Accelerating rare disease detection: an experience of multidisciplinary team model in undiagnosed diseases program in a children's hospital.

Background: A definite diagnosis goes undiscovered for a percentage of children with undiagnosed disorders, with significant medical, psychological, and social effects. Other than specialized clinical centers, exceptional molecular studies, common procedures, and devoted activities at the national and international levels, children with complex undiagnosed disorders require innovative approaches. Methods: In March 2016, Children's hospital of Fudan university represented the Children's Undiagnosed Diseases Program (UDP). The purpose of this study is to describe the project findings and underline the critical significance of multidisciplinary teamwork in China's undiagnosed rare illnesses program. We investigated the 758 cases in our UDP system retrospectively. Demographic information, laboratory test results, and genetic information were gathered. Results: Between January 2017 and December 2021, 758 cases were examined. Males made up 436 (57.5%) of the total. Over half of the patients were children under the age of five. The average patient course time preceding admission to UDP was 6.0 months (95% CI 10.512.6). These patients visited an average of 1.8 clinics during their diagnostic journey. Except for 69 individuals (90.9%), all had more than one presenting symptom in various organs: 460 (60.7%) had neurology difficulties, 151 (19.9%) had endocrine problems, and 141 (18.6%) had immunology problems. UDP has a diagnosis rate of 61.3%. Genetic testing was performed on 469 of the 758 patients, for a genetic diagnosis rate of 15.8%. The UDP method has a sensitivity of 94.5%, a specificity of 86.4%, a positive predictive value of 92.8%, and an negative predictive value of 89.5%. Conclusion: Our UDP targets an unmet need, namely the diagnosis of patients with complicated, multisystem illnesses. Using a multidisciplinary team model approach, this UDP pilot study achieved a reasonable diagnosis success rate, increasing the possibility of more diagnoses and new scientific discoveries of difficult and rare diseases.

Three patients with new mutations in the EPCAM variant gene for congenital tufting enteropathy and a mutation review in China: a case report.

Background: Congenital tufting enteropathy (CTE) is a rare cause of intractable congenital diarrhea in children, always resulting in parenteral nutrition (PN) dependency. We aimed to report novel mutations in Chinese patients and to illustrate the clinical, histopathological, and molecular features of CTE in China. Case Description: We report three cases of CTE diagnosed with whole-exome sequencing (WES) and MOC31 [a monoclonal antibody of epithelial cell adhesion molecule (EPCAM)] immunohistochemistry. The main manifestations in the three patients were watery diarrhea and growth retardation. Upper endoscopy in three patients revealed villous atrophy of the duodenal mucosa. Histological examination revealed villus abnormalities and two patients with focal tufting. All of the three patients revealed a complete absence of EPCAM expression through MOC31 immunohistochemistry. Five novel mutations, including c.319delG, c.505_507delGAG, c.491+1G>C, c.60del (p.F20Lfs*17), and c.353G>A, in EPCAM were identified through molecular analysis. In our review, there were 18 different mutations in 11 patients from nine studies, with 12 mutations reported only once. In China, 73% of the patients were compound heterozygotes, and most of the pathogenic variants were in exon 3. All patients presented with congenital diarrhea and needed PN because of growth retardation, even when diarrhea was improved. Of the 11 patients, 3 (27%) died. Conclusions: CTE is rare and fatal, and lacks characteristic changes during endoscopy. Patients with CTE require early diagnosis via histological examination and genetic detection to improve survival.

TeamSTEPPS improves patient safety.

BACKGROUND: Examine how Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) can be used to manage patient safety and improve the standard of care for patients. METHODS: In order to improve key medical training in areas like surgical safety management, blood transfusion closed-loop management, drug safety management and identity recognition, we apply the TeamSTEPPS teaching methodology. We then examine the effects of this implementation on changes in pertinent indicators. RESULTS: Our hospital's perioperative death rate dropped to 0.019%, unscheduled reoperations dropped to 0.11%, and defined daily doses fell to 24.85. Antibiotic usage among hospitalised patients declined to 40.59%, while the percentage of antibacterial medicine prescriptions for outpatient patients decreased to 13.26%. Identity recognition requirements were implemented at a rate of 94.5%, and the low-risk group's death rate dropped to 0.01%. Critical transfusion episodes were less common, with an incidence of 0.01%. The physician's TeamSTEPPS Teamwork Perceptions Questionnaire and Teamwork Attitudes Questionnaire scores dramatically improved following the TeamSTEPPS team instruction course. CONCLUSION: An evidence-based team collaboration training programme called TeamSTEPPS combines clinical practice with team collaboration skills to enhance team performance in the healthcare industry and raise standards for medical quality, safety, and effectiveness.

Fecal calprotectin in predicting small bowel capsule endoscopy findings in pediatric patients with known Crohn's disease.

Fecal calprotectin (FC) has been proposed as a noninvasive surrogate marker of intestinal inflammation in inflammatory bowel disease. This study aimed to assess the capability of FC in predicting small bowel capsule endoscopy (SBCE) findings in pediatric patients with known Crohn's disease (CD). We retrieved data of consecutive patients aged 2 to 17 years old with established CD who underwent SBCE from Janurary 2017 to April 2020 and had endoscopic remission on ileocolonoscopy. Sixty-eight patients were included in the analysis. There were 13 patients with a weighted pediatric CD activity index ≥ 12.5, 47 patients with FC ≥ 200 µg/g, and 45 patients with significant small bowel (SB) inflammation [Lewis score (LS) ≥ 135]. The LS correlated weakly with FC (R = 0.30, P < .05). The area under the curve of FC as a surrogate diagnostic test for LS ≥ 135 was 0.691, and the optimal FC cutoff values were 242 µg/g with the corresponding sensitivity and specificity of 78% and 65%, respectively. The area under the curve of FC for moderate-to-severe inflammatory activity in the SB was 0.718. In patients with FC level ≥ 670 µg/g, LS ≥ 790 was found in 33% (9/27) of patients, with the sensitivity and specificity of 69% and 67%, respectively. FC may be used to predict SB mucosal inflammation in pediatric patients with confirmed CD having endoscopic remission on ileocolonoscopy.

Efficacy of Phenotype-vs. Genotype-Guided Therapy Based on Clarithromycin Resistance for Helicobacter pylori Infection in Children.

Background: Clarithromycin resistance reduces the eradication rate of Helicobacter pylori (H. pylori). Cultures with susceptibility testing and molecular determination of genotypes are recommended to guide-tailored therapy. Methods: We retrospectively enrolled patients aged 6 and 18 years with H. pylori infection, who underwent an endoscopy and agreed to undergo both culture and genetic testing for clarithromycin resistance. Patients receiving tailored therapy based on traditional culture results (phenotype-guided therapy) or genetic testing results (genotype-guided therapy) were included in the study. 13C-urea breath test was used to evaluate the success of eradication at least 4 weeks after the completion of treatment. We aimed to determine whether the eradication rate of phenotype- or genotype-guided therapy based on clarithromycin resistance is greater than 90% in children. Results: Between September 2017 and October 2020, 226 eligible patients were enrolled. There were 71 with clarithromycin-sensitive strains in the phenotype-guided therapy group and 87 without 23S rRNA point mutations (A2142G, A2142C, and A2143G) in the genotype-guided therapy group. Eradication rates were 70.4% (50/71, [95% CI: 58.4-80.7%] for phenotype-guided therapy and 92.0% (80/87, [95% CI: 84.1-96.7%]) for genotype-guided therapy (P < 0.01). The incidence of side effects was 4.2% (3/71) and 10.3% (9/87), with no major differences between these two groups (P = 0.15), respectively. The compliance rate was also similar (97.2 vs. 95.4%, P = 0.87). Conclusion: Tailored therapy according to genetic testing results achieved eradication rates of 92% and was superior to tailored therapy guided by traditional culture results.

Clinical outcome of infantile-onset inflammatory bowel disease in 102 patients with interleukin-10 signalling deficiency.

BACKGROUND: Infantile-onset inflammatory bowel disease can be caused by defects in interleukin-10 signalling. The natural history and clinical outcomes of allogeneic haematopoietic stem cell transplantation, medical treatment and surgery have not been thoroughly described. AIMS: This study evaluates disease progression and clinical outcome in patients with interleukin-10 signalling deficiency. METHODS: One hundred and nine patients with interleukin-10 signalling deficiency were retrospectively reviewed from a single tertiary centre. The Kaplan-Meier method was applied to calculate probabilities of survival and interval between transplant and stoma closure. RESULTS: One hundred and nine patients were reviewed, and 102 patients were included in the survival analysis. One hundred and eight patients were identified with IL10RA mutations, and one patient harboured IL10RB mutation. Seventy-three patients received haematopoietic stem cell transplantation. The overall survival after transplantation was 64.2% (95% confidence interval, 52.8 to 75.6), and without transplantation, it was 47.5% (95% confidence interval, 14.8 to 80.2, P = 0.47). The median timeframe between transplant and stoma closure was 19.6 months. The probability of survival was significantly lower in patients with perforation (P < 0.001), ileus (P = 0.038) and without thalidomide treatment (P < 0.001) among patients who did not receive haematopoietic stem cell transplantation. The survival probability was not associated with timeframe between transplant and onset, graft source and genotypes. CONCLUSIONS: The survival probability was not significantly different between patients with transplantation and the non-transplanted patients.

Effect of Exclusive Enteral Nutrition on the Disease Process, Nutrition Status, and Gastrointestinal Microbiota for Chinese Children With Crohn's Disease.

BACKGROUND: The aim of this study was to prospectively study the effect of exclusive enteral nutrition (EEN) treatment on Chinese pediatric Crohn's disease (CD) patients. METHODS: Thirty-one newly diagnosed CD patients were enrolled in this study and treated with EEN for 8 weeks. Twelve healthy controls (HCs) donated their fecal samples. Statistical methods were used to compare the differences. RESULTS: According to the Simple Endoscopic Score for CD (SES-CD) at the end of the EEN treatment, 21 patients with SES-CD ≤4 were classified into the remission group (CD-RE), and 10 patients with SES-CD >4 were classified into the nonremission group (CD-NRE). After EEN therapy, there was a significant decrease in the SES-CD, the weighted Pediatric Crohn's Disease Activity Index (wPCDAI), and fecal calprotectin (FCP) in the CD-RE group (all P < .001). The wPCDAI and FCP also decreased in the CD-NRE group (both P < .05). In terms of nutrition improvement, the CD-RE group patients showed more improvement in weight gain, hemoglobin, and serum albumin level than the CD-NRE group patients (all P < .05). For the microbiota, the CD patients had a lower bacterial diversity and different bacterial community compared with HCs. EEN increased overall diversity and was able to shift the dysbiosis in CD patients toward a healthier state. Absence of improvement in wPCDAI and Shannon index at 2 weeks predicts poor response at the end of EEN. CONCLUSION: EEN can be used in most Chinese pediatric CD patients to induce remission and improve nutrition.

Long-term changes in the gut microbiota after 14-day bismuth quadruple therapy in penicillin-allergic children.

BACKGROUND: Penicillin-allergic children who are infected with Helicobacter pylori constitute a relatively common subgroup. We aimed to study the short-term and long-term effects of bismuth quadruple therapy on gut microbiota in penicillin-allergic children. METHODS: We prospectively recruited treatment-naive children with H pylori infection and H pylori-negative asymptomatic children as healthy controls. Patients received 14-day bismuth quadruple therapy consisting of omeprazole, clarithromycin, metronidazole, and bismuth. Fecal samples were collected at weeks 0, 2, 6, and 52. Alterations in the gut microbiota were analyzed by 16S rRNA gene sequencing. RESULTS: Twenty-two subjects (14 gastritis patients, 8 duodenal ulcer patients) and 23 controls participated in this study. At week 2, alpha diversity was reduced in both gastritis (P < .05) and ulcer (except P = .16 with Chao 1 index) patients compared with baseline. Some changes persisted at week 6, and all were restored at week 52. Beta diversity was significantly altered 2 weeks after treatment in the gastritis and duodenal ulcer groups (P = .001, P = .002, respectively) and restored at weeks 6 and 52. The mean relative abundance of Bacteroidetes (P < .001, P = .005, respectively) decreased and that of Proteobacteria increased (P < .001, P = .03, respectively). All alterations recovered at week 6 and 52. In both the gastritis and ulcer groups at week 2, some beneficial bacteria were decreased including Bacteroides (P < .001 and P = .003), Faecalibacterium (P < .001 and P = .02), Phascolarctobacterium (P = .002 and P = .004), Roseburia ( P < .001 and P = .13), Bifidobacterium (P = .08 and P = .04), and Blautia (P < .001 and P = .002). Some detrimental bacteria were increased including Escherichia-Shigella (P < .001 and P = .19), Klebsiella (P < .001, and P = .09), Enterococcus (P < .001 and P = .007), and Streptococcus (P = .002 and P = .004). The changes returned to almost the pre-eradication level 1 year after therapy. CONCLUSION: Bismuth quadruple therapy causes short-term dysbiosis of the gut microbiota. Most changes recovered 1-year post-eradication, indicating the long-term safety of H pylori therapy.

Intestinal dysbiosis in pediatric Crohn's disease patients with IL10RA mutations.

BACKGROUND: Several studies have employed animal models to explore the association between microbiota and interleukin (IL) 10 signaling; however, limited information is available about the human microbiome. AIM: To characterize the microbiome in patients with IL10RA mutations and to explore the association between gut dysbiosis and disease severity. METHODS: Fecal samples were collected from patients who were diagnosed with loss-of-function mutations in the IL10RA gene between January 2017 and July 2018 at the Children's Hospital of Fudan University. Age-matched volunteer children were recruited as healthy controls. Patients with Crohn's disease (CD) were used as disease controls to standardize the antibiotic exposure. Microbial DNA was extracted from the fecal samples. All analyses were based on the 16S rRNA gene sequencing data. RESULTS: Seventeen patients with IL10RA mutations (IL10RA group), 17 patients with pediatric CD, and 26 healthy children were included. Both patients with IL10RA mutations and those with CD exhibited a reduced diversity of gut microbiome with increased variability. The relative abundance of Firmicutes was substantially increased in the IL10RA group (P = 0.02). On further comparison of the relative abundance of taxa between patients with IL10RA mutations and healthy children, 13 taxa showed significant differences. The IL10RA-specific dysbiosis indices exhibited a significant positive correlation with weighted pediatric CD activity index and simple endoscopic score for CD. CONCLUSION: In patients with IL10RA mutations and early onset inflammatory bowel disease, gut dysbiosis shows a moderate association with disease severity.

Phenotypic Characterization of Very Early-Onset Inflammatory Bowel Disease with Interleukin-10 Signaling Deficiency: Based on a Large Cohort Study.

BACKGROUND: Interleukin-10 (IL10)/interleukin-10 receptor (IL10R) deficiency is a rare disease with life-threatening infantile-onset colitis. We sought to accurately phenotype this disorder based on a large cohort of patients with a proven defect of IL10 signaling and to clarify the effects of allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We analyzed the phenotypes of our 61 patients and reviewed 78 other previously reported cases with identified mutations in the genes encoding IL10 or IL10R. We also compared the clinical features of patients with interleukin-10 receptor B (IL10RB), interleukin-10 receptor A (IL10RA), and IL10 mutations. The therapeutic effects of allogeneic HSCT were evaluated. RESULTS: We found that the disease onset time was extremely early: 70.3% within 30 days postnatal and 94.9% within the first 6 months of life. In addition, 94.2% of patients typically presented with perianal lesions. Oral ulcers and skin rash were common extra-intestinal manifestations (33.8% and 51.8%, respectively). There was no statistically significant difference in disease onset time, perianal lesion involvement, or mortality rate among patients with IL10RB, IL10RA, or IL10 deficiency. However, the surgery rate was higher in patients with IL10RB mutations than in those with IL10 or IL10RA mutations (P < 0.05). Compared with those with IL10RA deficiency, a higher percentage (32%, 9 of 28) of patients with IL10RB mutations developed B-cell lymphoma (P < 0.01). Compared with other regions, a higher percentage (98.7%) of IL10RA mutations was detected among patients in East Asia countries (P < 0.01), with hot-spot mutation sites of c.C301T and c.G537A. Allogeneic HSCT is efficacious but has a high mortality rate (17.5%, 7 of 40). CONCLUSIONS: Our study expands the current knowledge on the genotype-correlated phenotypes with a defect of IL10 signaling. B-cell lymphoma was more frequent than would be expected in patients with IL10RB mutations. There may be a unique genetic architecture among Eastern Asia compared with other populations. Although allogeneic HSCT represents a causal therapeutic approach for IL10-and IL10R-deficient patients, a word of caution is warranted.

Peroral Endoscopic Myotomy in Children With Achalasia: A Relatively Long-term Single-center Study.

BACKGROUND: Achalasia is a disease caused by neuromuscular dysfunction in the esophagogastric junction, with a relatively low incidence among children. Peroral endoscopic myotomy (POEM) is a new endoscopic procedure for the treatment of achalasia; however, it is rarely applied in children. OBJECTIVES: We aim to study the feasibility, safety, and effectiveness of POEM as a treatment for pediatric achalasia. METHODS: A total of 21 pediatric patients (ages from 11 months to 18 years) diagnosed as having achalasia and treated with POEM from October of 2014 to October of 2016 in our hospital were included in our study. Indices such as clinical manifestations, nutritional status, Eckardt scores, high-resolution esophageal manometric measurements, gastroduodenoscopic findings, and upper gastroenterographic findings after treatment were respectively compared with those before treatment to analyze the effectiveness and safety of POEM. RESULTS: All of the 21 children successfully received POEM. The patients were followed up for duration ranged from 3 to 24 months. Among these children, symptoms such as vomiting and dysphagia were significantly alleviated or resolved. The Eckardt scores had an average drop of 7 points after treatment compared with those before treatment. Postoperative gastroduodenoscopy and upper gastroenterography showed that the opening of the cardiac orifice was significantly enlarged and obstruction at the lower esophagus was significantly relieved. CONCLUSIONS: POEM is a mini-invasive technique and a promising new treatment for pediatric patients, making it worthy of further clinical research and application.

Phenotype and Management of Infantile-onset Inflammatory Bowel Disease: Experience from a Tertiary Care Center in China.

BACKGROUND: Infantile-onset inflammatory bowel disease (IBD) comprises rare and clinically severe disorders. We examined the phenotypes and genetic causes of patients with infantile-onset IBD from a tertiary medical center. METHODS: We enrolled 38 patients with infantile-onset IBD and applied standardized treatment with medical, surgical, and supportive care. Targeted sequencing and whole-exome sequencing were performed. Clinical data were retrieved from medical records. RESULTS: Median age of onset of disease was 12.5 (interquartile range: 7.0-30.0) days. All patients had diarrhea, whereas 18 (47.4%) patients reported hematochezia. Thirteen (34.2%) patients had oral ulcers, 15 (39.5%) patients had perianal abscess, and 9 (52.9%) female patients had rectovaginal fistula. Six (18.8%) patients had intestinal strictures and 4 (12.1%) patients had perforation. Twelve (31.6%) patients underwent surgical procedures. Median age of surgery was 272.5 days, and cumulative probability for surgery during first year was 32.1%. One-year mortality of patients was 25.9%. Sequencing showed 24 (63.2%) patients had causative IL10RA mutations, 1 patient had EPCAM mutation, 1 patient had TNFAIP3 mutation, and 1 patient had LRBA mutation, whereas causative mutations cannot be identified in the other 11 (28.9%) patients. Umbilical cord blood stem cell transplantation has been applied to 8 cases with IL10RA mutations, of whom 5 (71.4%) patients have achieved clinical remission. CONCLUSIONS: Patients with infantile-onset IBD had severe phenotype and early onset. Medical, surgical interventions with supportive care are essential. High-throughput sequencing ensures appropriate treatment. Hematopoietic stem cell transplantation can be performed in selected patients with IL10RA mutations (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B657).

Clinical characteristics and STK11 gene mutations in Chinese children with Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin spots. Germline mutation of the serine/threonine kinase 11 (STK11) gene are responsible for PJS. In this study, we investigated the clinical characteristics and molecular basis of the disease in Chinese children with PJS. METHODS: Thirteen children diagnosed with PJS in our hospital were enrolled in this study from 2011 to 2015, and their clinical data on polyp characteristics, intussusceptions events, family histories, etc. were described. Genomic DNA was extracted from whole-blood samples from each subject, and the entire coding sequence of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. RESULTS: The median age at the onset of symptoms was 2 years and 4 months. To date, these children have undergone 40 endoscopy screenings, 17 laparotomies and 9 intussusceptions. Polyps were found in the stomach, duodenum, small bowel, colon and rectum, with large polyps found in 7 children. Mutations were found in eleven children, including seven novel mutations (c.481het_dupA, c.943_944het_delCCinsG, c.397het_delG, c.862 + 1G > G/A, c.348_349het_delGT, and c.803_804het_delGGinsC and c.121_139de l19insTT) and four previously reported mutations (c.658C > C/T, c.890G > G/A, c.1062 C > C/G, and c.290 + 1G > G/A). One PJS patient did not have any STK11 mutations. CONCLUSIONS: The polyps caused significant clinical consequences in children with PJS, and mutations of the STK11 gene are generally the cause of PJS in Chinese children. This study expands the spectrum of known STK11 gene mutations.