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.

Paediatric Endoscopy Global Rating Scale: Development of a Quality Improvement Tool and Results of a National Pilot.

INTRODUCTION AND OBJECTIVES: The endoscopy Global Rating Scale (GRS) is a web-based self-assessment quality improvement (QI) tool that provides a framework for service improvement. Widespread use of the GRS in adult endoscopy services in the United Kingdom (UK) has led to a demonstrable improvement in quality. The adult GRS is not directly applicable to paediatric endoscopy services. The objective of this study is to develop and pilot a paediatric endoscopy Global Rating Scale (P-GRS) as a QI tool. METHODS: Members of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) Endoscopy Working Group collaborated with the Joint Advisory Group on Gastrointestinal Endoscopy (JAG) to develop the P-GRS. After a period of consultation, this was piloted nationally at 9 centres and data were collected prospectively at 2 census points, May and December 2016. RESULTS: The P-GRS mirrors the adult GRS by dividing care into 4 domains and includes 19 standards with several measures that underpin the standards. Eight services completed the online P-GRS return in May 2016 and 6 in December 2016. All pilot sites identified areas that needed improvement and post-pilot reflected on the key challenges and developments. Several positive developments were reported by the pilot sites. CONCLUSIONS: The national pilot helped ensure that the P-GRS developed was relevant to the paediatric endoscopy services. The pilot demonstrated that even in the first year of engaging with this QI tool, services were starting to identify areas that needed improvement, share best practice documents, put in place QI plans, and support greater patient involvement in services.

Thymus transplantation for complete DiGeorge syndrome: European experience.

BACKGROUND: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). METHODS: Twelve patients with cDGS underwent transplantation with allogeneic cultured thymus. OBJECTIVE: We sought to confirm and extend the results previously obtained in a single center. RESULTS: Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). CONCLUSIONS: This study confirms the previous reports that thymus transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.

Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children.

The revised BSPGHAN guidelines for the diagnosis and management of coeliac disease represent an important shift in diagnostic strategy, aimed at simplifying and shortening the diagnostic process in selected cases. Guidance is given concerning the indications for testing for coeliac disease, which is still significantly underdiagnosed in the UK. While screening data suggest a likely incidence of 1 in 100 persons, only 10%-20% of this figure is currently being diagnosed.The BSPGHAN guidelines follow the new ESPGHAN guidelines in overall diagnostic strategy, while providing more didactic stratagems, which should be of assistance for paediatricians in specialties other than gastroenterology.

Resolution of parenteral nutrition-associated jaundice on changing from a soybean oil emulsion to a complex mixed-lipid emulsion.

BACKGROUND AND OBJECTIVE: Resolution of parenteral nutrition (PN)-associated jaundice has been reported in children given a reduced dose of intravenous fat using a fish oil-derived lipid emulsion. The aim of the present study was to examine the effect on PN-associated jaundice of changing from a soybean oil-derived lipid to a mixed lipid emulsion derived from soybean, coconut, olive, and fish oils without reducing the total amount of lipid given. METHODS: Retrospective cohort comparison examining serum bilirubin during 6 months in children with PN-associated jaundice who changed to SMOFlipid (n=8) or remained on Intralipid (n=9). RESULTS: At entry, both groups received most of their energy as PN (SMOFlipid 81.5%, range 65.5-100 vs Intralipid 92.2%, range 60.3-100; P=0.37). After 6 months, both tolerated increased enteral feeding but still received large proportions of their energy as PN (SMOFlipid 68.4%, range 36.6-100 vs Intralipid 50%, range 37.6-76; P=0.15). The median bilirubin at the outset was 143 µmol/L (range 71-275) in the SMOFlipid group and 91 µmol/L (range 78-176) in the Intralipid group. After 6 months, 5 of 8 children in the SMOFlipid and 2 of 9 children in the Intralipid group had total resolution of jaundice. The median bilirubin fell by 99 µmol/L in the SMOFlipid group but increased by 79 µmol/L in the Intralipid group (P=0.02). CONCLUSIONS: SMOFlipid may have important protective properties for the liver and may constitute a significant advance in PN formulation. Randomised trials are needed to study the efficacy of SMOFlipid in preventing PN liver disease.

A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation.

Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-kappaB in a variety of different cell types. The mechanisms/factors that negatively regulate NF-kappaB in the human gut and the pathways leading to the sustained NF-kappaB activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-beta1 (TGF-beta1) resulted in a marked suppression of TNF-alpha-induced NF-kappaB p65 accumulation in the nucleus, NF-kappaB binding DNA activity, and NF-kappaB-dependent gene activation. TGF-beta1 also increased IkappaBalpha transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-beta1 did not reduce TNF-induced NF-kappaB activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased IkappaBalpha expression and reduced NF-kappaB p65 accumulation in the nucleus. This effect was due to endogenous TGF-beta1. TGF-beta1 directly stimulated IkappaBalpha promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-beta1 is a negative regulator of NF-kappaB activation in the gut and that Smad7 maintains high NF-kappaB activity in gut inflammation by blocking TGF-beta1 signaling.