Long term outcomes in children with trichohepatoenteric syndrome.

Trichohepatoenteric syndrome (THES) is a rare autosomal recessive disorder caused by mutations in either TTC37 or SKIV2L, usually leading to congenital diarrhea as part of a multisystem disease. Here, we report on the natural history of the disease for the largest UK cohort of patients with THES from 1996 to 2020. We systematically reviewed the clinical records and pathological specimens of patients diagnosed with THES managed in a single tertiary pediatric gastroenterology unit. Between 1996 and 2020, 13 patients (7 female and 6 male) were diagnosed with THES either by mutation analysis or by clinical phenotype. Two patients died from complications of infection. All patients received parenteral nutrition (PN) of which six patients were weaned off PN. All patients had gastrointestinal tract inflammation on endoscopy. Almost half of the cohort were diagnosed with monogenic inflammatory bowel disease (IBD) by the age of 11 years, confirmed by endoscopic and histological findings. Protracted diarrhea causing intestinal failure improves with time in all patients with THES, but monogenic IBD develops in later childhood that is refractory to conventional IBD treatments. Respiratory issues contribute to significant morbidity and mortality, and good respiratory care is crucial to prevent comorbidity.

Anti-TNF therapy for inflammatory bowel disease in patients with neurodegenerative Niemann-Pick disease Type C.

Background:  Blockade of tumour necrosis factor (anti-TNF) is effective in patients with Crohn's Disease but has been associated with infection risk and neurological complications such as demyelination. Niemann-Pick disease Type C1 (NPC1) is a lysosomal storage disorder presenting in childhood with neurological deterioration, liver damage and respiratory infections. Some NPC1 patients develop severe Crohn's disease. Our objective was to investigate the safety and effectiveness of anti-TNF in NPC1 patients with Crohn's disease. Methods: Retrospective data on phenotype and therapy response were collected in 2019-2020 for the time period 2014 to 2020 from patients in the UK, France, Germany and Canada with genetically confirmed NPC1 defects and intestinal inflammation. We investigated TNF secretion in peripheral blood mononuclear cells treated with NPC1 inhibitor in response to bacterial stimuli . Results: NPC1 inhibitor treated peripheral blood mononuclear cells (PBMCs) show significantly increased TNF production after lipopolysaccharide or bacterial challenge providing a rationale for anti-TNF therapy. We identified 4 NPC1 patients with Crohn's disease (CD)-like intestinal inflammation treated using anti-TNF therapy (mean age of onset 8.1 years, mean treatment length 27.75 months, overall treatment period 9.25 patient years). Anti-TNF therapy was associated with reduced gastrointestinal symptoms with no apparent adverse neurological events. Therapy improved intestinal inflammation in 4 patients. Conclusions: Anti-TNF therapy appears safe in patients with NPC1 and is an effective treatment strategy for the management of intestinal inflammation in these patients.

An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease.

BACKGROUND & AIMS: Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis. METHODS: To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy individuals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4). RESULTS: Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8+ T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD. CONCLUSION: Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses.

Human interleukin-2 receptor ß mutations associated with defects in immunity and peripheral tolerance.

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) ß chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rß and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rß expression and function. IL-2Rß loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rß also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

Hepatic Lesions Associated With McCune Albright Syndrome.

McCune-Albright syndrome (MAS) results from a GNAS gene mutation. It is associated with café au lait macules, fibrous dysplasia, and several endocrinopathies to include gonadotropin-independent precocious puberty, growth hormone excess, Cushing syndrome, thyroid disease, and renal phosphate wasting. It is recognized to be a rare cause of neonatal cholestasis. We describe the hepatic outcome of 3 children with MAS referred to a single national liver unit. All presented with high gamma-glutamyl transpeptidase cholestasis and hepatitis. Cholestasis resolved by 1 year; but hepatic inflammation persisted, and 2 children developed progressive atypical focal nodular hyperplasia and 1 developed hepatoblastoma. This the first reported malignant hepatic lesion associated with MAS. MAS should be considered part of the differential diagnosis of neonatal cholestasis and affected children should be closely monitored for the development of hepatic lesions with regular liver ultrasound and alpha fetoprotein level.

Cystic fibrosis: an update for clinicians. Part 2: hepatobiliary and pancreatic manifestations.

This paper, the second in the series, will build on the first and explore the importance of liver and pancreatic manifestations of cystic fibrosis (CF) and the effect on morbidity and mortality of this multifaceted genetic condition. It will also further develop the critical role of the gastroenterologist as part of the multidisciplinary group of clinicians and allied health staff in the effective management of patients with CF.

Yellow is pale: the complications and challenges of late diagnosis of extrahepatic biliary atresia.

Extrahepatic biliary atresia classically presents in the neonatal period with jaundice and pale stools. The lack of bile pigment in stool can be unrecognised, delaying diagnosis and surgical treatment. Vitamin K is given at birth to reduce the risk of haemorrhagic disease of the newborn, but this may be inadequate to prevent the development of coagulopathy secondary to fat soluble vitamin malabsorption. We present the case of a 3 month old infant who presented with an intracerebral haemorrhage and coagulopathy thought to be secondary to fat malabsorption resulting from delayed diagnosis of extrahepatic biliary atresia. This was despite the perinatal administration of intramuscular vitamin K. His parents did not recognise the stool pallor as being abnormal. This case illustrates the importance of educating parents on the significance of pale stools, and also the risk of coagulopathy in extrahepatic biliary atresia despite perinatal intramuscular vitamin K.

Immune response to pandemic H1N1 2009 influenza a vaccination in pediatric liver transplant recipients.

After the announcement of a worldwide pandemic in June 2009, a single dose of a monovalent pandemic H1N1 2009 influenza A (pH1N1/09) vaccine was advocated for all Australians who were 10 years and older because of excellent immunogenicity trial results for healthy children and adults. Immunocompromised patients have previously been shown to have lower seroconversion rates after routine vaccinations. There is a lack of data concerning the immune response of this patient group after pH1N1/09 vaccination. The aim of this study was to assess the immunogenicity of a pH1N1/09 vaccine in pediatric liver transplant recipients 10 years of age or older. Liver transplant recipients ≥ 10 years were prospectively recruited. All participants were administered a single intramuscular injection of the pH1N1/09 vaccine (15 µg). Serum antibody levels were determined by hemagglutination immediately before and ≥ 6 weeks after vaccination. Clinical and laboratory data (age, time since transplantation, immunosuppression, and lymphocyte counts) were analyzed comparing seroconverters and nonconverters with the Student's t test. A second dose of the vaccine was offered to all those who displayed no seroprotective titers after the first vaccination. Antibody levels were again determined 6 weeks later. Twenty-one of 28 liver transplant patients completed the study. The seroconversion rate was 62% after the first dose and 89.5% after the second dose. At baseline, 7 of 21 patients (33.4%) were already seropositive. Increasing time since transplantation positively correlated with successful seroconversion. In conclusion, a single dose of a pandemic influenza A vaccine does not elicit a reliable immune response in adolescent pediatric liver transplant patients. A second dose of the vaccine is warranted in this group of patients, at least in a pandemic scenario. There is an urgent need to further assess vaccine strategies in this high-risk group.

Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle.

The mitochondrial translation system is responsible for the synthesis of 13 proteins required for oxidative phosphorylation (OXPHOS), the major energy-generating process of our cells. Mitochondrial translation is controlled by various nuclear encoded proteins. In 27 patients with combined OXPHOS deficiencies, in whom complex II (the only complex that is entirely encoded by the nuclear DNA) showed normal activities, and mutations in the mitochondrial genome as well as polymerase gamma were excluded, we screened all mitochondrial translation factors for mutations. Here, we report a mutation in mitochondrial elongation factor G1 (GFM1) in a patient affected by severe, rapidly progressive mitochondrial encephalopathy. This mutation is predicted to result in an Arg250Trp substitution in subdomain G' of the elongation factor G1 protein and is presumed to hamper ribosome-dependent GTP hydrolysis. Strikingly, the decrease in enzyme activities of complex I, III and IV detected in patient fibroblasts was not found in muscle tissue. The OXPHOS system defects and the impairment in mitochondrial translation in fibroblasts were rescued by overexpressing wild-type GFM1, establishing the GFM1 defect as the cause of the fatal mitochondrial disease. Furthermore, this study evinces the importance of a thorough diagnostic biochemical analysis of both muscle tissue and fibroblasts in patients suspected to suffer from a mitochondrial disorder, as enzyme deficiencies can be selectively expressed.

Successful treatment of mixed-type autoimmune hemolytic anemia with rituximab in a child following liver transplantation.

Development of a severe form of mixed-type AIHA after orthotopic liver transplantation is a rare, but a life-threatening event. We report a case of mixed-type AIHA that developed in a child after hepatocyte and living-related orthotopic liver transplantation for factor VII deficiency.

Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by newborn screening in Germany.

Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare neurometabolic disorder that is considered treatable if patients are identified before the onset of acute encephalopathic crises. To allow early identification of affected individuals, tandem mass spectrometry-based newborn screening for GCDH deficiency has been started in Germany in 1999. We prospectively followed neonatally screened patients (n=38) and compared the neurologic outcome with patients from a historical cohort (n=62). In the majority of neonatally screened children, the onset of encephalopathic crises has been prevented (89%), whereas acute encephalopathic crises or progressive neurologic impairment was common in the historical cohort. Neonatal screening in combination with intensive management is effective--even assuming ascertainment bias in the historical cohort. Similar proportions of commonest mutations and biochemical phenotypes (high and low excretors) were found in neonatally screened and historical patients. However, potential predictor variables for mild clinical phenotypes are not yet known and thus a selection of these patients by newborn screening is not excluded. No patient was known to be missed by newborn screening from 1999 to 2005. In conclusion, this study confirms that newborn screening for GCDH deficiency in combination with intensive management is beneficial.

Use of an amphoteric lavage solution for emergency treatment of eye burns. First animal type experimental clinical considerations.

PURPOSE: Severe eye burns occur rarely, but are related to a poor prognosis in rehabilitation. As emergency treatment has been identified as decisive factor for the prognosis of eye burns, new first aid rinsing solutions should be considered carefully in their clinical action. In a first approach, the new drug Diphoterine was subjected to a comparison with saline solution to evaluate the effects in a model of severe eye burns. METHODS: In a double-masked experiment 16 rabbits underwent a severe eye burn of one cornea followed by immediate rinsing with 0.9% sodium-chlorine solution (n=8) or Diphoterine (n=8). During 16 days after burn, an irrigation therapy with 0.9% saline solution three times daily 160 ml was applied in both groups following the recommendation of prolonged irrigation therapy performed in our clinic. In a similar setup, 16 eyes were subjected alkali burns with measurements of aqueous humor pH within 30s after burn and after a period of 5 min rinsing with 500 ml saline 0.9% or Diphoterine, respectively. RESULTS: The result of the severe eye burn with an opaque cornea was similar in both groups. During rinsing no fibrin precipitates occurred in the Diphoterine rinsed group whereas this was detectable in all eyes rinsed with saline solution. After 16 days there was no difference between both groups indicating no harmful effect of Diphoterine as emergency treatment compared to saline 0.9%. After 30s of burn with 1N NaOH and rinsing with 500 ml of the specified solutions the anterior chamber pH was 10+/-0 in the saline group and 9.35+/-0.3 in the Diphoterine group showing efficacy of the buffering capacity of Diphoterine. CONCLUSION: Diphoterine proves to be efficient in the primary treatment of burns. The anterior chamber pH could be lowered by 5min of rinsing. No harmful effects of Diphoterine could be observed compared to rinsing with saline solution in the course of an severe alkali burn of the cornea.