Chromosomal Numerical Aberrations and Rare Copy Number Variation in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numerical and structural chromosomal abnormalities. METHODS: We performed a systematic literature search of databases PubMed and Embase; and analysed gnomAD, Clinvar, the 100 000 Genomes Project, and DECIPHER databases. Further, we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility. RESULTS: A meta-analysis suggests that monosomy X [Turner syndrome] is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% confidence interval [CI] 1.48 to 2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low [<2.6%]. CONCLUSIONS: Turner syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.

Acute Infectious Gastroenteritis in Infancy and Childhood.

BACKGROUND: Despite the introduction of vaccination against rotavirus, and even though it can often be treated on an outpatient basis, acute infectious gastroenteritis is nevertheless the second most common non-traumatic cause of emergency hospitaliza - tion in children aged 1 to 5 years, accounting for approximately 9% of cases (39 410 cases in 2017). The most common path - ogens are viruses (47% rotavirus, 29% norovirus, and 14% adenovirus). METHODS: This review is based on publications retrieved by a selective search in PubMed employing the terms "acute gastro - enteritis children" AND "dehydration" OR "rehydration" OR "prevention," and by manual searching (based, for example, on reference lists and expert knowledge), with subsequent evaluation including consideration of the relevant guidelines. RESULTS: The degree of dehydration can be judged from weight loss and other clinical findings. In 17 randomized controlled trials conducted on a total of 1811 children with mild or moderate dehydration, oral rehydration with oral rehydration solution was just as effective as intravenous rehydration with respect to weight gain, duration of diarrhea, and fluid administration, and was associated with shorter hospital stays (weighted mean difference, -1.2 days; 95% confidence interval [-2.38; -0.02]). Oral rehydration therapy failed in 4% of patients [1; 7]. In children who are vomiting or who refuse oral rehydration solution, continuous nasogastric application is just as effective as intravenous rehydration and is the treatment of first choice. CONCLUSION: In Germany, children with mild or moderate dehydration are often hospitalized for intravenous rehydration therapy, despite the good evidence supporting ambulatory oral rehydration. Obstacles to intersectoral care, the nursing shortage, and inadequate reimbursement must all be overcome in order to reduce unnecessary hospitalizations and thereby lessen the risk of nosocomial infection.

Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency.

Inflammatory bowel disease (IBD) in young children can be a clinical manifestation of various primary immunodeficiency syndromes. Poor clinical outcome is associated with poor quality of life and high morbidity from the complications of prolonged immunosuppressive treatment and malabsorption. In 2012, mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified as the cause of an autoimmunity and immunodeficiency syndrome. Since then, several LRBA-deficient patients have been reported with a broad spectrum of clinical manifestations without reliable predictive prognostic markers. Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been performed in a few severely affected patients with complete or partial response. Herein, we present a detailed course of the disease and the transplantation procedure used in a LRBA-deficient patient suffering primarily from infantile IBD with immune enteropathy since the age of 6 weeks, and progressive autoimmunity with major complications following long-term immunosuppressive treatment. At 12 years of age, alloHSCT using bone marrow of a fully matched sibling donor-a healthy heterozygous LRBA mutant carrier-was performed after conditioning with a reduced-intensity regimen. During the 6-year follow-up, we observed a complete remission of enteropathy, autoimmunity, and skin vitiligo, with complete donor chimerism. The genetic diagnosis of LRBA deficiency was made post-alloHSCT by detection of two compound heterozygous mutations, using targeted sequencing of DNA samples extracted from peripheral blood before the transplantation.

Bowel preparation in pediatric colonoscopy: results of an open observational study.

BACKGROUND AND STUDY AIMS: The goal of this study was to analyze the bowel cleansing methods currently used for pediatric colonoscopy in terms of effectiveness, tolerance and safety. PATIENTS AND METHODS: Data from 768 colonoscopies reported by 28 centers were registered in an online database for further analysis. Binary logistic regression was used to determine how preparation methods affected the cleaning effect (Aronchick score) and the rate of adverse events (Aes) and complications. RESULTS: The most frequently reported cleansing agents were sodium picosulphate (54.2 %) and polyethylene-glycol (41.3 %) in various combinations. The cleaning effect was good to excellent in 72.6 % of patients. AEs during the preparation period occurred in 21.5 % of patients. Complications during endoscopy were reported in 12.1 % and were mostly mild. The different agents had no influence on the cleaning effect. In contrast the risk of AEs during preparation was significantly increased when polyethylene-glycol was used (odds ratio (OR) 2.112, P = 0.002) but reduced with the use of sodium picosulphate (OR 0.380, P < 0.001). In particular, the risk of needing a nasogastric tube to complete clean-out was about 10-fold higher when polyethylene-glycol was used. CONCLUSIONS: A large variety of regimens are used for bowel preparation in children. We found a good overall cleaning result independent of the agents used. Cleansing agents, on the other hand, had a significant influence on tolerance and safety.

Inflammatory bowel disease in pediatric patients: Characteristics of newly diagnosed patients from the CEDATA-GPGE Registry.

BACKGROUND: Inflammatory bowel disease (IBD) can arise at any age, with peak incidence in adolescence and young adulthood. A registry of pediatric cases of IBD offers the opportunity to document their diagnosis and treatment, with the ultimate aim of improving diagnosis and treatment in the future. METHODS: In the German-language CEDATA-GPGE registry, 3991 cases of IBD in patients less than 18 years of age were documented from 2004 to 2014. The 1257 patients who were prospectively included in the registry upon diagnosis and whose further course was documented for at least three months were analyzed in two separate groups--under 10 years old, and 10 years and above--with respect to the type and duration of their symptoms until diagnosis, the completeness of the diagnostic evaluation, the disease phenotype, and the initial treatment. RESULTS: Of the 958 patients for whom full documentation was available, 616 (64.3%) had Crohn's disease (CD), 278 (29%) had ulcerative colitis (UC), 64 (6.7%) had an unclassified IBD, and 23.2% were under 10 years old. The latency to diagnosis was longer for CD than for UC (0.5 versus 0.3 years), regardless of age. 62.5% of the CD patients had ileocolonic involvement, and more than half had involvement of the upper gastrointestinal tract. 71% of the patients with UC had subtotal colitis or pancolitis. Continuous improvement was seen in diagnostic assessment according to published guidelines. For example, in 2004/2005, 69% of patients were evaluated endoscopically with ileocolonoscopy and esophagogastroduodenoscopy; this fraction had risen to nearly 100% by 2013/2014. Similarly, the percentage of patients who underwent a diagnostic evaluation of the small intestine, as recommended, rose from 41.2% to 60.9% over the same period. The most common initial treatments were 5- amino - salicylates (86.8% CD, 100% UC) and glucocorticoids (60.6% CD, 65.6% UC). 32% of the patients with CD received exclusive enteral nutrition therapy. CONCLUSION: Most of these pediatric patients with IBD, whether in the younger or the older age group, had extensive bowel involvement at the time of diagnosis. The registry data imply that improvement in clinical course may be achieved by shortening the time to diagnosis and by closer adherence to the diagnostic and therapeutic guidelines.

Predicting weight loss and maintenance in overweight/obese pediatric patients.

BACKGROUND: Pediatric lifestyle interventions have positive short-term effects on obese patients. Studies on long-term effects are still scarce in Europe. We investigated long-term weight patterns and sociodemographic predictors of a weight change in a large Central European (Germany, Austria and Switzerland) overweight pediatric cohort. METHODS: The APV (Adiposity Patients Verlaufsbeobachtung) database was retrospectively analyzed; 157 specialized childhood obesity centers contributed standardized data of 29,181 patients [body mass index (BMI) ≥ 90th percentile; 5-25 years old] presenting between 2000 and 2012. BMI standard deviation scores (BMI-SDS) were analyzed in a 2-year follow-up and grouped according to BMI-SDS changes. Multiple logistic regression analyses were conducted to assess associations between sociodemographic factors and weight patterns. RESULTS: 2-year follow-up data were available in 3,135 patients (54.6% female). Five distinct weight trajectories 'rapid weight loss' (n = 735, 23.4%), 'delayed success' (n = 697, 22.2%), 'cycling weight' (n = 43, 1.4%), 'initial weight loss' and 'weight rebound' (n = 383, 12.2%) and 'no weight loss throughout' (n = 1,277, 40.7%) best characterized long-term BMI-SDS changes. Younger and male patients were more likely to reduce weight and maintain weight loss. CONCLUSIONS: Our results suggest that an intervention before the onset of puberty seems promising for long-term weight maintenance in overweight children. Thus, new concepts are needed to improve long-term treatment success in patients with lower success rates.

Mutations in the human UBR1 gene and the associated phenotypic spectrum.

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.

Does obesity lead to a specific lipid disorder? Analysis from the German/Austrian/Swiss APV registry.

Overweight and obese youth represent a challenge for the affected individual, the healthcare system as well as society as a whole. Increased long-term cardiovascular risk is one of the major consequences of early-onset obesity, affecting both life expectancy and quality of life. The aim of this report is to study the effects of age, gender and obesity category on the presence of individual components of dyslipidemia using normal-weight subjects from the population-based German KIGGS study including 17,641 randomly selected children and adolescents, aged 0-18 years (11,110 normal-weight subjects with lipid measurements) and the German-Austrian-Swiss APV registry, including 57,239 overweight or obese children, adolescents and young adults from 162 specialized obesity care centers (lipid measurements available in 29,711 subjects). Subjects were classified according to BMI category based on the age- and gender-adjusted BMI-z-scores as recommended by the AGA (German Pediatric Obesity working group). Cut-offs for dyslipidemia were based on the recommendations by the American Heart Association: total cholesterol: > 5.2 mmol/l, HDL-cholesterol < 0.9 mmol/l, LDL-cholesterol > 3.4 mmol/l, triglycerides > 1.7 mmol/l. Using SAS 9.2-software, hierarchic modeling with both linear and logistic regression analysis was applied. Within the group of normal-weight children, fasting triglycerides were elevated in 3.3%, LDL-cholesterol in 7.2% and HDL-cholesterol was reduced in 3.1%. With increasing BMI-category, the prevalence of hypertriglyceridemia and reduced HDL-cholesterol increased rapidly. A weaker relationship was present for LDL-cholesterol and total cholesterol. Among obese youth, 30.5% displayed any dyslipidemia, underlining the importance of adequate screening and intervention.

Childhood onset inflammatory bowel disease: predictors of delayed diagnosis from the CEDATA German-language pediatric inflammatory bowel disease registry.

OBJECTIVES: To examine predictors of delayed diagnosis of inflammatory bowel disease in children and adolescents. STUDY DESIGN: A total of 2,436 patients (age 0-18 years) with Crohn's disease, ulcerative colitis, or unclassified colitis were included from 53 pediatric gastroenterologists. Predictors were examined with the proportional hazards model, presented as hazard ratios (HR) with 95% confidence intervals. HR < 1.0 represent factors associated with late diagnosis. RESULTS: Median time to diagnosis was 4 (2-8) months. Crohn's disease (HR 0.62; 0.56-0.68), and within Crohn's disease, ileal disease (HR 0.77, 95% confidence interval 0.67 to 0.89) were associated with delayed diagnosis. Chances for early diagnosis increased with increasing age (HR 1.07 per year of age; 1.06 to 1.08). There was also an effect by center (HR 0.63, 0.52 to 0.67), but not by sex or country (Austria vs Germany). Growth failure was more common in those cases with delayed diagnosis. CONCLUSIONS: There is still concern about delays in the diagnosis of inflammatory bowel disease in the very young and in children with small bowel disease. Inequalities of care by region require further investigation.

Prevalence and specificity of antigastric autoantibodies in adolescents infected with Helicobacter pylori.

OBJECTIVES: Antigastric autoantibodies (AGA) can be detected in as many as 50% of adults infected with Helicobacter pylori. We investigated H pylori -associated antigastric autoimmunity in children and adolescents. STUDY DESIGN: Patients with dyspepsia (n = 78; mean age 10.9 years, range 2-21 years, SE 0.46 years) underwent gastroscopy. H pylori infection was determined by serologic and histologic features and breath tests. AGA were detected by immunohistochemistry and were characterized by immunoprecipitation with the gastric hydrogen ion, potassium ion, adenosine triphosphatase (H(+),K(+)-ATPase). In absorption assays, antibodies against H pylori were removed to determine the role of molecular mimicry. RESULTS: AGA were detected in 9 (18%) of the 51 infected patients and in 1 (4 %) of the 27 noninfected patients (P =.08; nonsignificant) and could not be absorbed to H pylori. Children with AGA were significantly older (P =.01). AGA in H pylori gastritis reacted against the gastric H(+),K(+)-ATPase in 3 (33%) of the 9 patients. CONCLUSIONS: The age of the patient or the duration of gastritis seem to be relevant factors for the formation of antigastric autoimmunity. The gastric H(+),K(+)-ATPase represents an autoantigen as early as childhood. No evidence for a role of molecular mimicry between H pylori and the host at this young age could be found.