7, p = 0.032). Body mass index measurements in CF patients were significantly lower than the control group (p < 0.001). Using regression analysis there was no statistically significant correlation between plasma ghrelin levels and serum albumin, weight, height or BMI values in CF patients and controls. CONCLUSIONS: The acylated ghrelin levels are increased in CF. So plasma levels of acylated ghrelin could be used as an indicator of food uptake and energy balance in them. Further studies should be established to find out the exact role of factors affecting energy metabolism.

Introduction Infection is a major cause of morbidity and mortality in patients with cystic fibrosis (CF). Antimicrobial resistance of the bacterial spp. particularly methicillin resistance in Staphylococcus aureus has caused a lot of attention. The aim of this study was to describe the prevalence of S. aureus, Pseudomonas aeruginosa and Burkholderia cepacia-complex as well as their antimicrobial susceptibility patterns in CF patients in an Iranian referral pediatrics Hospital. Material and methods From March 2011 until February 2012, 172 samples were collected at the Children Medical Center (CMC), an Iranian referral hospital in Tehran, Iran. Sputum specimens were cultured for the following bacterial pathogens: P. aeruginosa, S. aureus, B. cepacia complex. Antimicrobial susceptibility was performed according to the Clinical Laboratory Standards Institute recommendations. Results In our study, 54% of the patients (n = 93) harbored at least once S. aureus, 30% (n = 52) P. aeruginosa, and 2% (n = 3) Burkholderia cepacia. In 40 patients (23%), none of these organisms was grown. An increasing colonization rate of P. aeruginosa in the second decade of life was found. In contrast, the colonization rate of S. aureus was constant in both decades of life. Methicillin resistant S. aureus (MRSA) was detected in 40 isolates (43%). Among MRSA, no resistance against vancomycin, linezolid and quinupristin/dalfopristin occurred. The susceptibility of P. aeruginosa isolates to meropenem, imipenem, doripenem, levofloxacin and polymixin B were more than 90%. Conclusion The prevalence of MRSA has been rising. Since its impact on clinical outcomes, optimal prevention and treatment strategies are unclear, further studies to expand the knowledge about the infection control strategies and MRSA treatment are highly recommended.