BACKGROUND:Prostaglandin E-major urinary metabolite (PGE-MUM) is an emerging noninvasive biomarker used to evaluate clinical and endoscopic activity in patients with inflammatory bowel disease. Previous studies have shown that PGE-MUM values correlate with colonic inflammation in pediatric ulcerative colitis; however, reference values for children without inflammation have not been defined yet. This study aimed to determine the normal reference values of PGE-MUM in healthy pediatric subjects without inflammatory conditions. METHODS:Between December 2018 and January 2022, we prospectively enrolled 221 participants (cross-sectional study, aged 0-15 years) who were undergoing growth hormone stimulation testing for diagnostic purposes and exhibited no symptoms of inflammation or elevated C-reactive protein levels at a single pediatric center in Japan. PGE-MUM values were measured using a chemiluminescent enzyme immunoassay and assessed for age- and sex-related differences. RESULTS:A total of 218 participants were included in the analysis. Based on age, the participants were classified as young children (2-6 years, n = 147) and older children (7-14 years, n = 66); the reference ranges for the two groups were identified as 18.4-58.7 μg/g·Cr and 12.4-50.3 μg/g·Cr, respectively. The PGE-MUM values tended to decrease with increasing age; however, no significant sex-related differences were observed (median 29.1 μg/g·Cr for boys versus 30.4 μg/g·Cr for girls). CONCLUSIONS:Healthy pediatric subjects generally have higher PGE-MUM values than healthy adults, with particularly elevated values in young children (2-6 years). These observations suggest that age-related variability must be taken into account when using PGE-MUM as a biomarker in young children with ulcerative colitis.

Very-early-onset inflammatory bowel disease (VEO-IBD), representing cases diagnosed before age 6 years, is increasing in prevalence. Although VEO-IBD often presents as severe, treatment-resistant disease requiring biologic agents, studies showing the effectiveness of biologics, such as ustekinumab (UST) and vedolizumab (VDZ), remain limited. We retrospectively analyzed patients with VEO-IBD treated for at least a year from 13 institutions in Japan, evaluating clinical course including effectiveness of biologics, such as infliximab (IFX), adalimumab (ADL), UST, and VDZ. Patients with monogenic IBD were excluded. Steroid-free clinical remission (SFCR) and treatment persistence were assessed separately for first-line and for second-line or subsequent biologic therapies. We studied 101 VEO-IBD patients (56

Purpose:Functional dyspepsia (FD) is a chronic disorder characterized by upper abdominal symptoms in the absence of an identifiable organic cause. Although the efficacy of acotiamide has been demonstrated in adults with FD, its effectiveness in pediatric patients remains unclear. This study aimed to evaluate the efficacy of acotiamide in pediatric patients with FD. Methods:We conducted a retrospective analysis of 33 patients with FD, aged <16 years, who received acotiamide at a single children's hospital between August 2013 and March 2022. Results:Symptomatic improvement was observed in 57.6% (19/33) of patients one month after acotiamide administration. The improvement rates were 63.6%, 20.0%, and 66.7% among patients with epigastric pain syndrome (EPS), postprandial distress syndrome (PDS), and overlap PDS-EPS, respectively. No statistically significant differences in symptomatic improvement rates were noted among the subtypes (p=0.213). Two patients discontinued acotiamide because of abdominal pain, but no serious adverse events were reported. Conclusion:Acotiamide demonstrated efficacy in pediatric FD, which is consistent with previously reported outcomes in adults. Acotiamide may be a beneficial treatment option for pediatric FD across all subtypes.

Enterolithiasis is typically associated with gastrointestinal tract stasis. Here, we report on a rare case of chronic intestinal pseudo-obstruction with sand-like enterolithiasis in an 18-year-old Japanese female admitted to our hospital with high fever and abdominal pain. Despite initiating antibiotic treatment, the fever persisted. A contrast-enhanced computed tomography revealed colonic enlargement and a large amount of residue with a high-density area in the ascending colon. A colonoscopy revealed sand-like enteroliths in the ascending colon, which were drained using a colonoscope. The patient’s symptoms improved significantly after the drainage and antibiotic therapy. The granules were white-brown in color and smaller than 300 μm in size. Infrared spectroscopy indicated similar peaks for crystals and hydroxypropyl cellulose which is an additive used in certain medications. We hypothesized that hydroxypropyl cellulose contributed to the formation of sand-like enteroliths in cases of severe intestinal dysmotility. Intestinal failure may cause enterolithiasis due to an unharmful additive and require careful follow-up.

INTRODUCTION:Outbreaks of acute hepatitis of unknown etiology (AHUE) in children were reported in Western countries in 2022. Previous studies found that adeno-associated virus 2 (AAV2) and its helper viruses, such as human adenovirus (HAdV) and human herpesvirus-6 (HHV-6), are frequently detected in patients with AHUE. However, the existence of hepatitis associated with AAV2 prior to AHUE outbreaks in 2022 had not yet been investigated. We aimed to investigate the association between AAV2 and pediatric acute hepatitis in Japanese children, as well as the incidence of AAV2-related hepatitis prior to 2022. METHODS:Preserved blood samples obtained from 49 pediatric patients with acute hepatitis between 2017 and 2023 were retrospectively analyzed. Blood samples from 50 children with acute illnesses and 50 children with chronic conditions were used as controls. Viral DNA loads were quantitated using real-time PCR. RESULTS:AAV2 DNA was detected in 12 % (6/49) of acute hepatitis cases but in only one acute illness and none of the chronic-condition control cases. The concentration of AAV2 DNA in the six acute hepatitis cases was higher than that in the acute-illness control case. Co-infection with one or more helper viruses, including HAdV, HHV-6, cytomegalovirus, and Epstein-Barr virus, was observed in five AAV2-positive cases. CONCLUSIONS:Our results indicated the sporadic occurrence of pediatric severe hepatitis associated with AAV2 infection in Japan prior to the AHUE outbreaks in 2022. Our findings suggest that co-infection with AAV2 and helper viruses plays a role in developing severe hepatitis.

Obesity is a major complication in individuals with 21-hydroxylase deficiency (21-OHD) and excessive hydrocortisone (HC) dosing is a likely contributing factor. However, the association between the HC dosage and body mass index (BMI) during childhood remains unclear. We previously reported a positive correlation between HC dosage during late infancy and a subsequent increase in BMI. In this study, we expanded our research to assess the impact of HC dosage during childhood. We retrospectively collected data on HC dosages and BMI in 28 patients with 21-OHD (9 boys and 19 girls) at both 3 and 10 yr of age and conducted correlation analyses between HC dosage and BMI. No significant cross-sectional associations were observed between the body-surface-area adjusted HC dosage (HC/BSA) and BMI standard deviation score (BMI-SDS) at either 3 or 10 yr of age. However, the HC/BSA at 3 yr positively correlated with the BMI-SDS at 10 yr, indicating a longitudinal relationship. Furthermore, children whose HC/BSA at 3 yr fell almost within the guideline-recommended range exhibited significantly lower BMI-SDS at 10 yr compared to those receiving higher doses. The longitudinal association between HC dosage and BMI suggests the importance of careful HC dose monitoring, although causality could not be established.

OBJECTIVE:Accurate evaluation of thyroid dysfunction in children with Down syndrome is challenging because of the lack of age-specific reference intervals in these individuals. This study aimed to establish age-specific reference intervals for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels in children with Down syndrome. METHODS:A retrospective cross-sectional study was conducted on children with Down syndrome, aged 6 months to 15 years, who visited the Osaka Women's and Children's Hospital between April 2019 and March 2020. Subjects who had used medications that influenced thyroid function or who lacked thyroid hormone data were excluded from the study. The final analysis included 301 subjects. Serum TSH and FT4 levels were measured, and reference intervals were calculated using nonparametric methods. RESULTS:The reference intervals for TSH in children with Down syndrome were 2.03-14.22, 1.79-12.98, 1.26-10.24, and 0.58-10.11 mIU/L in infants, toddlers, school children, and adolescents, respectively, which were higher than those observed in the general paediatric population. The reference intervals for FT4 were 13.57-26.42, 13.20-22.70, 13.15-22.36, and 11.97-24.77 pmol/L, respectively, which were comparable to those of the general paediatric population. Multivariate regression analyses revealed a significant inverse association between age and the levels of TSH and FT4 (p < 0.01). CONCLUSIONS:We provide evidence for age-specific reference intervals for TSH and FT4 levels in children with Down syndrome, which may help clinicians accurately evaluate thyroid hormone status.

Impaired linear growth is an important morbidity in childhood cancer survivors (CCS); however, chemotherapy-associated factors that affect height outcomes remain elusive. Accordingly, we conducted a single-center, retrospective cohort study that included survivors of childhood-onset acute lymphoblastic leukemia (ALL) diagnosed between 2002 and 2021 who achieved complete remission through chemotherapy alone. Anthropometric parameters and treatment protocols were evaluated based on medical records. Individuals with background disorders or impaired growth were excluded from the study. Associations between anthropometric parameters during chemotherapy and height standard deviation scores (height-SDS) at the current visit were investigated. The results are expressed as the median (interquartile range). Seventy-three individuals (males, N = 44) were included in the study. The median age (years) at diagnosis, end of chemotherapy, and current visit were 4.2 (3.2 to 7.9), 6.3 (5.1 to 10.0), and 15.9 (11.4 to 19.2), respectively. Height-SDS at diagnosis was -0.25 (-0.65 to 0.35), which significantly declined during chemotherapy and recovered thereafter, resulting in a current height-SDS of -0.31 (-0.84 to 0.22). The height-SDS at the investigated time points and its changes during chemotherapy did not differ among the treatment protocols. Multivariate analysis revealed that height-SDS at the current visit was positively associated with changes in body mass index (BMI)-SDS during chemotherapy (β = 0.22, p = 0.01) after adjusting for sex, current age, height-SDS at diagnosis, changes in height-SDS during chemotherapy, and treatment protocols. Since changes in BMI are potentially influenced by nutritional status, our results may underscore the importance of nutritional status during chemotherapy on height outcomes in childhood ALL survivors.

Abstract Background Outbreaks of acute hepatitis of unknown etiology (AHUE) in children were reported in Western countries in 2022. Previous studies found that the adeno-associated virus 2 (AAV2) and other viruses, such as human adenovirus (HAdV) and human herpesvirus-6 (HHV-6), were frequently detected in patients with AHUE. As HAdV and HHV-6 are known as “helper viruses” that facilitate AAV2 replication, co-infection with AAV2 and helper viruses has been postulated as a potential trigger of AHUE. However, whether hepatitis associated with AAV2 existed prior to the AHUE outbreaks in 2022 has not yet been investigated. We aimed to investigate the association between AAV2 and pediatric acute hepatitis in Japanese children as well as the incidence of AAV2-related hepatitis before 2022. Visual abstract Methods Preserved blood samples from 49 pediatric patients (median age: 3 years) with acute hepatitis of unknown etiology between 2017 and 2023 were retrospectively analyzed. Blood samples from 50 children with acute illnesses, such as infectious diseases and 50 children with chronic conditions were used as controls. Viral DNA loads were quantified using real-time PCR. Results AAV2 DNA was detected in 12% (6/49) of acute hepatitis cases (median age: 2.5 years), but in only one acute illness case and none of the chronic condition control cases. The concentration of AAV2 DNA (range: 2.5×103 to 5.0×108 copies/mL) in the six patients in the acute hepatitis group was higher than that in the patient in the acute-illness control case (7.8×102 copies/mL). Co-infection with one or more helper viruses, including HAdV, HHV-6, cytomegalovirus, and Epstein–Barr virus, was observed in five of six AAV2-positive acute hepatitis cases. Conclusion Our results indicate the sporadic occurrence of severe pediatric hepatitis associated with AAV2 infection in Japan prior to AHUE outbreaks in Western countries in 2022. Conversely, the detection rate of AAV2 in this study was much lower than that of AHUE in Western countries, suggesting that the outbreak of AHUE related with AAV2 is an exceptional phenomenon associated with mitigation measures against COVID-19. Our findings suggest that coinfection with AAV2 and helper viruses plays a role in the development of severe hepatitis. Disclosures All Authors: No reported disclosures

Noonan syndrome (NS) is caused by pathogenic variants in genes encoding components of the RAS/MAPK pathway and presents with a number of symptoms, including characteristic facial features, congenital heart diseases, and short stature. Advances in genetic analyses have contributed to the identification of pathogenic genes in NS as well as genotype-phenotype relationships; however, updated evidence for the detection rate of pathogenic genes with the inclusion of newly identified genes is lacking in Japan. Accordingly, we examined the genetic background of 116 individuals clinically diagnosed with NS and the frequency of short stature. We also investigated genotype-phenotype relationships in the context of body mass index (BMI). Genetic testing revealed the responsible variants in 100 individuals (86%), where PTPN11 variants were the most prevalent (43%) and followed by SOS1 (12%) and RIT1 (9%). The frequency of short stature was the lowest in subjects possessing RIT1 variants. No genotype-phenotype relationships in BMI were observed among the genotypes. In conclusion, this study provides evidence for the detection rate of pathogenic genes and genotype-phenotype relationships in Japanese patients with NS, which will be of clinical importance for accelerating our understanding of the genetic backgrounds of Japanese patients with NS.

Pathogenic variants of polycomb repressive complex-2 (PRC2) subunits are associated with overgrowth syndromes and neurological diseases. EZH2 is a major component of PRC2 and mediates the methylation of H3K27 trimethylation (H3K27me3). Germline variants of EZH2 have been identified as a cause of Weaver syndrome (WS), an overgrowth/intellectual disability (OGID) syndrome characterized by overgrowth, macrocephaly, accelerated bone age, intellectual disability (ID), and characteristic facial features. Germline variants of SUZ12 and EED, other components of PRC2, have also been reported in the WS or Weaver-like syndrome. EZH1 is a homolog of EZH2 that interchangeably associates with SUZ12 and EED. Recently, pathogenic variants of EZH1 have been reported in individuals with dominant and recessive neurodevelopmental disorders. We herein present sisters with biallelic loss-of-function variants of EZH1. They showed developmental delay, ID, and central precocious puberty, but not the features of WS or other OGID syndromes.

AIM:Few data on spontaneous clearance rates of cases of mother-to-child transmission of hepatitis C viral (HCV) infection are available in Japan. Furthermore, the treatment courses of interferon-based and direct-acting antiviral agent (DAA) therapies for children are also unclear. Our aim was thus to clarify the long-term natural progression of HCV infection and the treatment outcomes of children in Japan. METHODS:We conducted a combined multicenter, observational survey involving 65 pediatric institutions in Japan. Pediatric HCV infection cases with patients born between 1973 and 2021 were collected over the 11-year period from 2012 to 2022. A total of 563 patients were enrolled, with 190 excluded for having insufficient laboratory data or treatment information, resulting in 373 eligible cases. RESULTS:Of 328 cases of mother-to-child infection, 34 (10.4%) had spontaneous clearance, with a median time to spontaneous clearance of 3.1 years (range 0.9-7.2 years). Of the total 373 eligible cases, 190 received antiviral therapy (interferon-based therapy, 158; DAA therapy, 32). Sustained virologic response rates after first-line treatment were 75.3% (119/158) and 100% (32/32) for interferon-based therapy and DAA therapy, respectively, with the DAA group showing a shorter time from therapy initiation to viral negativity (2.7 vs. 1.0 months; p = 0.0031). CONCLUSIONS:Approximately 10% of Japanese children infected by mother-to-child transmission achieve spontaneous resolution of HCV infection. Our findings indicate that DAA therapy is safe and highly effective in Japanese children, achieving higher sustained virologic response rates and shorter time to clearance of the virus compared with interferon-based therapy.

We report the case of twins diagnosed with chronic enteropathy associated with the SLCO2A1 gene (CEAS) based on characteristic ulcer findings, which required 8 years to diagnose. Both twins had similar symptoms, including anemia and growth failure but the gastrointestinal tract was not evaluated initially because of mild symptoms that were considered consistent with psychological etiology. The endoscopic findings of the firstborn child showed spiral ulcer scars and pseudodiverticulum formation without Helicobacter pylori infection or eosinophilic infiltration in the duodenum. Since the twins presented with ulcers of an unknown cause simultaneously and the first-born child had a spiral ulcer, CEAS was suspected. Genetic analysis and high levels of prostaglandin E major urinary metabolites in the urine led to a definitive diagnosis of CEAS.

Purpose: To evaluate prolonged esomeprazole use in Japanese pediatric patients for reflux esophagitis (RE) maintenance therapy and prevention of gastric (GU) and/or duodenal ulcers (DU) while using non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: This multicenter, open-label, parallel-group, phase III study (NCT03553563) included patients who were administered esomeprazole according to body weight (10 mg/day [Groups 1 and 3] and up to 20 mg/day [Groups 2 and 4] for patients weighing 10-20 kg and >= 20 kg, respectively). Efficacy outcomes for Groups 1 and 2 (maintenance therapy for healed RE) and Groups 3 and 4 (prevention of long-term NSAID/LDA use-associated GU/DU) were the presence/absence of RE relapse and GU/DU recurrence, respectively. Results: Esomeprazole as maintenance therapy was associated with a low RE recurrence rate, independent of body weight or dosage. Recurrence rates of RE were 0.0% and 5.3% for Groups 1 and 2, respectively. In patients previously diagnosed with GU and/or DU due to long-term NSAID/LDA use, the recurrence rates of GU/DU during weeks 0-32 were 11.1% and 0.0% in Groups 3 and 4, respectively. Conclusion: Long-term use of 10- or 20-mg, once-daily esomeprazole demonstrated a favorable benefit-risk balance in preventing RE and suppressing recurrence of GU and/or DU secondary to NSAID or LDA therapy in Japanese pediatric patients. No new safety concerns were identified. Esomeprazole may be a viable option for managing RE and preventing GU and DU in Japanese pediatric patients.

Context Thyroglobulin (Tg), encoded by TG, is essential for thyroid hormone synthesis. TG defects result in congenital hypothyroidism (CH). Most reported patients were born before the introduction of newborn screening (NBS). Objective We aimed to clarify the phenotypic features of patients with TG defects diagnosed and treated since the neonatal period. Methods We screened 1061 patients with CH for 13 CH-related genes and identified 30 patients with TG defects. One patient was diagnosed due to hypothyroidism-related symptoms and the rest were diagnosed via NBS. Patients were divided into 2 groups according to their genotypes, and clinical characteristics were compared. We evaluated the functionality of the 7 missense variants using HEK293 cells. Results Twenty-seven rare TG variants were detected, including 15 nonsense, 3 frameshift, 2 splice-site, and 7 missense variants. Patients were divided into 2 groups: 13 patients with biallelic truncating variants and 17 patients with monoallelic/biallelic missense variants. Patients with missense variants were more likely to develop thyroid enlargement with thyrotropin stimulation than patients with biallelic truncating variants. Patients with biallelic truncating variants invariably required full hormone replacement, whereas patients with missense variants required variable doses of levothyroxine. Loss of function of the 7 missense variants was confirmed in vitro. Conclusion To our knowledge, this is the largest investigation on the clinical presentation of TG defects diagnosed in the neonatal period. Patients with missense variants showed relatively mild hypothyroidism with compensative goiter. Patients with only truncating variants showed minimal or no compensative goiter and required full hormone replacement.

BACKGROUND:Pediatric inflammatory bowel disease (PIBD) subtypes are classified according to the PIBD-classes criteria, comprising 23 items. These criteria were later simplified to 19 diagnostic items. Inflammatory bowel diseases (IBDs) are classified as ulcerative colitis (UC), atypical UC, IBD-unclassified (IBD-U), Crohn's disease (CD), or isolated colonic CD. This study aimed to validate the simplified PIBD-classes criteria in an Asian population and evaluate IBD-U characteristics. METHODS:Patients diagnosed with PIBD between 2007 and 2022 were retrospectively enrolled. Data regarding PIBD phenotypes, age at diagnosis, endoscopic and pathological findings, and biologics and/or steroid use were collected from medical records. Physician-assigned diagnoses were compared with simplified PIBD-classes criteria-based diagnoses. Differences in the clinical features of patients with IBD-U and other IBDs classified using the simplified PIBD-class criteria were also evaluated. RESULTS:Eighty-six patients were included, of whom 54 (63%) had UC, 21 (24%) had CD, and 11 (13%) had IBD-U. Using the simplified PIBD-classes criteria, 48 (56%) patients were diagnosed with UC, 3 (3%) with atypical UC, 22 (26%) with CD, 1 (1%) with isolated colonic CD, and 12 (14%) with IBD-U. The diagnoses were changed in 10 cases based on the simplified PIBD-classes criteria. There were no significant differences in age at diagnosis or rates of steroid and biologic use between IBD subtypes. CONCLUSIONS:Simplified PIBD-classes criteria-based diagnoses matched physician-assigned diagnoses in almost all cases. This study suggests that the simplified PIBD-classes criteria are useful at reducing diagnostic variability in multicenter and international PIBD studies.