Serum Eosinophilic Cationic Protein as a Useful Noninvasive Marker of Eosinophilic Gastrointestinal Disease in Children.

Purpose: Recently, the prevalence of eosinophilic gastrointestinal disease (EGID) has shown an increasing trend worldwide. As the diagnosis of EGID requires invasive endoscopy with biopsy, noninvasive markers for detecting EGID in suspected patients, particularly children, are urgently needed. Therefore, this study aimed to evaluate the diagnostic accuracy of serum eosinophil cationic protein (ECP) beyond peripheral eosinophil counts in pediatric patients with EGID. Methods: Overall, 156 children diagnosed with EGID were enrolled and 150 children with functional abdominal pain disorder (FAPD) were recruited as controls. All participants underwent endoscopic biopsy in each segment of the gastrointestinal (GI) tract and serum ECP measurement, as well as peripheral eosinophil percent and absolute eosinophil count. Results: Comparing EGID (n=156) with FAPD (n=150) patients, serum ECP levels were significantly higher in pediatric patients with EGID than in those with FAPD (25.8±28.6 µg/L vs. 19.5±21.0 µg/L, p=0.007), while there was no significant difference in peripheral eosinophil percent and absolute eosinophil counts between the two groups. Serum ECP levels were correlated with peripheral eosinophil percent (r=0.593, p<0.001) and the absolute eosinophil count (r=0.660, p<0.001). The optimal cutoff value of serum ECP for pediatric EGID was 10.5 µg/mL, with a sensitivity of 69.9% and a specificity of 43.4% with an area under the receiver operating characteristic curve of 0.562. Conclusion: The combination of serum ECP levels and peripheral eosinophil counts, when employed with appropriated thresholds, could serve as a valuable noninvasive biomarker to distinguish between EGID and FAPD in pediatric patients manifesting GI symptoms.

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

PARVB and HSD17B13 variants are associated with nonalcoholic fatty liver disease in children.

BACKGROUND AND AIM: The aim of this study was to investigate the comprehensive genetic effects of exploratory variants of LYPLAL1, GCKR, HSD17B13, TRIB1, APOC3, MBOAT7, and PARVB on pediatric nonalcoholic fatty liver disease in addition to the previously reported variants of TM6SF2, PNPLA3, and SAMM50 in Korean children. METHODS: A prospective case-control study was conducted involving 309 patients diagnosed using ultrasound and 339 controls. Anthropometric measurements, liver function tests, and metabolic marker analysis were conducted, and fibrosis scores were calculated. Transient elastography was performed in 69 some patients with nonalcoholic fatty liver disease. TaqMan allelic discrimination assays were used for genotyping. The genetic risk scores were calculated using significant variants, namely, HSD17B13, PARVB, PNPLA3, SAMM50, and TM6SF2, to evaluate the additive effect. RESULTS: Risk allele carriers of the PARVB variant showed significantly higher levels of aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, pediatric nonalcoholic fatty liver disease fibrosis score, and aspartate aminotransferase/platelet ratio index. Individuals with a homozygous variant of HSD17B13 showed significantly lower levels of aminotransferase, gamma-glutamyl transferase, liver stiffness measurement, and aspartate aminotransferase/platelet ratio index than those with other genotypes. These parameters did not significantly differ among other variants of LYPLAL1, GCKR, TRIB1, APOC3, and MBOAT7. The genetic risk scores was identified as an independent risk factor for nonalcoholic fatty liver disease and had a positive association with severity. CONCLUSION: HSD17B13 has protective effects on the severity of pediatric nonalcoholic fatty liver disease. Variants of HSD17B13, PARVB, PNPLA3, SAMM50, and TM6SF2 had an additive effect on nonalcoholic fatty liver disease.

Diagnostic algorithm for neonatal intrahepatic cholestasis integrating single-gene testing and next-generation sequencing in East Asia.

BACKGROUND AND AIM: Advances in molecular genetics have uncovered causative genes responsible for neonatal cholestasis. Panel-based next-generation sequencing has been used clinically in infants with neonatal cholestasis. We aimed to evaluate the clinical application of single-gene testing and next-generation sequencing and to develop a diagnostic algorithm for neonatal intrahepatic cholestasis. METHODS: From January 2010 to July 2021, patients suspected of having neonatal intrahepatic cholestasis were tested at the Seoul National University Hospital. If there was a clinically suspected disease, single-gene testing was performed. Alternatively, if it was clinically difficult to differentiate, a neonatal cholestasis gene panel test containing 34 genes was performed. RESULTS: Of the total 148 patients examined, 49 (33.1%) were received a confirmed genetic diagnosis, including 14 with Alagille syndrome, 14 with neonatal intrahepatic cholestasis caused by citrin deficiency, 7 with Dubin-Johnson syndrome, 5 with arthrogryposis-renal dysfunction-cholestasis syndrome, 5 with progressive familial intrahepatic cholestasis type II, 1 with Rotor syndrome, 1 with Niemann-Pick disease type C, 1 with Kabuki syndrome, and 1 with Phenylalanyl-tRNA synthetase subunit alpha mutation. Sixteen novel pathogenic or likely pathogenic variants of neonatal cholestasis were observed in this study. Based on the clinical characteristics and laboratory findings, we developed a diagnostic algorithm for neonatal intrahepatic cholestasis by integrating single-gene testing and next-generation sequencing. CONCLUSIONS: Alagille syndrome and neonatal intrahepatic cholestasis caused by citrin deficiency were the most common diseases associated with genetic neonatal cholestasis. Single-gene testing and next-generation sequencing are important and complementary tools for the diagnosis of genetic neonatal cholestasis.

A Report on a Nationwide Surveillance System for Pediatric Acute Hepatitis of Unknown Etiology in Korea.

BACKGROUND: Several cases of pediatric acute hepatitis of unknown etiology related to adenoviral infections have been reported in Europe since January 2022. The aim of this study was to compare the incidence, severity, possible etiology, and prognosis of the disease with those in the past in Korea. METHODS: The surveillance group collected data between May and November 2022 using a surveillance system. Acute hepatitis of unknown etiology was defined in patients aged < 16 years with a serum transaminase level > 500 IU/L, not due to hepatitis A-E or other underlying causes. For comparison, data from 18 university hospitals were retrospectively collected as a control group between January 2021 and April 2022. RESULTS: We enrolled 270 patients (mean age, 5 years). The most common symptom was fever. However, the incidence was similar between 2021 and 2022. Liver function test results, number of patients with acute liver failure (ALF), liver transplantation (LT), death, and adenovirus detection rates did not differ between the two groups. None of the adenovirus-positive patients in either group experienced ALF, LT, or death. In the surveillance group, adenovirus-associated virus-2 was detected in four patients, one of whom underwent LT. Patients with an unknown etiology showed significantly higher bilirubin levels, a lower platelet count, and a higher LT rate than patients with a possible etiology. CONCLUSION: The incidence of pediatric acute hepatitis of unknown etiology and adenovirus detection rate have not increased in Korea.

Global incidence and prevalence of autoimmune hepatitis, 1970-2022: a systematic review and meta-analysis.

Background: Autoimmune hepatitis (AIH) varies significantly in incidence and prevalence across countries and regions. We aimed to examine global, regional, and national trends in incidence and prevalence of AIH from 1970 to 2022. Methods: We conducted a thorough search of the PubMed/MEDLINE, Embase, CINAHL, Google Scholar, and Cochrane databases from database inception to August 9, 2023, using the search term "autoimmune hepatitis" in combination with "incidence," "prevalence," or "trend." Only general population-based observational studies with larger samples sizes were considered for inclusion. Studies that recruited convenience samples, and those with fewer than 50 participants were excluded. Summary data were extracted from published reports. A random effects model was used and pooled estimates with 95% CI were used to calculate the incidence and prevalence of AIH. Heterogeneity was evaluated using the I2 statistic. The study protocol was registered with PROSPERO, CRD42023430138. Findings: A total of 37 eligible studies, encompassing more than 239 million participants and 55,839 patients with AIH from 18 countries across five continents, were included in the analysis. Global pooled incidence and prevalence of AIH were found to be 1.28 cases per 100,000 inhabitant-years (95% CI, 1.01-1.63, I2 = 99·51%; number of studies, 33; sample population, 220,673,674) and 15.65 cases per 100,000 inhabitants (95% CI, 13.42-18.24, I2 = 99·75%; number of studies, 26; sample population, 217,178,684), respectively. The incidence of AIH was greater in countries with high Human Development Index (>0.92), in North America and Oceania (compared with Asia), among females, adults (compared with children), and high latitude (>45°). Similar patterns in AIH prevalence were observed. Pooled AIH prevalence increased gradually from 1970 to 2019 (1970-1999; 9.95 [4.77-15.13], I2 = 95·58% versus 2015-2022; 27.91 [24.86-30.96], I2 = 99·32%; cases per 100,000 inhabitants). The overall incidence and prevalence of AIH, as well as some subgroup analyses of the studies, displayed asymmetry in the funnel plots, suggesting potential evidence of publication bias. Interpretation: AIH incidence and prevalence have increased significantly and exhibit substantial variation across regions worldwide. Further research is required to assess the incidence and prevalence of AIH, specifically in South America and Africa. Funding: National Research Foundation of Korea.

Clinical and genetic spectrum of GSD type 6 in Korea.

BACKGROUND: Glycogen storage disease type VI (GSD VI) is a rare disease in which liver glycogen metabolism is impaired by mutations in the glycogen phosphorylase L (PYGL). This study aimed to examine the clinical features, genetic analyses, and long-term outcomes of patients with GSD VI in Korea. METHODS: From January 2002 to November 2022, we retrospectively reviewed patients diagnosed with GSD VI using a gene panel at Seoul National University Hospital. We investigated the clinical profile, liver histology, molecular diagnosis, and long-term outcomes of patients with GSD VI. RESULTS: Five patients were included in the study. The age at onset was 18-30 months (median, 21 months), and current age was 3.7-17 years (median, 11 years). All patients showed hepatomegaly, elevated liver transaminase activity, and hypertriglyceridaemia. Hypercholesterolaemia and fasting hypoglycaemia occurred in 60% and 40% of patients, respectively. Ten variants of PYGL were identified, of which six were novel: five missense (p.[Gly607Val], p.[Leu445Pro], p.[Gly695Glu], p.[Val828Gly], p.[Tyr158His]), and one frameshift (p.[Arg67AlafsTer34]). All patients were treated with a high-protein diet, and four also received corn starch. All patients showed improved liver function tests, hypertriglyceridaemia, hepatomegaly, and height z score. CONCLUSIONS: The GSD gene panel is a useful diagnostic tool for confirming the presence of GSD VI. Genetic heterogeneity was observed in all patients with GSD VI. Increased liver enzyme levels, hypertriglyceridaemia, and height z score in patients with GSD VI improved during long-term follow-up.

Global Incidence and Prevalence of Eosinophilic Esophagitis, 1976-2022: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Owing to 2018 expanded diagnostic criteria for eosinophilic esophagitis (EoE) and thus a possible increase in diagnosis, previous studies on the global incidence and prevalence of EoE may need to be updated. We aimed to describe global, regional, and national trends in the incidence and prevalence of EoE from 1976 to 2022 and analyze their associations with geographic, demographic, and social factors through a systematic review. METHODS: We searched the PubMed/MEDLINE, Embase, CINAHL, Google Scholar, and Cochrane databases from their inception dates to December 20, 2022, for studies that reported the incidence or prevalence of EoE in the general population. We calculated the global incidence and prevalence of EoE using pooled estimates with 95% confidence intervals (CIs) and performed subgroup analysis based on age, sex, race, geographical area, World Bank income group, and diagnostic criteria of EoE. RESULTS: Forty studies met the eligibility criteria, including over 288 million participants and 147,668 patients with EoE from 15 countries across the five continents. The global pooled incidence and prevalence of EoE were 5.31 cases per 100,000 inhabitant-years (95% CI, 3.98-6.63; number of studies, 27; sample population, 42,191,506) and 40.04 cases per 100,000 inhabitant-years (95% CI, 31.10-48.98; number of studies, 20; sample population, 30,467,177), respectively. The pooled incidence of EoE was higher in high-income countries (vs low- or middle-income countries), males, and North America (vs Europe and Asia). The global prevalence of EoE followed a similar pattern. The pooled prevalence of EoE gradually increased from 1976 to 2022 (1976-2001; 8.18; 95% CI, 3.67-12.69 vs 2017-2022; 74.42; 95% CI, 39.66-109.19 cases per 100,000 inhabitant-years). CONCLUSIONS: The incidence and prevalence of EoE have increased substantially and vary widely across the world. Further research is needed to evaluate the incidence and prevalence of EoE in Asia, South America, and Africa.

The Effectiveness and Safety of Methotrexate as the First-Line Immunomodulator of Maintenance Therapy in Pediatric Crohn Disease.

OBJECTIVES: Methotrexate (MTX) has been used as maintenance therapy for Crohn disease (CD) in adults and children. However, there are only a few studies on the MTX's effectiveness in thiopurine-naïve CD adult patients and children. This study aimed to evaluate the MTX's effectiveness and safety as first immunomodulator for maintenance therapy in pediatric CD. METHODS: This retrospective cohort study recruited 64 pediatric CD patients treated with MTX as a first-line immunomodulator. Clinical remission (CR) was assessed at weeks 14, 26, and 52. Mucosal healing (MH) was assessed at weeks 26 and 52. RESULTS: Of 64 patients who received MTX, CR was noted in 60.9% at week 14, 29.7% with MH in 68.0% at week 26, and 27.8% with MH in 81.8% at week 52. When comparing age subtypes according to the Paris classification, the CR rate was higher in A1a than in the other subtypes at week 26 (60.0% in A1a, 26.5% in A1b, 0% in A2; P = 0.038). There were no differences in disease location, behavior, or perianal involvement. Adverse effects were noted in 30 of 64 (46.9%) patients, including 1 patient who stopped MTX before 26 weeks owing to side effects; increased liver enzymes in 25 (39.0%) patients, leukopenia in 5 (7.8%), nausea in 5 (7.8%), skin erosion in 1 (1.6%), and headache in 1 (1.6%). CONCLUSION: MTX as a first-line immunomodulator may be an effective and safe maintenance therapy for pediatric CD patients.

Long-Term Survival Outcomes beyond the First Year after Liver Transplantation in Pediatric Acute Liver Failure Compared with Biliary Atresia: A Large-Volume Living Donor Liver Transplantation Single-Center Study.

Pediatric acute liver failure (PALF) is a common cause of liver transplantation (LT) but showed poor post-LT outcomes. We reviewed 36 PALF patients and 120 BA patients who underwent LT in our institution. The cause of PALF was unknown in 66.7%. PALF patients were older (6.2 vs. 2.9 years) with higher PELD scores (31.5 vs. 24.4) and shorter waitlist time (15.7 vs. 256.1 days) (p < 0.01). PALF patients showed higher rates of post-transplant renal replacement therapy (RRT) (13.9% vs. 4.2%) and hepatic artery complications (13.9% vs. 0.8%), while portal vein complications rates were lower (0% vs. 10.8%), (p < 0.05). Although PALF patients showed lower 5-year survival rates (77.8% vs. 95.0 %, p < 0.01), the 5-year survival rates of patients who lived beyond the first year were comparable (96.6% vs. 98.3%, p = 0.516). The most common cause of deaths within one year was graft failure (75.0%) in PALF patients, but infection (67.7%) in BA patients. In multivariate analysis, lower body weight, hepatic artery complications and post-transplant RRT were associated with worse survival outcomes (p < 0.05). In conclusion, physicians should be alert to monitor the immediate postoperative graft dysfunction and hepatic artery complications and patients on post-transplant RRT in order to improve survival outcomes in PALF patients.

Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome.

Atypical progeroid syndrome (APS) is a rare type of progeroid syndrome mainly caused by heterozygous missense mutations in the LMNA (MIM 150330) gene. APS has heterogeneous clinical manifestations, and its kidney manifestations, particularly in children, are rarely documented. Here, we report the first pediatric case of APS with focal segmental glomerulosclerosis (FSGS). A 10-year-old boy with progeroid features was referred to the nephrology clinic because of hyperuricemia. He had dark skin, protruding eyes, and beaked nose and was very thin, suggesting lipodystrophy. He had been treated for recurrent urinary tract infection during infancy, and liver biopsy for persisting hepatitis showed steatohepatitis. He also had hypertrophic cardiomyopathy (HCMP) with mitral and tricuspid valve regurgitation. Genetic studies were performed considering his multisystem symptoms, and he was diagnosed as having APS according to exome sequencing findings (c.898G > C, p.Asp300His of LMNA). During the first visit to the nephrology clinic, he had minimal proteinuria (urine protein/creatinine ratio of 0.23 mg/mg), which worsened during follow-up. In three years, his urine protein/creatinine ratio and N-acetyl-b-D-glucosaminidase/creatinine ratio increased to 1.52 and 18.7, respectively. The kidney biopsy result was consistent with findings of FSGS, peri-hilar type, showing segmental sclerosis of 1 (5%) glomerulus out of 21 glomeruli. An angiotensin receptor blocker was added to manage his proteinuria. This is the first pediatric report of FSGS in an APS patient with confirmed LMNA defect, who manifested progeroid features, lipodystrophy, HCMP with heart valve dysfunction, and steatohepatitis. Our case suggests that screening for proteinuric nephropathy is essential for managing APS patients since childhood.

Association of Metabolic Signatures with Nonalcoholic Fatty Liver Disease in Pediatric Population.

Several adult omics studies have been conducted to understand the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, the histological features of children are different from those of adults, and the onset and progression of pediatric NAFLD are not fully understood. In this study, we aimed to evaluate the metabolome profile and metabolic pathway changes associated with pediatric NAFLD to elucidate its pathophysiology and to develop machine learning-based NAFLD diagnostic models. We analyzed the metabolic profiles of healthy control, lean NAFLD, overweight control, and overweight NAFLD groups of children and adolescent participants (N = 165) by assessing plasma samples. Additionally, we constructed diagnostic models by applying three machine learning methods (ElasticNet, random forest, and XGBoost) and multiple logistic regression by using NAFLD-specific metabolic features, genetic variants, and clinical data. We identified 18 NAFLD-specific metabolic features and metabolic changes in lipid, glutathione-related amino acid, and branched-chain amino acid metabolism by comparing the control and NAFLD groups in the overweight pediatric population. Additionally, we successfully developed and cross-validated diagnostic models that showed excellent diagnostic performance (ElasticNet and random forest model: area under the receiver operating characteristic curve, 0.95). Metabolome changes in the plasma of pediatric patients with NAFLD are associated with the pathophysiology of the disease and can be utilized as a less-invasive approach to diagnosing the disease.

Clinical characteristics of neonatal cholestasis in a tertiary hospital and the development of a novel prediction model for mortality.

BACKGROUND: Few studies have described the aetiologies of neonatal cholestasis, and the overall neonatal cholestasis-related mortality (NCM) rate is unclear. We investigated the aetiology and outcome of neonatal cholestasis in a tertiary hospital and developed an NCM prediction model for these patients. METHODS: Patients aged <100 days with serum direct bilirubin (DB) levels of >1.0 mg/dL were retrospectively screened. Diagnostic and laboratory data during the 8-week follow-up period after enrolment between 2005 and 2020 were extracted digitally, and medical charts were reviewed manually by clinicians. Logistic regression was used to derive a prediction model for the 1-year mortality outcome of neonatal cholestasis, and performance evaluation and external validation were conducted for the NCM prediction model. FINDINGS: We enrolled 4028 neonates with DB of >1.0 mg/dL at least once. Prematurity and birth injury (35.4%), complex heart anomalies (18.6%), liver diseases (11.4%), and gastrointestinal anomalies (9.2%) were the most common aetiologies; 398 (9.9%) patients died before one year of age. The peak value of DB was positively correlated to the 1-year mortality rate. In the multivariate analysis, simple laboratory indices, including platelet, prothrombin time, aspartate aminotransferase, albumin, direct bilirubin, creatinine, and C-reactive protein, were independent predictors of 1-year mortality outcome of complete-case subjects. Using these laboratory indices, a logistic regression-based NCM prediction model was constructed. It showed acceptable performances on discrimination (area under the curve, 0.916), calibration (slope, 1.04) and Brier scoring (0.072). The external validation of the sample (n = 920) from two other centres also revealed similar performance profiles of the NCM model. INTERPRETATION: Various aetiologies of neonatal cholestasis were identified in a tertiary hospital, resulting in unfavourable outcomes of a large proportion. The NCM prediction model may have the potential to help clinicians to be aware of high-risk neonatal cholestasis. FUNDING: Ministry of Health & Welfare, Republic of Korea.

ACTG2 Variants in Pediatric Chronic Intestinal Pseudo-obstruction With Megacystis.

BACKGROUND/AIMS: Chronic intestinal pseudo-obstruction (CIPO) is a clinically heterogeneous syndrome characterized by compromised peristalsis and intestinal obstruction. Variants of actin gamma 2 (ACTG2), a protein crucial for correct enteric muscle contraction, have been found in CIPO patients. The aim of this study is to examine the clinical features and ACTG2 variants in Korean patients with CIPO. METHODS: From January 1995 to August 2020, 12 patients diagnosed with CIPO were included and genetic analysis testing of ACTG2 was performed. RESULTS: Heterozygous ACTG2 missense variants were found in 6 patients (50.0%). The p.Arg257Cys variant was found in 3 patients, and p.Arg63Gln and p.Arg178His variants were found in 1 patient each. A novel variant, p.Ile193Phe, was found in 1 patient. Three patients were diagnosed at birth, 2 at the age of 1 year, and 1 at 3 years of age. Abnormal prenatal genitourinary ultrasonographic findings were found in all 6 patients; microcolon was found in 4 patients (66.7%), and megacystis in all 6 patients. The pathology showed abnormal ganglion cells as well as myopathic findings. All patients are dependent on total parenteral nutrition and are to date alive. CONCLUSIONS: ACTG2 variants are commonly found in Korean patients with CIPO. In CIPO patients with megacystis and abnormal prenatal ultrasonography, genetic testing of ACTG2 should be considered. Molecular diagnosis of CIPO is more important than pathologic diagnosis.

Effects of PNPLA3, TM6SF2 and SAMM50 on the development and severity of non-alcoholic fatty liver disease in children.

BACKGROUND: Although genetic variants of PNPLA3, TM6SF2 and SAMM50 have been reported to increase the risk of non-alcoholic fatty liver disease (NAFLD), no pediatric studies have evaluated the association between SAMM50 and NAFLD. OBJECTIVE: This study aimed to investigate the risk factors, including genetic variants, of pediatric NAFLD. METHODS: NAFLD was defined as the presence of hepatic steatosis on ultrasound. We included 228 patients with NAFLD (body mass index-Z [BMI-Z] = 2.51 ± 1.01) and 225 controls (BMI-Z = 0.22 ± 1.48). We genotyped four variants of PNPLA3 (rs738409), TM6SF2 (rs58542926) and SAMM50 (rs2073080 and rs3761472) by TaqMan allelic discrimination. The pediatric NAFLD fibrosis score, aspartate transaminase (AST)/platelet ratio index and fibrosis-4 score were used to evaluate the degree of fibrosis. We calculated the genetic risk score for additive effects according to the sum of risk alleles. RESULTS: The mean age was 12.6 ± 3.5 years. The four genetic variants, male sex and BMI-Z, independently increased susceptibility to NAFLD. These four variants, in addition to fasting insulin and triglycerides, remained significant risk factors with higher odds ratios in children with overweight. These variants increased the alanine aminotransferase (ALT) level and three fibrosis scores independently. As the genetic risk score increased, AST, ALT and the fibrosis scores increased independently. CONCLUSION: PNPLA3, TM6SF2 and SAMM50 are associated with the development and severity of pediatric NAFLD. The impact of genetic variants is greater in children with overweight. The four genetic variants have synergetic effects on the severity of pediatric NAFLD.

Colorectal Cancer associated with pediatric inflammatory bowel disease: a case series.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased risk of Colorectal cancer (CRC), and its most important risk factors are the duration and extent of the disease. Pediatric-onset inflammatory bowel disease has a tendency for a more extensive, more severe, and longer predicted disease duration than adult-onset inflammatory bowel disease. This study aimed to identify the clinical characteristics of patients with CRC related to pediatric-onset IBD and consider the appropriateness of current surveillance endoscopy recommendations for the detection of premalignant lesions and early-stage CRC. METHODS: We searched a research platform based on the SUPREME electronic medical record data-mining system to identify cases of colorectal malignancy in patients with pediatric IBD that presented between 2000 and 2020. RESULTS: During the follow-up, 4 (1.29 per 1000 person years) out of 443 patients with PIBD was diagnosed with CRC. The median age at diagnosis of CRC was 18.5 (range: 15-24) years, and the median period from diagnosis of IBD to CRC was 9.42 (range: 0.44-11.96) years. The sigmoid colon was the most frequent location of CRC (in 3 of the 4 cases). Adenocarcinoma was the most common histological type (in 2 of the 4 cases). CONCLUSIONS: Patients with pediatric-onset IBD exhibited a much shorter disease duration than that of adult-onset IBD at the time of diagnosis of CRC, suggesting that surveillance endoscopy for the detection of precancerous lesions and early-stage cancer should be initiated earlier in pediatric patients than in adult patients.

Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel.

Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder caused by mutations in the NPC1 and NPC2 genes. These mutations cause the accumulation of unesterified cholesterol and other lipids in the lysosomes. NPC has a broad spectrum of clinical manifestations, depending on the age of onset. A 15-day-old infant presented at the Seoul National University Children's Hospital with neonatal cholestasis and hepatosplenomegaly, with the onset of jaundice at 5 days of age. Despite supportive treatment, the patient was considered for a liver transplant because of progressive liver failure. Unfortunately, the patient died from gastrointestinal bleeding before undergoing the transplant. The neonatal cholestasis gene panel revealed two novel likely pathogenic variants in the NPC1 gene (c.1145C>G [p.Ser382*] and c.2231_2233del [p.Val744del]). The patient was diagnosed with NPC, and both parents were found to be carriers of each variant. In infants presenting with neonatal cholestasis, a gene panel can help diagnose NPC.

Ssu72 phosphatase directly binds to ZAP-70, thereby providing fine-tuning of TCR signaling and preventing spontaneous inflammation.

ZAP-70 is required for the initiation of T cell receptor (TCR) signaling, and Ssu72 is a phosphatase that regulates RNA polymerase II activity in the nucleus. However, the mechanism by which ZAP-70 regulates the fine-tuning of TCR signaling remains elusive. Here, we found that Ssu72 contributed to the fine-tuning of TCR signaling by acting as tyrosine phosphatase for ZAP-70. Affinity purification-mass spectrometry and an in vitro assay demonstrated specific interaction between Ssu72 and ZAP-70 in T cells. Upon TCR stimulation, Ssu72-deficient T cells increased the phosphorylation of ZAP-70 and downstream molecules and exhibited hyperresponsiveness, which was restored by reducing ZAP-70 phosphorylation. In vitro assay demonstrated that recombinant Ssu72 reduced tyrosine phosphorylation of ZAP-70 via phosphatase activity. Cd4-CreSsu72fl/fl mice showed a defect in the thymic development of invariant natural killer T cells and reductions in CD4+ and CD8+ T cell numbers in the periphery but more CD44hiCD62Llo memory T cells and fewer CD44loCD62Lhi naïve T cells, compared with wild-type mice. Furthermore, Cd4-CreSsu72fl/fl mice developed spontaneous inflammation at 6 mo. In conclusion, Ssu72 phosphatase regulates the fine-tuning of TCR signaling by binding to ZAP-70 and regulating its tyrosine phosphorylation, thereby preventing spontaneous inflammation.

Increased GM-CSF-producing NCR- ILC3s and neutrophils in the intestinal mucosa exacerbate inflammatory bowel disease.

OBJECTIVES: Inflammatory bowel disease (IBD) is characterised by dysregulated mucosal immune responses associated with genetic, environmental and microbial factors. Recent therapies targeting key inflammatory mediators such as tumor necrosis factor (TNF)-α emphasise the importance of innate immunity in the development of IBD. METHODS: We examined the distribution of innate immune cells such as innate lymphoid cells (ILCs) and myeloid cells in the intestinal epithelium from children diagnosed as IBD and murine models of colitis induced by dextran sulphate sodium (DSS) or an anti-CD40 antibodies. RESULTS: We found an increased number of type 3 ILCs (ILC3s) that do not express the natural cytotoxicity receptor (NCR) and neutrophils, in both human IBD patients and colitis-induced mice. A co-culture experiment of neutrophils with NCR- ILC3s revealed that NCR- ILC3s stimulate neutrophils by producing granulocyte-macrophage colony-stimulating factor (GM-CSF). Furthermore, a blockade of GM-CSF could inhibit the development of IBD by inhibiting neutrophil activity. CONCLUSION: The NCR- ILC3: GM-CSF: neutrophil axis could contribute to the development of IBD.

Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS; OMIM #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present 3 unrelated Korean SDS patients who carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiologic consequences. However, the milder EFL1 variant was still solely able to impair 80S ribosome assembly and induce SDS features in cell line and animal models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligopyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.