Efficacy of infliximab after loss of response of/intolerance to adalimumab in pediatric Crohn's disease: A retrospective multicenter cohort study of the "GETAID pédiatrique".

BACKGROUND: Infliximab (IFX) and adalimumab (ADA) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD). ADA is now often used in first line due to its efficacy and tolerability, but a loss of response (LOR) can occur over time. The aim was to assess the efficacy of IFX as second line therapy after LOR or intolerance to ADA in pediatric CD patients at 1 year. METHODS: We conducted a retrospective and multicenter study in France among the "GETAID pédiatrique" centers between April 2019 and April 2022. CD patients under 18 years old and treated with IFX after ADA failure or intolerance were included. We collected anthropometric, clinical, and biological data at baseline (start of IFX), at 6 and 12 months. Clinical remission was defined by a Weighted Pediatric CD Activity Index (wPCDAI) score less than 12.5 points. RESULTS: Of the 32 patients included in our study, 27 (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At M12, 22 patients were in corticosteroid free clinical remission (68.7%). Under IFX, the wPCDAI decreased over time (47.5 ± 24.1, 16.6 ± 21.2 and 9.7 ± 19.0 at M0, M6 and M12 respectively). The only factor associated with clinical remission at 12 months was absence of perianal disease at the end of the IFX induction. CONCLUSIONS: IFX is effective in maintaining remission at 1 year in pediatric CD patients experiencing a LOR or intolerance with ADA, and IFX could be an interesting therapeutic choice instead of other biologics in this situation.

Clinicopathological and molecular characterization of a case classified by DNA­methylation profiling as "CNS embryonal tumor with BRD4-LEUTX fusion".

Central Nervous System (CNS) embryonal tumors represent a heterogeneous group of highly aggressive tumors occurring preferentially in children but also described in adolescents and adults. In 2021, the CNS World Health Organization (WHO) classification drastically changed the diagnosis of the other CNS embryonal tumors including new histo-molecular tumor types. Here, we report a pediatric case of a novel tumor type among the other CNS embryonal tumors classified within the methylation class "CNS Embryonal Tumor with BRD4-LEUTX Fusion". The patient was a 4-year girl with no previous history of disease. For a few weeks, she suffered from headaches, vomiting and mild fever associated with increasing asthenia and loss of weight leading to a global deterioration of health. MRI brain examination revealed a large, grossly well-circumscribed tumoral mass lesion located in the left parietal lobe, contralateral hydrocephalus and midline shift. Microscopic examination showed a highly cellular tumor with a polymorphic aspect. The majority of the tumor harbored neuroectodermal features composed of small cells with scant cytoplasm and hyperchromatic nuclei associated with small "medulloblastoma-like" cells characterized by syncytial arrangement and focally a streaming pattern. Tumor cells were diffusely positive for Synaptophysin, CD56, INI1 and SMARCA4 associated with negativity for GFAP, OLIG-2, EMA, BCOR, LIN28A and MIC-2. Additional IHC features included p53 protein expression in more than 10% of the tumor's cells and very interestingly, loss of H3K27me3 expression. The Heidelberg DNA-methylation classifier classified this case as "CNS Embryonal Tumor with BRD4:LEUTX Fusion". RNA-sequencing analyses confirmed the BRD4 (exon 13)-LEUTX (exon 2) fusion with no other molecular alterations found by DNA sequencing. Our case report confirmed that a new subgroup of CNS embryonal tumor with high aggressive potential, loss of H3K27me3 protein expression, BRDA4-LEUTX fusion, named "Embryonal CNS tumor with BRD4-LEUTX fusion", has to be considered into the new CNS WHO classification.

Novel partial loss-of-function variants in the tyrosyl-tRNA synthetase 1 (YARS1) gene involved in multisystem disease.

Cytoplasmic aminoacyl-tRNA synthetases (ARSs) are emerging as a cause of numerous rare inherited diseases. Recently, biallelic variants in tyrosyl-tRNA synthetase 1 (YARS1) have been described in ten patients of three families with multi-systemic disease (failure to thrive, developmental delay, liver dysfunction, and lung cysts). Here, we report an additional subject with overlapping clinical findings, heterozygous for two novel variants in tyrosyl-tRNA synthetase 1 (NM_003680.3(YARS1):c.176T>C; p.(Ile59Thr) and NM_003680.3(YARS1):c.237C>G; p.(Tyr79*) identified by whole exome sequencing. The p.Ile59Thr variant is located in the highly conserved aminoacylation domain of the protein. Compared to subjects previously described, this patient presents a much more severe condition. Our findings support implication of two novel YARS1 variants in these disorders. Furthermore, we provide evidence for a reduced protein abundance in cells of the patient, in favor of a partial loss-of-function mechanism.

Can diffusion weighting replace gadolinium enhancement in magnetic resonance enterography for inflammatory bowel disease in children?

BACKGROUND: Contrast-enhanced MRI is often used for diagnosis and follow-up of children with inflammatory bowel disease. OBJECTIVE: To compare the accuracy of diffusion-weighted MRI (DWI) to contrast-enhanced MRI in children with known or suspected inflammatory bowel disease. MATERIALS AND METHODS: This retrospective, consecutive study included 55 children. We used ileo-colonoscopy and histology as the reference standard from the terminal ileum to the rectum, and contrast-enhanced MRI as the reference standard proximal to the terminal ileum. DWI and contrast-enhanced MRI sequences were independently reviewed and compared per patient and per segment to these reference standards and to the follow-up for each child. RESULTS: We obtained endoscopic data for 340/385 colonic and ileal segments (88%). The rate of agreement per segment between DWI and endoscopy was 64%, and the rate of agreement between contrast-enhanced MRI and endoscopy was 59%. Per patient, sensitivity and specificity of bowel wall abnormalities as compared to the endoscopy were 87% and 100% for DWI, and 70% and 100% for contrast-enhanced MRI, respectively. Positive and negative predictive values were, respectively, 100% and 57% for DWI, and 96% and 41% for contrast-enhanced MRI. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of DWI compare to contrast-enhanced MRI in the segments proximal to the terminal ileum were 90%, 98%, 90%, 98% and 96%, respectively. CONCLUSION: The diagnostic performance of DWI is competitive to that of contrast-enhanced MRI in children with known or suspected inflammatory bowel disease.

Management of syndromic diarrhea/tricho-hepato-enteric syndrome: A review of the literature.

Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare disease linked to the loss of function of either TTC37 or SKIV2L, two components of the SKI complex. It is characterized by a combination of 9 signs (intractable diarrhea, hair abnormalities, facial dysmorphism, immune abnormalities, IUGR/SGA, liver abnormalities, skin abnormalities, congenital heart defect and platelet abnormalities). We present a comprehensive review of the management of SD/THE and tested therapeutic regimens. A review of the literature was conducted in May 2017: 29 articles and 2 abstracts were included describing a total of 80 patients, of which 40 presented with mutations of TTC37, 14 of SKIV2L. Parenteral nutrition was used in the management of 83% of the patients and weaned in 44% (mean duration of 14.97 months). Immunoglobulins were used in 33 patients, but data on efficacy was reported for 6 patients with a diminution of infection (n = 3) or diarrhea reduction (n = 2). Antibiotics (n = 11) provided no efficacy. Steroids (n = 17) and immunosuppressant drugs (n = 13) were used with little efficacy and mostly in patients with IBD-like SD/THE. Hematopoietic stem cell transplantation (HSCT) was performed in 4 patients: 2 died, for one it corrected the immune defects but not the other features and for the last one, it provided only a partial improvement. Finally, no specific diet was effective except for some contradictory reports for elemental formula. In conclusion, the management of SD/THE mainly involves parenteral nutrition and immunoglobulin supplementation. Antibiotics, steroids, immunosuppressants, and HSCT are not recommended as principle treatments since there is no evidence of efficacy.

Somatic mutation, a cause of biliary atresia: A hypothesis.

Despite many years of research, the causes of biliary atresia still remain elusive. Infection, immune disorder, toxins or maternal microchimerism have been cited as potential triggers of biliary atresia. This is a rare disease with a stable incidence over the years although with sizeable ethnic variations. This stability suggests that environmental factors have in fact only a slight influence. During the search for etiologies, twin studies have often helped disentangle the genetic from the environmental. For this condition, twin studies have mainly demonstrated a lack of concordance between twins (either monozygotic or dizygotic), ruling out Mendelian, infectious or toxic causes. Indeed, for toxic or infectious embryopathy, the concordance for twins (especially monozygotic) is about 80%. Paradoxically, these data suggest that biliary atresia has neither a genetic nor an environmental cause. One way of severing the Gordian knot is to hypothesize a role for post zygotic somatic mutation, leading to genetic mosaicism (as a cause of biliary atresia). In recent years, post zygotic mutation has been identified as a cause of non-cancerous disease ranging from dysmorphic syndrome to specific organ abnormalities. A potential model for this condition could be post zygotic mutation or copy number variations in genes or regulatory regions, triggering the cascade of events leading to inflammatory and obliterative cholangiopathy. These events could be enhanced by genetic susceptibility explaining the ethnic variations. In these models, the rate of mosaicism in different parts of the liver could explain the success rate of the Kasai procedure. This hypothesis can be tested: as most children with biliary atresia are eligible for the Kasai procedure, genetic material from the liver and ductal plate can be collected easily. If the hypothesis is correct, whole genome sequencing or copy number variation studies at individual cell level should allow to identify the expected low level of genetic mosaicism. Thus, we hypothesize that postzygotic somatic mutation may play a part in the physiopathology of biliary atresia.

Management of choledochal cyst: Evolution with antenatal diagnosis and laparoscopic approach.

BACKGROUND/AIM: Laparoscopic excision of a choledochal cyst (CC) with hepaticojejunostomy gained a wide acceptance in the treatment of children even in neonatal period. Although, the use of prenatal diagnostic techniques causes a significant increase in antenatal diagnosis of CC, the time of surgical intervention during infancy is still controversial. A retrospective study was performed to evaluate the results of laparoscopic management of CC with special emphasis on antenatal diagnosis and treatment, and to compare the results with open procedure. MATERIALS AND METHODS: The patients who were diagnosed with choledochal cyst and underwent either open or laparoscopic hepaticojejunostomy in two centres, hopital d'enfant de La Timone from Marseille and hopital Robert Debre from Paris between November 2000 and December 2009 were included in the study. The data obtained from medical reports were evaluated for sex, time of antenatal diagnosis, age at time of operation, operative time, time of postoperation. RESULTS: A total of 19 hepaticojejunostomy were performed, including 10 open procedures (group A), and 9 laparoscopic procedures (group B, 4 were diagnosed prenatally, without conversion to open procedure). There were 3 boys and 16 girls, ranging in age from 2 weeks to 16 years. Patients in the group A were older than patients in the group B. The mean hospital stay and time to return of bowel fuction was longer in the group B. there were 60% of pre-operative complications in group A versus 22% in group B. There was one postoperative complications in group B (biliary leakage nedeed redo surgery). No significant differences were found between different parameters except for operative time (288.56 min in the group B versus 206 min in the group A. (p = 0.041)). CONCLUSIONS: Our initial experience indicates that the laparoscopic approach in infancy is technically feasible, safe, and effective, with a low morbidity and a comparable outcome to the open approach. Therefore, we propose a laparoscopic approach for antenatally diagnosed CC as early as possible, before the onset of complications.

Wandering liver: ultrasound and magnetic resonance imaging diagnosis.

"Wandering liver" describes an excessive mobility of the liver caused by abnormalities of hepatic fixation that could lead to hepatic pedicle torsion or bowel obstruction. It is considered a rare entity, but because of the evolution in medical imaging techniques, this unusual condition is being identified more often. We report 2 cases presenting with chronic vague abdominal pain, diagnosed by abdominal ultrasonography and the use of cine-magnetic resonance imaging sequences with dynamic maneuvers. We tried to correlate our ultrasound and magnetic resonance imaging findings to peroperative findings and insist on the usefulness of dynamic maneuvers when confronted with atypical symptoms and a normal abdominal ultrasound scan finding.

Anti-mitochondrial-2 antibodies (anti-PDC-E2): a marker for autoimmune hepatitis of children?

In an 8-year-old boy with biochemical hepatic disorders, an histological examination of a liver biopsy showed a severe chronic hepatitis without cirrhosis. The biliary tract was normal and no toxic or infectious etiologies were found. Spontaneous improvement of the clinical status was observed in the following weeks but biochemical abnormalities were persistent and a second episode occurred 3 years after. Immunological studies showed anti-mitochondrial-2 antibodies (AMA-2) confirmed by an immunoblot performed with rat mitochondrial proteins resolved by two-dimensional electrophoresis. We described here the second case in the literature of paediatric autoimmune hepatitis associated with well documented AMA-2.

Congenital portocaval fistula associated with hepatopulmonary syndrome: ligation vs liver transplantation.

A 4-year-old boy underwent pulmonary testing for diagnosis of exercise-induced dyspnea and subsequent cyanosis. Findings demonstrated the presence of multiple pulmonary arteriovenous fistulas resulting in oxygen desaturation owing to shunting (PaO2, 44 mm Hg). Abdominal ultrasound, abdominal computer tomography, and mesenteric angiography revealed an extrahepatic portocaval fistula (PCF), absence of a patent portal vein, and no evidence of portal hypertension. Because these findings were consistent with hepatopulmonary syndrome (HPS), liver transplantation was initially considered. However, subsequent workup using cavofistulography revealed the presence of a hypoplastic portal vein that selective catheterization showed to be threadlike but patent. Based on this finding, a definitive diagnosis of a congenital PCF with hypoplasia of the portal vein (type 2 Abernethy malformation) was made and surgical ligation with transection of the fistula was performed at the age of 5. Treatment was successful without subsequent development of portal hypertension and pulmonary symptoms disappeared. Follow-up examination 4 years later showed that the boy was asymptomatic and that the intrahepatic portal system was patent with normal hepatopetal flow. This is the first reported case of HPS because of portal type 2 Abernethy malformation. Anatomical types of PCF and corresponding therapeutic options in case of HPS are discussed.