Background and Aims
Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the ...clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant‐free survival, extrahepatic manifestations may cause relevant morbidity.
Methods
We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited.
Results
Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver‐associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT.
Conclusion
The spectrum of extrahepatic manifestations in PFIC highlights essential, non‐redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health‐related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.
Abstract
Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of ...infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07–0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase–AKT–mTOR pathway mitigates the detrimental synergistic effects of combined PTEN–BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.
Graphical Abstract
Graphical Abstract
This study was performed to determine the rate of Helicobacter pylori reinfection after its successful eradication in children living in Germany.
A total of 102 children (48 boys; 31 German and 71 ...other nationalities; age 1.8-18 years) with a negative (13)C-urea breath test 8 weeks after triple therapy were followed up by a (13)C-urea breath test every 6 months. The cohort included 11 children aged <6 years, 58 children aged > or =6 to 12 years, and 33 children > or =12 years.
The mean duration (+/- standard deviation) of follow-up was 15.5 +/- 11.9 months with a maximum of 4.9 years, representing 132 patient years. Only three children (aged 9.7-14.9 years, one German, two Turkish) tested positive at 6, 12, and 18 months, respectively. The calculated reinfection rate was 2.3% per person per year.
The risk of reinfection with H. pylori is low in children living in Germany. There is no evidence that the reinfection rate depends on the age, sex, or nationality of the child. The low reinfection rate indicates that it is unnecessary to screen or treat asymptomatic family members in order to prevent reinfection.
The number of inconspicuous results of esophagogastroduodenoscopies (EGDs) in childhood appears to be disturbingly high. The aim of this study was to analyze the diagnostic yield of EGD and to ...determine its relevance of specific clinical indications.
We performed a retrospective analysis of 380 consecutive pediatric patients who underwent diagnostic EGD in two German level I pediatric gastroenterology departments in 2015 and 2016.
44% of the 380 patients were male and 17% were younger than 5 years old. 55% of all EGDs (n=210) did not yield a pathological result. 27% (n=104) of all EGDs were performed due to nonspecific symptoms (epigastralgia, nausea). Strikingly, in this group, 88% (n=91) showed normal results and in only 12% a diagnosis was made: reflux esophagitis (n=5), Helicobacter pylori (HP) gastritis (n=6) or hemorrhagic gastritis (n=1). Fewer inconspicuous EGDs were performed in patients with dysphagia (68%) or heartburn and reflux (61%). 59 patients were examined due to serologically elevated celiac antibodies. Here, the diagnosis could be confirmed histopathologically in 78% (n=46). Of the 37 patients with abdominal pain and a previously positive non-invasive HP test, EGD served to establish the diagnosis of HP gastritis in 84%.
The diagnostic yield for EGDs is increased in patients with more specific symptoms (i. e. dysphagia, heartburn, HP, celiac disease). Consequently, as an invasive procedure, EGD warrants a strict indication.
Microvillus inclusion disease (MVID) is a congenital enteropathy characterized by accumulation of vesiculo‐tubular endomembranes in the subapical cytoplasm of enterocytes, historically termed ...“secretory granules.” However, neither their identity nor pathophysiological significance is well defined. Using immunoelectron microscopy and tomography, we studied biopsies from MVID patients (3× Myosin 5b mutations and 1× Syntaxin3 mutation) and compared them to controls and genome‐edited CaCo2 cell models, harboring relevant mutations. Duodenal biopsies from 2 patients with novel Myosin 5b mutations and typical clinical symptoms showed unusual ultrastructural phenotypes: aberrant subapical vesicles and tubules were prominent in the enterocytes, though other histological hallmarks of MVID were almost absent (ectopic intra‐/intercellular microvilli, brush border atrophy). We identified these enigmatic vesiculo‐tubular organelles as Rab11‐Rab8‐positive recycling compartments of altered size, shape and location harboring the apical SNARE Syntaxin3, apical transporters sodium‐hydrogen exchanger 3 (NHE3) and cystic fibrosis transmembrane conductance regulator. Our data strongly indicate that in MVID disrupted trafficking between cargo vesicles and the apical plasma membrane is the primary cause of a defect of epithelial polarity and subsequent facultative loss of brush border integrity, leading to malabsorption. Furthermore, they support the notion that mislocalization of transporters, such as NHE3 substantially contributes to the reported sodium loss diarrhea.
Microvillus Inclusion Disease (MVID) is a fatal hereditary diarrheal disorder caused by Myosin 5b or Syntaxin3 mutations, characterized by facultative brush border atrophy and pathological accumulation of vesiculo‐tubular endomembranes in the small intestinal enterocytes of neonates. Here we identified these ill‐defined, subapical organelles as aberrant Rab11‐Rab8‐positive recycling compartments, harboring pivotal apical membrane proteins. This provides further substantial evidence for the concept of disrupted apical traffic and mistargeting of apical transporters as the primary cause of diarrhea and malabsorption in MVID.
Peginterferon plus ribavirin is standard therapy for adults with chronic hepatitis C. As no data are available for children, the aim of the study was to evaluate the efficacy and tolerability of ...peginterferon alfa-2b in combination with ribavirin in chronically infected children. Genotypes, alanine aminotransferase levels, and different routes of viral transmission were considered. In an open-labeled, uncontrolled pilot study, 62 children and adolescents (range, 2-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 microg/kg body weight once per week plus oral ribavirin (15 mg/kg x day) for 48 weeks. Sixty-one patients completed the study. Twenty-three children discontinued therapy after 6 months according to study protocol. Sustained viral response was documented in 22 (47.8%)of 46 patients with genotype 1, in 13 (100%) of 13 with genotype 2 or 3, in 1 of 2 with genotype 4, in 19 (70.4%) of 27 children with parenteral, in 12 (48%) of 25 with vertical, and in 5 of 9 with unknown route of infection. Overall, treatment was well tolerated. Nevertheless, some side effects were present in all treated patients. Eighty-three percent had leucopenia, but only 3 individuals required dose reduction and 10.3% developed thyroid autoantibodies and thyroid dysfunction. In conclusion, combination treatment of peginterferon alfa-2b with ribavirin showed encouraging results and was well tolerated in children and adolescents with chronic hepatitis C. Weekly dosing of peginterferon alfa-2b is a considerable advance for this age group. The treatment is not approved for children. Further controlled trials are needed.
ObjectiveWe describe school performance and experience in children with inflammatory bowel disease (IBD) across Germany and Austria. Predictors of compromised performance and satisfaction were ...evaluated to identify subgroups of increased risk.DesignThis cross-sectional analysis was based on a postal survey in children aged 10–15 with Crohn’s disease, ulcerative colitis or unclassified IBD and their families. Multivariate regression analysis was used to assess influential factors on parental satisfaction with school, attending advanced secondary education (ASE), having good marks and having to repeat a class. Satisfaction was assessed based on the Child Healthcare–Satisfaction, Utilisation and Needs instrument (possible range 1.00–5.00).ResultsOf 1367 families contacted, 675 participated in the study (49.4%). Sixty-eight participants (10.2%) had repeated a year, 312 (46.2%) attended ASE. The median school satisfaction score was 2.67 (IQR 2.00–3.33). High socioeconomic status (SES) and region within Germany were predictive for ASE (OR high SES 8.2, 95% CI 4.7 to 14.2). SES, female sex and region of residence predicted good marks. Grade retention was associated with an active disease course (OR 2.7, 95% CI 1.4 to 5.3) and prolonged periods off school due to IBD (OR 3.9, 95% CI 1.8 to 8.6).ConclusionsA severe disease course impacted on the risk of grade retention, but not on type of school attended and school marks. Low satisfaction of parents of chronically ill children with the school situation underlines the need for a more interdisciplinary approach in health services and health services research in young people.
Aim: Genome‐wide association studies have described an association of the ATG16L1 (autophagy 16‐like 1) gene rs2241880 variant with Crohn’s disease (CD). Therefore, we evaluated this polymorphism in ...early‐onset CD in 152 children and 253 controls and for the first time determined ATG16L1 colonic expression in German CD children.
Methods: Investigation of rs2241880 allele frequencies using a predesigned single nucleotide polymorphism genotyping assay. Analysis of digenic epistasis between rs2241880 and the three common nucleotide‐binding oligomerization domain containing two (NOD2/CARD15) mutations. Determination of ATG16L1 gene expression in large‐bowel biopsies of selected patients and controls using real‐time polymerase chain reaction.
Results: The rs2241880G risk allele frequency was higher in CD compared with controls (63.0% vs. 47.4%; p = 0.0002). No epistasis between NOD2/CARD15 mutations and rs2241880 was observed; however, carriers of both variants had significantly increased disease risk. Transcriptional analysis did not reveal over‐ or underexpression of ATG16L1 in CD patients compared with controls.
Conclusion: We confirmed the association of CD with ATG16L1 rs2241880 variant in early‐onset CD. As no epistatic interaction with three common NOD2/CARD15 mutations was observed, the p.Thr300Ala substitution is an independent risk factor for paediatric CD and supports the role for autophagy in disease pathogenesis.
Abstract Backgroud/Purpose Three common mutations of the NOD2 / CARD15 gene have been associated with Crohn disease (CD), ileal disease location, and fibrostenotic behavior. The aim of this study was ...to investigate the effect of these mutations on disease manifestation and the risk of surgery in a cohort of German childhood–onset CD patients. Methods Genotyping for the NOD2 mutations p.Arg702Trp, p.Gly908Arg, and p.1007fs was performed in 171 CD children (onset of disease <17 years; mean 11.8 years) and in 253 controls. NOD2 mutation status was correlated with the need for surgery during childhood. Results Seventy-eight children (45.6%) were carriers of at least 1 NOD2 mutation versus 36 (14.2%) in the control group ( P < .0001). NOD2 mutations were highly associated with CD and stricturing behavior ( P < .0001), with the p.1007fs mutation also conferring a risk for isolated ileal disease ( P = .003). Thirty-two children (18.7%) needed an intestinal resection with a significant association between the need of surgery and NOD2 carrier status. Surgery occurred at an earlier stage of disease in children with p.1007fs mutations. Conclusions In children with pediatric-onset CD, the need for surgical therapy younger than 17 years is associated with the NOD2 genotype. Genetic testing therefore may identify children with CD who are at risk.
Abstract Backgroud/Purpose Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although ...multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis ( NOD2 ) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC. Methods Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp rs2066844), exon 8 (p.Gly908Arg rs2066845), and exon 11 (p.1007fs rs2066847) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease. Results Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants. Conclusion Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.
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