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BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC.METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 μg/kg, or odevixibat 120 μg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 μmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238.FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 μg/kg per day (n=23), or odevixibat 120 μg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 μg/kg per day group and 52% in the 120 μg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 μg/kg per day group and four in the 120 μg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients.INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC.FUNDING: Albireo Pharma.

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion:: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Rotaviruses are the most common cause of viral gastroenteritis with the highest mortality and morbidity rates in children aged 0-5 years. The aim of this study was to determine the frequency of rotavirus infection in patients whose stool samples were sent to microbiology laboratory to investigate the etiology of diarrhea, to investigate the rotavirus genotypes that are common in our region and G10, G12 genotypes that have recently become common in the world. Fecal samples of 476 patients aged between 0-92 years who applied between November 2016 and February 2018 were studied via immunochromatographic rapid test and enzyme-linked immunosorbent assay (ELISA) methods. ELISA positive samples were studied by nested reverse transcriptase chain reaction (RT-PCR) and genotyped by agarose gel electrophoresis. Rotavirus was found positive in 18.3% and 17% of stool samples by immunochromatographic test and ELISA, respectively. All ELISA positive samples were also detected as positive by RT-PCR. 18.5% of female patients and 15.7% of male patients were found to be positive and rotavirus positivity was not statistically significant between genders. The frequency of rotavirus in different age groups was 23.5% (6-12 years), 17.3% (13-24 months) and 16% (25-36 months). It was determined that rotavirus cases were most common in the spring. G1, G2, G3, G4, G9, G10, and G12 were detected in 37%, 7.4%, 16.1%, 6.2%, 9.9%, 2.5%, 26% of the samples, respectively. G12 was the most common genotype after G1. The most common G and P genotype combination was G1P[8] (17.2%). This was followed by G12P[8] (11.11%) and G3P[8] (11.11%). P[8] (53%) was found to be the dominant P genotype. In this study, it was observed that rotavirus, which is the cause of childhood diarrhea, can also be encountered in advanced ages and even new genotypes that infect humans worldwide may also be the causative agents. Therefore, we concluded that it is important to investigate new genotypes such as G10 and G12 in molecular epidemiological studies.

Food protein-induced enterocolitis syndrome (FPIES) is an under-recognized and frequently misdiagnosed non-IgE-mediated gastrointestinal food hypersensitivity disorder. We describe the first case of FPIES only to wheat confirmed by an oral food challenge (OFC). The male patient, who was breast fed for the first 2 months, and then was feeding with cow's milk-based formula until he became 4.5 months old, was given a tarhana soup (wheat and yoghurt) for the initial food trial. Two hours later, he started retching and vomited consecutively, suffering from watery diarrhea. He was taken to a medical center, where he was diagnosed acute gastroenteritis. He suffered from three more episodes after feeding wheat-containing foods. When the patient was 12 months old, an OFC with wheat was performed. Two hours after he had been challenged, he vomited repetitively, became lethargic, his systolic blood pressure dropped from 95 to 80 mm Hg and stool examination revealed eosinophils and leukocytes, which were negative before the challenge. The serum eosinophil count decreased from 460 to 270 mu L and the neutrophil count increased from 2,200 to 10,500 mu L at 6 h. The skin prick test with wheat extract, prick to prick test with whole wheat and serum-specific Ig E for wheat were negative. We conclude that FPIES can emerge with food in connection with eating habits or culture. In view of its potentially serious clinical course, it is critical to consider this diagnosis in young children presenting with acute onset of gastrointestinal symptoms or shock.

To determine the accuracy of 2D shear-wave elastography (2D-SWE) in pediatric age group patients in differentiating clinically insignificant and significant liver fibrosis using METAVIR fibrosis scoring system as the gold standard. Liver biopsy has long been the gold standard in liver fibrosis diagnosis. However, due to probable complications and sampling variabilities, the need for more accurate and non-invasive techniques has increased. 2D-SWE is a non-invasive technique used in the evaluation of liver stiffness and utilized more and more in routine clinical practice with recent advances and researches. In this retrospective single-center study, we included 46 pediatric age group patients who had a liver parenchymal biopsy and 2D-SWE evaluation regardless of etiology. For 2D-SWE, the LOGIQ E9 system (GE Medical Systems, Wisconsin, USA) and, for histopathological evaluation, METAVIR fibrosis scoring system were utilized. Patients were further subgrouped as clinically insignificant (METAVIR Score F0–1) and significant (METAVIR Score F2–4). The Kolmogorov–Smirnov and Mann–Whitney U tests were employed for statistical analysis. The diagnostic accuracy of 2D-SWE was assessed, and cutoff values were set by ROC curve analysis. kPa values were statistically different between clinically significant and insignificant fibrosis patient groups (p

Poster-Abstract

Dysphagia is the most troublesome symptom of eosinophilic esophagitis (EoE). This study aimed to investigate oropharyngeal dysphagia in children with EoE and possible related factors. Children with a definite diagnosis of EoE were included in the study. Medical and feeding histories were recorded. A disease control level was determined for each child. An oral structure examination, the Turkish version of the Mastication and Observation Evaluation (T-MOE), the Pediatric version of the Eating Assessment Tool-10 (PEDI-EAT-10) and the 3-oz water swallow test were applied in screening for oropharyngeal dysphagia. Fifty-two children participated in the study. Oropharyngeal dysphagia took the form of abnormal swallowing (PEDI-EAT-10 score ≥ 4) and increased aspiration risk (PEDI- EAT-10 score ≥ 13) in 51.9% and 25.0% of the children, respectively. Seven children failed the 3-oz water swallow test. Abnormal swallowing and aspiration risk were significantly higher in children with prolonged mealtimes, impaired chewing function, and uncontrolled disease (p 0.05). Chewing function was the most important risk factor for abnormal swallowing and increased aspiration (R

Amac: Bu calismada; a kut pankreatit, akut tekrarlayan pankreatit ve kronik pankreatit tanisi ile izlenen cocuklarin klinik, laboratuvar ve etyolojik farkliliklarinin degerlendirilmesi amaclanmistir. Gerec ve Yontem: Ocak 2009 - Eylul 2018 tarihleri arasinda pankreatit tanisi ile izlenen cocuklar geriye donuk olarak degerlendirilmistir. Akut pankreatit tanisi, tipik karin agrisi, serum amilaz ve/veya lipaz duzeyinin normalden 3 kat veya daha fazla yuksek olmasi ve goruntuleme yontemlerinde akut pankreatit dusunduren bulgulardan 2 tanesinin bulunmasi ile koyulmustur. Akut tekrarlayan pankreatit; ataklar arasinda tum bulgularin tamamen normale dondugu 2 veya daha fazla atak olarak tanimlanmistir. Kronik pankreatit ise; tipik karin agrisi ile birlikte goruntulemede karakteristik bulgularin varligi veya ekzokrin veya endokrin pankreas yetmezligi ile birlikte goruntulemede karakteristik bulgular ile koyulmustur. Akut pankreatit (grup 1) ve akut tekrarlayan ve kronik pankreatit (grup 2) gruplari arasinda etyoloji, demografik ozellikler, laboratuvar ve radyolojik bulgular karsilastirilmistir. Bulgular: Akut pankreatit grubunda (grup 1) 21 hasta (%38,2) mevcuttur. Grup 2; akut tekrarlayan pankreatit tanisi alan 27 olgu ve kronik pankreatit tanisi ile izlenen 7 olgu icermektedir [toplam 34 olgu (%61,8)] . Pankreatitin sik gorulen nedenleri grup 1’de idiyopatik (%61,9) ve ilaclar (%19); grup 2’de ise idiyopatik (%47), herediter pankreatit (%17,6), pankreatikobiliyer bilesim anomalisi (%14,7) ve pankreatik kanalin konjenital anomalileridir (%8,8). Grup 2’deki gamma-glutamil transferaz yuksekligi disinda, iki grup arasinda demografik, klinik ve laboratuvar bulgulari acisindan istatiksel bir fark bulunmamistir. Sonuc: Calismamizda tum gruplarda cogunlukla pankreatitin nedeni tanimlanamamistir yani idiyopatiktir. Akut pankreatit olgularinda nedenler arasinda ikinci sirada ilaclar yer alirken, akut tekrarlayan pankreatit ve kronik pankreatitte sik gorulen diger nedenler pankreatikobiliyer bilesim anomalileri ve herediter nedenlerdir.

Introduction: Rotavirus infection is a major cause of morbidity and mortality in infants and young children with diarrhea throughout the world. Material and Methods: In this study, we aimed to determine the detection rate of rotavirus infection in 181 children less than 5 years of age presenting with acute gastroenteritis and admitted to a tertiary care hospital in Ankara, Turkey, from April to November 2012. We documented the epidemiological data by elucidating the prevalent genotypes. Stool specimens were collected, and rotavirus antigen in the samples was detected using ELISA. G and P genotypes were determined by RT-PCR via type specific primers. The nucleotide sequence of the concerned genes was determined by Sanger sequencing and phylogenetic analysis was performed by neighbor-joining method. Results: Of the 181 samples, 28 (15.5%) were positive for the rotavirus antigen. Twenty-seven samples were positive for G genotypes and 21 were positive for P genotypes. Genotypes G1 (7.1%), G2 (7.1%), G3 (7.1%), G4 (3.6%), G9 (71.5%) and P4 (3.6%), P8 (71.4%) were identified. Genotype G9P[8] (50%) was predominant in the combination of G and P genotypes. Most of the G9 strains of this study formed an independent cluster in Lineage III, except two strains which clustered with an Ethiopian G9 strain of 2012. Conclusions: It seems that during 2012 season, genotype G9P[8] increased significantly in Ankara due to a new circulating strain of G9.

Fabry disease results from deficiency of the lysosomal enzyme alpha-galactosidase A. The families of 11 index cases were screened by enzyme and molecular assays. Further clinical and laboratory investigations were carried out in all cases. Including 33 new patients, a total of 28 females (Age 25,82 ± 12,1 Range 8–46) and 16 males (Age 24,56 ± 15,04 Range 2–48) were investigated. Ten different disease-causing variants were found two of them being novel. One patient had co-existing familial mediteranian fever, one had celiac disease and three had rheumatological disorders. Lipoprotein (a) levels were elevated in 17,6%, homocysteine in 22,2%, total and low density cholesterol in 12% and antithrombin 3 levels were elevated in 13,3%. One patient was found to be heterozygous for prothrombin p.G20210A disease-causing variant (5,8%) and two for factor V Leiden disease-causing variant (11,7%). Anticardiolipin IgM antibody was found to be positive in 11,7%. The patients with abnormal cranial imaging were also noticed to have additional risk factors for thrombosis. This study provides the largest data about Fabry patients from Turkey and implies that co-existing risk factors unrelated to Fabry Disease have significant association with the presence of clinical symptoms in females and might cause an early and severe clinical course in males.

Both plasma and cerebrospinal fluid (CSF) are rich in cholesterol and its metabolites. Here we describe in detail a methodology for the identification and quantification of multiple sterols including oxysterols and sterol-acids found in these fluids. The method is translatable to any laboratory with access to liquid chromatography – tandem mass spectrometry. The method exploits isotope-dilution mass spectrometry for absolute quantification of target metabolites. The method is applicable for semi-quantification of other sterols for which isotope labelled surrogates are not available and approximate quantification of partially identified sterols. Values are reported for non-esterified sterols in the absence of saponification and total sterols following saponification. In this way absolute quantification data is reported for 17 sterols in the NIST SRM 1950 plasma along with semi-quantitative data for 8 additional sterols and approximate quantification for one further sterol. In a pooled (CSF) sample used for internal quality control, absolute quantification was performed on 10 sterols, semi-quantification on 9 sterols and approximate quantification on a further three partially identified sterols. The value of the method is illustrated by confirming the sterol phenotype of a patient suffering from ACOX2 deficiency, a rare disorder of bile acid biosynthesis, and in a plasma sample from a patient suffering from cerebrotendinous xanthomatosis, where cholesterol 27-hydroxylase is deficient., Graphical abstract Image 1, Highlights • Absolute quantification of oxysterols and cholestenoic acids. • Methodology applicable to plasma and cerebrospinal fluid. • Data generated for non-esterified and total sterols. • Diastereoisomers at C-24 and C-25 separated and quantified.

To evaluate the relationship between the severity of autism, severity of gastrointestinal symptoms and serum zonulin levels as a marker of increased intestinal permeability in children. Serum zonulin levels were determined in 56 children with ASDs and 55 healthy children. The severity of gastrointestinal symptoms and ASD symptoms was assessed with the Gastrointestinal Symptom Rating Scale (GSRS) and Childhood Autism Rating Scale (CARS), respectively. Serum zonulin levels were significantly higher than healthy controls in children with severe autism. A positive correlation was found between the CARS score, GSRS score and serum zonulin levels (r = ; P

It is well-known that in children with type 1 diabetes (T1D), the frequency of Celiac disease (CD) is increased due to mechanisms which are not fully elucidated but include autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is the gold standard for diagnosis, avoiding unnecessary endoscopy is crucial. Therefore, for both clinicians and patients’ families, the diagnosis of CD remains challenging. In light of this, a joint working group, the Type 1 Diabetes and Celiac Disease Joint Working Group, was convened, with the aim of reporting institutional data and reviewing current international guidelines, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tissue transglutaminase-immunoglobulin A (tTG-IgA) and/or endomysial-IgA antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors’ own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision for endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are seven times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD., NA

Objectives There are many unknowns about primary eosinophilic gastrointestinal disease (EGID) in childhood. The aim of this study is to provide data about the frequency, management, control level, and prognosis of well documented primary EGID in childhood. Methods This study was conducted in children who underwent endoscopy and/or colonoscopy at a single center over 10-year period up to August 2018. Primary EGID was diagnosed after exclusion of secondary EGID and classified as eosinophilic gastritis (EG), eosinophilic enteritis (EE), eosinophilic gastroenteritis (EGE: eosinophilic gastritis with eosinophilic enteritis) and eosinophilic colitis (EC) according to histopathological evaluation. The pathological number of eosinophil counts were accepted as >30 hpf for gastric mucosa in 5 hpf area, ≥20/hpf for duodenal, jejunal, and ileal mucosa, >50/hpf for right colonic mucosa, >35/hpf for transverse colonic mucosa, and >25/hpf for left colonic mucosa. Presenting symptoms, signs, management, follow-up, disease control level, and remission were analyzed. Remission is defined if the patient is controlled with all clinical, endoscopic/colonoscopic, and histopathologic parameters without any treatments or diet for at least a year. Results During the study period, 7457 biopsies were taken in 8262 endoscopy and/or colonoscopy procedures. Primary and secondary EGID frequencies were found 0.23% (n = 17 patients) and 0.1% (n =8 patients) per procedure with biopsy in children, respectively. Endoscopy/colonoscopy procedures were not able to performed in 9 patients because of short follow-up period (n = 6) or patients leaving follow-up (n = 3). Nine of the primary EGID patients had esophageal eosinophilia (EsE) at the time of diagnosis, 5 of them were previously managed as EoE. The median follow-up period of primary EGID patients excluding the ones without a control endoscopy/colonoscopy procedure was 3.35 years (min-max: 1.1-9.0 years). Proton pump inhibitors (PPI) were the most frequently used treatment alone or in combination with diet, systemic and/or topical corticosteroids. Disease control was evaluated in 8 of 17 patients and it was uncontrolled in 4, partially controlled in 1, and controlled in 3 patients. Remission was achieved in 2 patients. Conclusions The frequency of primary EGID beyond eosinophilic esophagitis (EoE) in children is low. It may be difficult to achieve control in children with primary EGID in the long-term follow-up.

Genomic analysis of families with unexplained portal hypertension reveals GIMAP5 as a critical regulator of liver sinusoidal endothelial cells and hepatic vascular homeostasis. This study identifies a novel genetic cause of portal hypertension and provides new insight into its pathogenesis., Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH). Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS. © 2019, American College of Medical Genetics and Genomics. Dietmar Hopp Stiftung: 23011235 Wellcome Trust: 210585/B/18/Z Jeffrey Modell Foundation S163/10052/2018 We thank Yoo-Mi Kim for providing additional, updated clinical information on patients NBAS 42 and NBAS 43 and John Christodoulou and Shanti Balasubramaniam for providing additional, updated clinical information on patient NBAS 63. Anne Davit Spraul is acknowledged for genetic diagnosis of patients NBAS 46 and NBAS 82, Oanez Ackermann and Dalila Habes are acknowledged for follow-up and Philippe Yakonowsky for his contribution to data collection of these patients. We thank Selina Wächter and Caterina Terrile for excellent technical assistance and Katharina Mayerhanser for organizational support. C.S. is supported by the Dietmar Hopp Foundation, St. Leon-Rot, Germany (grant number 23011235). D.L. is supported by the Deutsche Leberstiftung (grant number S163/10052/2018). J.A.C. is supported in part by the Jeffrey Model Foundation. R.B.R. and G.D.D. are supported by the Wellcome Trust grant 210585/B/18/Z (Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies).

Chronic granulomatous disease (CGD) is a primary immune deficiency that is commonly diagnosed under the age of 5 years (95%) and is rarely seen in adulthood. CGD may manifest as inflammatory bowel disease (IBD) in childhood. Without proper diagnosis, these patients may be monitored for years as IBD; some may even be regarded as steroid-resistant ulcerative colitis (UC) and end up having a colectomy. In this case report, we described a patient who had been followed-up for years as UC and subsequently underwent colectomy, but was finally diagnosed in adulthood as primary immune deficiency.

Ozcay, Figen/0000-0002-5214-516X; celikel, cigdem/0000-0002-9360-8116 WOS: 000604865800004 PubMed: 33398182 CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth. Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, BCBB Support Services [HHSN316201300006W/HHSN27200002]; Marmara University, Scientific Research Projects Committee (BAPKO)Marmara University [SAG-C-TUP-230119-0018]; NIAID Microbiome Program, NIAID, NIH; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-GM129325] This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, BCBB Support Services Contract HHSN316201300006W/HHSN27200002, and The Marmara University, Scientific Research Projects Committee (BAPKO, grant no. SAG-C-TUP-230119-0018). We thank the Turkish National Society of Allergy and Clinical Immunology (TNSACI) for supporting travel expenses for the screening studies. We thank C. Kemper of the National Heart, Lung and Blood Institute for thoughtful editing of the final manuscript. We thank M. Quinones, the Center for Human Immunology and the NIAID Microbiome Program, NIAID, NIH, for research support. We also thank A. Kiykim for patient care, A. Dalga and I. Tatli for technical assistance and H. Su and X. He for advice and assistance; D. Comrie, S. Kubo and J. Ravell for critical reading of the manuscript; and R. Kissinger for artwork. We thank important colleagues at Regeneron: A. N. Thomas for sample processing; C. Huang for biomarker analysis; H. Qiu, and E. Sook Yen for eculizumab analysis; and C. H. Lai, L. DeStefano and K. Donohue for total C5 analysis. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco, with support from NIH R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, NIAID.

Internal hernia through the foramen of Winslow is a very rare condition, especially in children. Here we report a 16-month-old girl who presented with obstructive jaundice and elevation of pancreatic enzymes and was ultimately diagnosed with internal hernia and malrotation by radiologic investigation and open approach surgery. To the best of our knowledge, obstructive jaundice with pancreatitis and other congenital abnormalities in children with the foramen of Winslow hernia have not been reported previously in the literature.

Recently, sirolimus was demonstrated to be effective in treating vascular lesions and lessening the frequency of bleeding and secondary iron deficiency anemia. We present a child with blue rubber bleb nevus syndrome who had prolonged history of iron deficiency anemia secondary to unrecognized gastrointestinal bleeding. Treatment with propranolol, omeprazole and iron had failed. After 2.5 months of sirolimus therapy (trough levels 1 to 5 ng/mL), his hemoglobin concentration improved into the normal range and remained stable. Vascular malformations on both the patient's tongue and in the fundus of his stomach shrank within 5 months of the initiation of sirolimus. In gastrointestinal involvement of blue rubber bleb nevus syndrome sirolimus was found to be effective even in the tongue's vascular lesions.

Objectives Our aim was to determine potentially adverse effects of immunosuppressive protocols after liver transplantation in children. Materials and methods The medical records of 60 children who underwent liver transplant retrospectively analyzed. Corticosteroid, tacrolimus, and mycophenolate mofetil were the primary immunosuppressive agents used in our center. Results The mean age of children was 6.1 years, ranging from 3 months to 17 years (34 boys, 26 girls). The most common indication for liver transplant was biliary atresia (26.7%). Thirty-nine patients (65%) received livers from living donors, and 21 patients (35%) received from livers from deceased donors. The main complications of immunosuppressive therapy were diarrhea associated with mycophenolate mofetil, hyperglycemia and hypertension associated with corticosteroid, and seizures and tremors associated with tacrolimus. Two patients developed post transplant lymphoproliferative disorder. The diagnosis was based on histologic findings of cervical lymphadenopathy and duodenal biopsy. One patient was diagnosed with acute lymphoblastic lymphoma. In addition to these predictable adverse effects, unusual adverse effects of immunosuppression were also observed. Hemolytic anemia (n = 3) (one was also diagnosed with Evans syndrome), eosinophilic gastroenteritis (n = 2), de novo food allergy (n = 2), posttransplant lymphoproliferative disorder (n = 2), Burkitt lymphoma (n = 1), and renal tubular acidosis (n = 1) were thought to be related to tacrolimus therapy. Conclusions Adverse effects of immunosuppression represent a major cause of postoperative morbidity. The common effects of immunosuppression are recognized easily by clinicians. It should be kept in mind that unexpected symptoms and signs may be related to immunosuppression in pediatric liver transplant patients.

BACKGROUND The aim of this study was to evaluate the effect of Helicobacter pylori (H. pylori) eradication on dyspepsia symptom scores in children with functional dyspepsia (FD). MATERIALS AND METHODS One hundred and fifty functional dyspeptic children (ages 8-18 years, mean: 13.3 ± 2.84 years; 30% male) were enrolled to this prospective study. Upper gastrointestinal endoscopy was performed on all patients, and the samples from the gastric antrum and corpus were obtained for the existence of H. pylori. 13 Carbon-urea breath test was performed to evaluate the eradication therapy's efficacy. The symptoms were assessed at first visit and at the 8th week and 16th week. RESULTS Forty-nine (33%) children were in the H. pylori-positive group, and 101 (67%) children were in the H. pylori-negative group. Dyspepsia symptom scores improved at 8th week in both groups (P

This article was unintentionally published twice in this journal, by the same authors. Following should be considered the version of record and used for citation purposes: "Mitui, M.T., Bozdayi, G., Dalgic, B. et al. Molecular characterization of a human group C rotavirus detected first in Turkey, Virus Genes (2009) 39, 2, 157-164, https://doi.org/10.1007/s11262-009-0420-8 ". The duplicate "Mitui, M.T., Bozdayi, G., Dalgic, B. et al. Molecular characterization of a human group C rotavirus detected first in Turkey, Virus Genes (2009), https://doi.org/10.1007/s11262-009-0381-y " is to be ignored. Springer apologizes to the readers of the journal for not detecting the duplication during the publication process.

Introduction: The aim of this retrospective study is to investigate the relationship between clinic and presence of Epstein-Barr virus (EBV) DNA and viral load by real-time polymerase chain reaction (PCR) in patients with high risk.Methods: A total of 168 samples obtained from 160 patients, hospitalized in Gazi University Hospital between March 2014 and May 2015, were included in the study. EBV antibodies were investigated by ELISA (Dia.Pro, Milano, Italy) in clinical samples of patients, and serological profiles of patients were determined. Nucleic acid isolation was performed by High Pure Viral Nucleic Acid Kit (Roche, Germany). Isolated DNAs were amplified by LightCycler® EBV Quantitative Kit (Roche, Germany) in LightCycler 2.0 (Roche, Germany) device, and results were evaluated quantitatively.Results: EBV DNA was positive for 4.2% (7/168) of the samples. The distributions of positive rates were 14.2% (1/7) for oncology, 12.5% (1/8) for intensive care units, 4.8% (4/42) for pediatric gastroenterology, and 4.1% (1/24) for pediatric hematology. Three of the patients that EBV DNA detected had liver transplant, one had non-Hodgkin’s lymphoma, one had Burkitt’s lymphoma, one had acute renal failure, and one had gingivostomatitis and pharyngotonsillitis while follow-up. In 6/7 of the samples, EBV DNA detected 104 copies/ml, and 1/7 of the samples 105 copies/ ml. The patient whose EBV DNA load was 105 copies/ml had Burkitt’s lymphoma. EBV DNA and viral capsid antigen IgM positive were detected simultaneously only in one patient (17%).Conclusion: Early diagnosis by real-time PCR is of great importance in terms of follow-up of patients by monitoring DNA amounts and prognosis. Therefore, in immunosuppressive patients who have high levels of EBV DNA, Burkitt’s lymphoma disease should be considered.

Congenital diarrheal disorders are caused by disruption in nutrient digestion, absorption, or transport, enterocyte development and functioning, or enteroendocrine functioning. Many additional rare forms of congenital diarrhea are expected to be linked to genes associated with appropriate intestinal fluid and electrolyte balance. Neurogenin-3 mutation, a very rare form of congenital diarrhea, disrupts enteroendocrine cell differentiation and is characterized by malabsorption and the absence of pancreatic islet cells. Diabetes mellitus is typically associated with malabsorptive diarrhea at early onset or at later presentation in neurogenin-3 mutation. Here, we describe the case of an infant with homozygous neurogenin-3 mutation who had severe malabsorptive diarrhea and episodes of hyperchloremic metabolic acidosis after birth. Remarkably, cholestyramine was effective at reducing stool volume and frequency and improved the consistency of the stools; diabetes was not present in this patient.

Human protothecosis is a rare microalgae infection, and its dissemination typically occurs in immunocompromised individuals, but no specific immune defect has been reported. Here, we describe an 8-year-old daughter of a consanguineous union with abdominal pain and bloody diarrhea for 3 months who was found to have pancolitis with numerous microalgae identified as Prototheca zopfii. In the absence of a known immunodeficiency, exome sequencing was performed, which uncovered a novel recessive frameshift mutation in CARD9 (p.V261fs). This report highlights that CARD9 deficiency should be investigated in patients with unexplained systemic/visceral protothecosis and suggests a new mechanistic insight into anti-Prototheca immunity.

The link between Helicobacter pylori and iron deficiency (ID) or iron deficiency anemia (IDA) has been investigated recently. We suggested that IDA/ID associated with H. pylori infection might be mediated by inflammation-driven hepcidin production. Patients with complaints of recurrent abdominal pain and dyspepsia aged between 7-16 years were included in this study. Patients were divided into two groups according to H. pylori status in upper gastrointestinal endoscopy. Group I who had H. pylori gastritis (n = 50) received triple antibiotic therapy. Group II (n = 50) who had H. pylori-negative gastritis only received proton pump inhibitor. Thirty healthy children with the similar age and gender were included in the study as a control group. Complete blood count, serum iron levels, iron-binding capacity, ferritin levels, prohepcidin and interleukin-6 (IL-6) values were evaluated in all children at the first visit. Initial tests were repeated after H. pylori eradication. Initial levels of ferritin (p = 0.002), prohepcidin (p = 0.003), and IL-6 (p = 0.004) were found significantly lower in group I compared to group II and the control group. The mean prohepcidin level was lower in the anemic H. pylori-positive group than in non-anemic H. pylori-positive group; however, the difference was not statistically significant. While significant increases in hematocrit and mean corpuscular volume were observed, no significant difference was found in serum ferritin, prohepcidin, or IL-6 level after eradication treatment in H. pylori-positive group. Conclusion: H. pylori-induced gastritis appears to cause an increase in prohepcidin levels and a decrease in ferritin levels, supporting our hypothesis; but this relationship has not been proven.

BACKGROUND: As being the first bacteria determined to be carcinogenic, Helicobacter pylori (H. pylori) is a pathogen localized in the stomach in more than half of the world population. Some earlier studies have found a relation between tissue histocompatibility antigens and gastric cancers depending on the regions. OBJECTIVE: The present study aimed to determine the distribution of human leukocyte antigen (HLA) class I and class II antigens in H. pylori-positive pediatric patients with active gastritis and duodenal ulcer, excluding cancer cases, in our center. METHODS: The study included 40 patients diagnosed with H. pylori-positive active gastritis and duodenal ulcer and 100 controls consisting of healthy donor candidates. The HLA class I and class II antigens were studied in the isolated DNA samples using the polymerase chain reaction sequence-specific oligonucleotide probes. RESULTS: The frequency of HLA-B*51 antigen was significantly higher in the patient group than in the control group (40% vs 17%; P=0.003). There was no difference between the two groups in terms of the frequencies of HLA-A, HLA-C, HLA-DR, and HLA-DQ antigens. CONCLUSION: It was determined that HLA-B*51 plays a critical role in H. pylori infection. RESUMO CONTEXTO: Determinada como sendo a primeira bactéria cancerígena, o Helicobacter pylori (H. pylori) é um patógeno localizado no estômago em mais da metade da população mundial. Alguns estudos anteriores têm encontrado uma relação entre câncer gástrico e antígenos de histocompatibilidade de tecido dependendo das regiões. OBJETIVO: O presente estudo teve como objetivo determinar a distribuição em nosso centro do antígeno leucocitário humano (HLA) de classe I e antígenos classe II em pacientes pediátricos H. pylori-positivos com gastrite e úlcera duodenal ativas, excluindo casos de câncer. MÉTODOS: O estudo incluiu 40 pacientes H. pylori-positivos diagnosticados com gastrite e úlcera duodenal ativas e 100 controles consistindo de candidatos doadores saudáveis. Foram estudadas nas amostras de DNA isoladas o antígeno leucocitário humano classe I e antígenos classe II, utilizando-se as cadeias de sequência específica de polimerase do oligonucleotideo. RESULTADOS: A frequência do antígeno HLA - B * 51 foi significativamente maior no grupo de pacientes do que no grupo controle (40% vs 17%; P=0,003). Não houve diferença entre os dois grupos em termos das frequências dos antígenos HLA-A, HLA-DR, HLA-DQ e HLA-C. CONCLUSÃO: Determinou-se que o HLA - B * 51 desempenha um papel crítico na infecção pelo H. pylori.

p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen gamma. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB-lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.

Introduction LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency categorized as common variable immunodeficiency associated with autoimmune manifestations and inflammatory bowel diseases; however, the clinical spectrum has been extended. Here, we present our cohort of Turkish LRBA-deficient patients from a single center, demonstrating a diversity of clinical manifestations. Method Seven affected individuals from five families were assessed retrospectively in this study. Results Of the seven patients with LRBA deficiency, four had homozygous, and two had compound heterozygous mutations. One patient remained disease free until the last follow-up (age 17 years). The most common clinical manifestations of the six symptomatic patients were organomegaly (6/6), autoimmunity (6/6), and chronic diarrhea (5/6). Recurrent infectious episodes were observed in three patients. None of the patients had hypogammaglobulinemia at presentation. B cell subpopulation analysis revealed low numbers of switched-memory B cell numbers in two of the four tested patients. During the disease course, three of the patients died, two of them underwent successful hematopoietic stem cell transplantation (HSCT) from matched sibling donors, and one is under abatacept therapy. Conclusion LRBA defects should always be kept in mind as a differential diagnosis for patients with autoimmune disease affecting multiple organs, chronic diarrhea, and organomegalies. In our experience, early HSCT is a life-saving therapeutic strategy.

OBJECTIVES The clinical importance and etiology of colonic lymphoid nodular hyperplasia (LNH) are not clear. It has been considered a response to some antigenic stimuli. Although food allergies, infections, inflammatory bowel diseases, and immunodeficiencies may be listed in the etiology of colonic LNH, the etiology has remained unclear in many cases. This study investigated the etiology of colonic LNH and its relation to familial Mediterranean fever (FMF) in children. FMF as an etiologic factor for colonic LNH has not been reported before in the literature. METHODS Medical files of patients who underwent colonoscopy between 2007 and 2011 were examined retrospectively. Demographic features, presenting symptoms, colonoscopy indications, colonoscopic findings, and final diagnoses of patients were evaluated. According to etiologies, patients with colonic LNH were divided into 2 groups: group A consisted of patients with FMF and group B consisted of diseases other than FMF. RESULTS A total of 311 patients were included in the study. Forty (12.6%) patients had isolated colonic LNH. In 23 (57.5%) patients, isolated LNH was observed in some colonic segments and total colonic LNH was noted in 17 (42.5%) patients. FMF was the etiologic factor in 6 (15%) patients. Thirty-four patients (85%) had etiologic factors other than FMF. We did not find any etiologic factor for LNH in 3.53% (11/311) of patients. CONCLUSIONS FMF may be an etiologic factor for colonic LNH in children besides food allergies, infections, inflammatory bowel diseases, and immunodeficiencies.

BACKGROUND AND OBJECTIVES: Familial Mediterranean fever (FMF) and inflammatory bowel disease togetherness is well described in the literature. Abdominal pain and various gastrointestinal manifestations may arise directly from FMF or secondary to FMF-associated diseases such as inflammatory bowel disease, vasculitidies, or amyloidosis. The aim of the study was to document gastrointestinal involvement in familial Mediterranean fever. METHODS: The medical files of the patients who were diagnosed as having FMF at the Department of Pediatric Gastroenterology, Gazi University School of Medicine between 2007 and 2012 were examined retrospectively. FMF diagnosis was made through performing clinical, laboratory, colonoscopy, endoscopy, and genetic analysis. RESULTS: Thirty-six patients were diagnosed as having FMF during this period. Among them, 11 patients were admitted with vomiting or diarrhea. Colonoscopy and upper gastrointestinal endoscopy were performed. Colonic inflammation and multiple gastric aphthous ulcerations were observed. CONCLUSIONS: In this report, we described 11 patients who presented with gastrointestinal symptoms and eventually diagnosed as having FMF. Gastrointestinal mucosal involvement without amyloidosis is documented by endoscopic and histopathologic investigations in these patients. We concluded that mucosal involvement of the gastrointestinal tract may be attack-related manifestations in these patients.

Cytomegalovirus infection can cause gastrointestinal disease, especially in immunocompromised patients and premature infants. In the neonatal period, however, gastrointestinal involvement is infrequent. A case of cytomegalovirus enteritis and jejunal stricture in a preterm neonate is presented. The diagnosis was established after the histopathology of the surgical specimen demonstrated the presence of cytomegalovirus inclusion bodies. Every neonatal gastrointestinal cytomegalovirus infection case has been described in the literature as a necrotizing enterocolitis-like illness, but none of them clearly identifies whether cytomegalovirus was the pathogen responsible for causing necrotizing enterocolitis or whether cytomegalovirus occured as an infection during the course of necrotizing enterocolitis.

Yüce A, Dalgıç B, Çullu-Çokuğraş F, Çokuğraş H, Kansu A, Alptekin-Sarıoğlu A, Şekerel BE. Cow`s milk protein allergy awareness and practice among Turkish pediatricians: A questionnaire-survey. Turk J Pediatr 2017; 59: 233-243. Region-specific recommendations for the prevention, diagnosis, and treatment of cow`s milk protein allergy (CMPA) are not available in Turkey. This cross-sectional questionnaire-survey was designed to evaluate CMPA awareness and practice among Turkish pediatricians. A total of 410 pediatricians were included based on their voluntary participation. Questionnaires elicited demographic data and pediatricians` awareness and practice of CMPA in infants and children. Atopic dermatitis (91.5%), diarrhea (88.0%) and significant blood in stool (85.9%) were the most common symptoms considered suggestive of CMPA. Continuation of breast feeding via elimination of CMP containing products from maternal diet was the most commonly selected (79.0%) therapeutic option in exclusively breast-fed infants diagnosed with CMPA. Amino acid-based formula was the most commonly selected formula in a non-exclusively breast-fed infant with CMPA, for infants presenting with anaphylaxis (58.8%), enterocolitis (40.7%) or multiple food allergies (52.0%), and also for at-risk infants (40.2%). Earliest time to re-challenge was identified to be 6 months by 52.0% of pediatricians. In conclusion, our findings revealed high awareness of CMPA among Turkish pediatricians in terms of clinical presentation and first priority diagnostic tests. However, CMPA practice among Turkish pediatricians needs to be improved in terms of avoidance of other mammalian milks, selection of therapeutic formulas among non-exclusively breast-fed infants and at-risk infants consistent with guideline-based indications and cost-effectivity.