Search Results (52)

The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase. However, significant inter-individual response variety and high risk of myelosuppression often disrupt therapy efficacy. Pharmacogenetics offer crucial strategies to personalized therapy. While thiopurine methyltransferase (TPMT) was initially the primary focus, the discovery of nudix hydrolase 15 (NUDT15) appears as a more comprehensive determinant of thiopurine intolerance. This review aims to consolidate and critically evaluate the advancement achieved in unraveling the biological mechanism and clinical significance of NUDT15 pharmacogenetics in thiopurine therapy. Foundational studies showed the vital role of NUDT15 in the detoxification of active thiopurines, with common genetic variants (for instance, p. Arg139Cys) significantly disrupting its activity, leading to the accumulation of toxic metabolites. Observational studies consistently associated NUDT15 variants with severe myelosuppression, notably in Asian populations. Recent randomized controlled trials (RCTs) confirmed that NUDT15 genotype-guided dosing effectively reduces thiopurine-induced toxicity without interfering with the therapeutic outcome. Despite these advancements, challenges remain present, including the incomplete characterization of rare variants, limited data in the diverse Asian populations, and the need for standardized integration with metabolite monitoring. In conclusion, NUDT15 pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines. Full article

Background: Developmental delay and intellectual disability (DD/ID) are frequently accompanied by epilepsy, and growing evidence implicates variants in voltage-gated calcium channel genes in their pathogenesis. This study aimed to investigate the association of polymorphisms in CACNA1A, CACNA1C, and CACNA1H with DD/ID and epilepsy comorbidity in Korean children. Methods: We retrospectively analyzed 141 pediatric patients diagnosed with DD/ID who underwent whole-exome sequencing (WES) and were not found to have pathogenic monogenic variants. Nine single-nucleotide polymorphisms (SNPs) across CACNA1A, CACNA1C, and CACNA1H were selected based on functional annotation scores and prior literature. Genotype data were extracted from WES variant files, and allele and genotype frequencies were compared with control data from the gnomAD East Asian population and the Korean Reference Genome Database (KRGDB). Subgroup analyses were performed according to epilepsy comorbidity. Results: The CACNA1A rs16023 variant showed a significantly higher B allele frequency in DD/ID patients than in both control datasets and was also associated with epilepsy comorbidity. Genotype distribution analysis revealed that the BB genotype of rs16023 was more frequent in patients with epilepsy. Conclusions: The CACNA1A rs16023 variant may contribute to genetic susceptibility to DD/ID and epilepsy in Korean children, potentially through regulatory mechanisms. These findings support the relevance of calcium channel genes in neurodevelopmental disorders and highlight the importance of integrating functional annotation in variant prioritization. Full article

Children may suffer knee injuries due to motor vehicle crashes, sports, and falls. Additionally, children can suffer from rheumatic, neurological, musculoskeletal, and neuromuscular disorders which restrict joint movement. These types of injuries and disorders often result in knee joint impairment, thereby affecting joint mobility. Understanding the range of motion (ROM) of the pediatric knee is vital in diagnosing, examining, and treating these injuries and disorders. This study was undertaken to establish normative values for passive (PROM) and active (AROM) range of motion of the pediatric knee and to examine the effects of anthropometric and demographic factors on knee joint ROM. Normative reference values for both passive and active knee ROM were established for 295 children in the United Arab Emirates (Arab and South Asian ethnicity). The subjects’ PROM averaged 131.2° (117.2°, 140.2°) for boys and 132.8° (120.9°, 140.3°) for girls. Similarly, the observed PROM for children was 132.2° (118.6°, 141.2°), versus 130.8° (119.9°, 139.3°) for adolescents. Conversely, the subjects’ AROM averaged 129.3° (118.8°, 137.9°) for boys and 130.5° (120.9°, 137.4°) for girls. The observed AROM averaged 130.2° (119.5°, 137.8°) for children and 128.6° (121.5°, 137.4°) for adolescents. Significant differences in knee ROM based on ethnicity were identified. Additionally, significant correlations were observed between anthropometric factors and knee joint ROM. The gender and age-based normative values established in this study can be used in medical and vehicle safety analyses of knee injuries sustained by children as well as in the evaluation of knee joint impairments due to rheumatic, neurological, musculoskeletal, and neuromuscular disorders, thereby improving the outcomes of knee injuries and the treatment of joint impairments in children. Full article

Background/Objectives: Despite the striking prevalence of pediatric chronic pain (20% of youth), its impact on culturally diverse populations, particularly Asian families, remains underexplored. The existing literature on parent protective behaviors predominantly focuses on Non-Hispanic White (NHW) families, where such behaviors often exacerbate pain outcomes, therefore informing a core treatment target in clinical practice. This study aims to explore the role of parent protective behaviors in relation to global and pain-related distress in Asian families in comparison to NHW counterparts. Methods: A sample of 1415 youth (Asian: n = 236; NHW: n = 1179) aged 8 to 17 completed a survey prior to their evaluation at a tertiary pain clinic. Bivariate correlations and independent-sample t-tests were conducted to assess differences in anxiety, depression, pain-related distress, and parent protective behaviors between groups. Multiple regression analyses were used to determine whether parent protective behaviors moderated the relationship between global distress and pain-related outcomes. Results: Asian youth reported significantly lower pain intensity and pain interference than NHW youth, while Asian parents reported significantly higher protective behaviors. Parent protective behaviors moderated the association between global distress (depression and anxiety) and pain catastrophizing for Asian families only. A three-way interaction (ethnicity x parent protective behaviors, global distress, B = −0.22, p < 0.001; B = −0.18, p < 0.01) revealed that protective behaviors influenced the distress–pain catastrophizing link differently by ethnicity. Conclusions: Differences were observed in the Asian youth’s experience of pain in comparison to their NHW counterparts. This study highlights the importance of considering culturally nuanced approaches in treating pediatric chronic pain, particularly when working with Asian families. Full article

Background: Vascular malformations (VAMs) impose multifaceted burdens extending beyond physical impairments to psychosocial dysfunction. While prior studies predominantly utilized generic quality-of-life instruments, disease-specific tools are critical for addressing heterogeneous symptom profiles and sociocultural variability, particularly in understudied Asian populations. This study investigated psychosocial impacts across pediatric and adult VAM patients via validated, condition-specific measures. Methods: A prospective cohort of 233 hospitalized VAM patients (114 pediatric patients, 119 adult patients) completed the OVAMA questionnaire, and 114 adult, 68 pediatric patients, and 115 parent-proxies completed corresponding PROMIS questionnaires. The subtypes included arteriovenous malformations (AVMs), venous/lymphatic/lymphovenous malformations (VMs/LMs/LVMs), port-wine stains (PWSs), and other vascular malformations. Statistical analyses (Mann–Whitney U test, Kruskal–Wallis test, linear regression) were used to evaluate associations between demographics, clinical characteristics, and psychosocial outcomes. Results: Compared with children, adults reported significantly greater distress related to general (p = 0.004) and appearance (p = 0.003) problems. Compared with AVM (p = 0.01) and PWS (p = 0.041) patients, VM/LM/LVM patients presented elevated general problem scores. Pain and bleeding were related to general problems, whereas temporary enlargement was related togeneral and appearance problems. The PROMIS results revealed that 42.1% of adults had below-normal psychosocial-positive scores, whereas 33% demonstrated abnormal psychosocial-negative scores. Pediatric self-reports were associated with higher anxiety and depression rates than parent proxies were, with the VM/LM/LVM subgroups reporting poorer family relationships (p = 0.0062) and life purposes (p = 0.0075). Treatment frequency was correlated with increased psychological stress in children (p = 0.007). Conclusion: VAMs significantly impair psychosocial functioning across all ages, with adults experiencing heightened distress and social role deficits. Pediatric patients with low-flow malformations (VMs/LMs/LVMs) face compound depressive symptoms and familial strain. Disease-specific tools such as OVAMA and PROMIS are essential for comprehensive assessments, guiding tailored interventions to address both physical and psychosocial burdens. Full article

Introduction: Childhood malnutrition remains a risk factor for morbidity and mortality. Children admitted to the Pediatric Intensive Care Unit (PICU) are at a higher risk of worsening nutritional status with adverse clinical outcomes. The burden of malnutrition is strongly linked to various well-defined social determinants of health, including race, socioeconomic status, and geography, as these factors influence household food insecurity. This study aimed to analyze the interrelationships of nutritional status, social determinants of health, and health outcomes in critically ill children. Methods: Retrospective cohort study of 6418 critically ill children admitted to PICU from January 2014 to December 2017. Demographic and anthropometric measurements were collected upon admission and outcomes. Based on the patient’s zip code, and median household income, we estimated the percentage of the population living in poverty, and the percentage of the population experiencing food insecurity for 5912 children. Results: The prevalence of underweight, chronic, and acute malnutrition was 13.2%, 17.9%, and 5.6%, respectively. Malnourished children had longer duration of mechanical ventilation and longer PICU and hospital lengths of stay (LOS) compared to nourished children. Underweight and chronic malnutrition were associated with higher mortality. Hispanic children had the highest prevalence of poverty level, while non-Hispanic Black children had the highest food insecurity level and lowest median income. Ethnicity was not associated with mortality. Conclusions: Malnourished critically ill children who were disproportionately non-Hispanic Black, Hispanic, and Asian had worse hospital outcomes, including prolonged hospital and PICU length of stay, increased time on mechanical ventilation, and a higher risk of mortality. Full article

Background: Eosinophilic esophagitis (EoE) is a chronic disease defined by esophageal dysfunction and >15 eosinophils per high-power-field on biopsy. Despite its increased incidence across the United States, studies evaluating its incidence at any state level are lacking. Methods: Record review of pediatric patients (<18 years) newly diagnosed with EoE based on ICD coding seen at the main two pediatric gastroenterology centers in the state: Children’s Nebraska (1 January 2016–31 December 2022) and Boys Town National Research Hospital (1 January 2022–31 December 2022). Data included demographics, age, and zip codes. Descriptive analysis focused on Nebraska residents. Results: The average point incidence of EoE between 2016 and 2022 was 10.84/100,000 inhabitants based on data from Children’s Nebraska. Considering both centers, the point incidence in Nebraska for 2022 was 32.45/100,000 inhabitants. Caucasians were 3.7 times more likely to be affected and older at time of diagnosis (average 9.7 years) compared to African Americans (7.0), Hispanics (7.4), and Asians (4.4). Conclusions: This is the first study evaluating the incidence of EoE in a specific U.S.A state. Studies at the state level are important to direct policy and interventions aiming limit its burden in communities. Full article

Introduction: Psoriasis (PSO) and atopic dermatitis (AD) have traditionally been considered distinct diseases, respectively, mediated by T-helper 1 (Th1) and the T-helper 2 (Th2) immune pathway. In recent years, there has been a growing body of evidence highlighting an overlap between the two conditions, such as Asian AD, pediatric PSO, or “psoriasis dermatitis/PSOREMA”. Moreover, psoriasis dermatitis can be induced by therapeutic interventions. For instance, anti-IL-4/IL-13 monoclonal antibodies, commonly used to treat AD, can induce psoriasiform reactions by inhibiting the Th2 pathway, thereby unmasking Th1/Th17-driven PSO. Conversely, anti-TNFα and anti-IL-17 therapies, effective for PSO, may induce eczematous reactions promoting a switch toward Th2-driven inflammation. Janus Kinase Inhibitors (JAK-i) and IL-23 antagonists may represent valid therapeutic options for managing psoriasis dermatitis. JAK-i exert broader immunomodulatory effects, inhibiting both Th1 and Th2 pathways; however, they require careful monitoring due to potential adverse events. In contrast, IL-23 antagonists specifically suppress the IL-23/IL-17 axis inhibiting the p19 subunit of IL-23 and could represent a safer option for patients with psoriasis dermatitis. Materials and Methods/Results: We present a series of five cases of psoriasis dermatitis, including both patients who had the condition from the onset and those who developed it during treatment, with tailored therapeutic strategies based on individual patient profiles, comorbidities, and the specific characteristics of their overlapping disease presentation. Conclusion: JAK-i and IL-23 antagonists are both valid therapeutic options for managing psoriasis dermatitis, but with different immunomodulatory effects and safety profiles. Future research should focus on a better understanding of the immune pathway and identifying specific biomarkers of psoriasis dermatitis, to optimize therapeutic strategies. Full article

Familial hypercholesterolemia is an autosomal hereditary disease defined by an increased level of low-density lipoprotein cholesterol (LDL-C), which predisposes significant risks for premature cardiovascular disorders. We present a family trio study: proband, a 13-year-old Kazakh girl with homozygous familial hypercholesterolemia (HoFH) and her parents. HoFH is much more rare and severe than a heterozygous form of the disorder. HoFH patients generally present with LDL-C levels exceeding 13 mmol/L, resulting in early and life-threatening cardiovascular events within the first decades of life. In cases of neglected treatment, young patients have a risk of death from coronary diseases before the age of 30. The aim of this research was to identify genetic mutations in the affected patient and her parents. Genetic testing was necessary due to highly elevated LDL-C levels and the presence of multiple xanthomas. Targeted next-generation sequencing (NGS) was performed in this study using the Illumina TruSight cardio panel, which targets 174 genes related to cardiac disorders. The girl was diagnosed with HoFH based on the results of genetic testing. A biallelic mutation was observed in exon 3 of the low-density lipoprotein receptor (LDLR): c. 295 G>A (p.Glu99Lys). Sanger sequencing confirmed that the mutant gene was inherited from both parents. After confirming the genetic diagnosis of HoFH, the patient was treated with LDL apheresis and statins. This case report is the first study of HoFH in a pediatric patient from the Central Asian region. Globally, it emphasizes the need for increased clinical awareness among healthcare providers, as early detection and intervention are important for improving outcomes, particularly in pediatric patients with this rare genetic disorder. Full article

Background: Pneumococcal disease (PD) is a major cause of morbidity and mortality in young children in Asia and globally. Pneumococcal conjugate vaccines (PCVs) have significantly reduced the burden of PD when included in pediatric national immunization programs (NIPs). This study estimates the clinical and economic burden of PD due to serotypes contained in different PCVs in children aged < 5 years in eight Asian countries/territories. Methods: Based on published data, a cohort-based decision analytic model was used to estimate annual PD cases, deaths, and direct medical costs associated with serotypes contained in PCV10, PCV13, PCV15, and PCV20. Results: PD incidence rates were lower in regions with PCV13 in their NIP than those without. Serotypes contained in higher but not lower valency PCVs resulted in a significant incremental clinical and economic burden, although the difference between PCV13 and PCV15 serotypes was generally small. Moving from PCV13 to PCV20 was estimated to result in greater clinical and economic burden reductions. Conclusions: This study demonstrates the remaining and incremental burden of PD from PCV10 to PCV20 serotypes in young children in selected Asian regions. Extending NIP access to higher-valency PCVs with broader serotype coverage and improving vaccine uptake will help prevent morbidity and deaths and save healthcare costs. Full article

The COVID-19 vaccine is safe and effective for children, yet parental hesitancy towards vaccinating children against the virus persists. We conducted a telephone-administered weighted survey in Texas to examine parents’ sociodemographic factors and medical conditions associated with COVID-19 vaccination intention for parents with unvaccinated children ages 5–17 years. We collected responses from 19,502 participants, of which 4879 were parents of children ages 5–17 years. We conducted multiple logistic regression with Lasso-selected variables to identify factors associated with children’s vaccination status and parents’ intention to vaccinate their children. From the unweighted sample, less than half of the parents (46.8%) had at least one unvaccinated child. These parents were more likely to be White, English-speaking, not concerned about illness, privately insured, and unvaccinated for COVID-19 themselves (p < 0.001). In the adjusted regression model, parents who were unvaccinated (vs. having COVID-19 booster, aOR = 28.6) and financially insecure (aOR = 1.46) had higher odds of having unvaccinated children. Parents who were Asian (aOR = 0.50), Black (aOR = 0.69), Spanish-speaking (aOR = 0.57), concerned about illness (aOR = 0.63), had heart disease (aOR = 0.41), and diabetes (aOR = 0.61) had lower odds of having unvaccinated children. Parents who were Asian, Black, Hispanic, Spanish-speaking, concerned about illness for others, and vaccine-boosted were more likely to have vaccination intention for their children (p < 0.001). Children’s vaccination is essential to reduce COVID-19 transmission. It is important to raise awareness about the value of pediatric COVID-19 vaccination while considering parents’ sociodemographic and medical circumstances. Full article

Since atopic dermatitis (AD) is a heterogeneous condition, the subtyping of AD is a crucial issue. The classical subtypes of AD are represented by extrinsic and intrinsic subtypes, European–American and Asian subtypes, and adult and pediatric subtypes. While the subtyping of AD was historically conducted based on the phenotype, recent findings on the mechanisms of AD have revealed the importance of the endotype, which can characterize individual patients more accurately. Considering the current development of AD therapies, AD endotyping is a prerequisite for a personalized therapeutic choice. Endotypes of AD can be stratified from different viewpoints, including cytokine expression patterns, allergen properties, epidermal barrier conditions, ceramide variation, the involvement of innate immunity, and serum biomarkers. Among them, the cytokine-based endotype seems to be the most useful one and is categorized into type 2 cytokine (IL-4, IL-13 and IL-31)-high, type 1 cytokine (IFN-γ)-high, and/or type 3 cytokine (IL-22 and IL-17)-high, or mixed subtypes. Recently proposed biomarker endotyping aims at individualized treatment options, although the daily clinical use of endotypes is a future issue. To better understand the endotypes for clinicians, attempts to adjust each of the classical subtypes to endotypes are required. This review will discuss the correspondence of the classical subtypes to the various endotypes that have recently been proposed. Full article

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with an increasing worldwide incidence. IBD is frequently diagnosed during childhood in the adolescent period of ongoing growth and development, and it can affect patients’ linear growth, puberty, nutrition, and bone health. Therefore, its treatment and monitoring are critical to prevent secondary outcomes. However, few studies have highlighted the association between pediatric IBD and skeletal outcomes in Asian populations. We aimed to identify the prevalence and risk factors for low bone mineral density (BMD) in Korean children and adolescents with newly diagnosed IBD. Patients aged 10–18 years diagnosed with either Crohn’s disease (CD) or ulcerative colitis (UC) who underwent lumbar spine bone mineral density (LSBMD) and femoral bone mineral density (FBMD) analyses via dual-energy X-ray absorptiometry at the time of IBD diagnosis were included. Low BMD was considered when the age- and sex-matched BMD Z-score was <−1.0. The LSBMD and FBMD Z-scores were correlated with clinical parameters, including general characteristics, anthropometry, and IBD-associated laboratory markers. Regression analyses were performed to identify the risk factors for low BMD. Although the general characteristics between CD (n = 42) and UC (n = 9) groups did not differ, the mean Z-scores of LSBMD and FBMD of the 51 subjects were −0.11 ± 1.24 and −0.58 ± 1.38, respectively. Furthermore, 7.8% and 18% of the study subjects had LSBMD and FBMD Z-scores < −2.0, whereas more than 50% had scores of 0–−1.0. Among the clinical factors, body mass index (BMI) Z-score, duration of clinical manifestations, and serum alanine aminotransferase and selenium levels were associated with LSBMD Z-scores in the final multivariate regression analyses. Odds ratios of BMI < −2.0 standard deviation for low LSBMD and FBMD Z-scores were 31.97 and 41.45, respectively. A BMI Z-score < −0.93 was determined as the best cut-off for predicting low BMD. In newly diagnosed pediatric IBD, a substantial number of children are likely to have low BMD in prior to initial treatment while lower BMI, longer duration of clinical manifestation, and higher selenium concentration could affect initial BMD status. Routine bone health surveillance from initial IBD diagnosis throughout the treatment’s completion is recommended for preventing the early development of secondary osteoporosis. Full article

Background: The recommended chronic kidney disease (CKD) first-line diagnostic test is based on the creatinine-derived (estimated) glomerular filtration rate (eGFR). Cystatin C use may provide a better assessment. Methods: We compared creatinine- and cystatin C-derived eGFR determination as the first-line diagnostic test for 112 hospital patients aged > 60 years (median = 76 years). The patients were judged to not have CKD (no-CKD group) according to the first-line diagnostic recommendations (n = 61, eGFR (CKD Epidemiology Collaboration (CKD-EPI)) ≥ 60 mL/min/1.73 m², total urine protein < 150 mg/g creatinine, urinary red/white blood cells not increased) or classified to be at risk for kidney insufficiency due to aortic valve dysfunction (at-risk group; n = 51). The accuracy of the eGFR values was evaluated retrospectively with the final case diagnoses. Results: The eGFR (Caucasian, Asian, pediatric, and adult formula (CAPA)) was found to be linearly correlated to the eGFR (CKD-EPI) (R² = 0.5, slope = 0.69, p < 0.0001). In 93/112 (>80%) cases, the eGFR (CAPA) yielded lower values (on average ≈−20%). In 55/112 (49%) cases, the cystatin C-derived CKD stage was lower. CKD reclassification from no-CKD to a kidney-insufficient state (i.e., CKD1/2 to CKD3a/b or 4) or reclassification to a more severe kidney insufficiency (i.e., CKD3a → 3b/4 or 3b → 4) was found in 41/112 (37%) cases. A worse CKD classification (no-CKD → kidney-insufficient) based on the eGFR (CAPA) was plausible in 30% of cases in light of the final case diagnoses. Conclusion: In elderly patients (>60 years), renal function appears to be systematically overestimated by the creatinine-based eGFR (CKD-EPI), indicating that, for this group, the cystatin C-based eGFR (CAPA) should be used as the first-line diagnostic test. Full article

Background: Few reports of benign recurrent intrahepatic cholestasis (BRIC) have focused on East Asian patients. We describe the clinicopathologic features, genetics, treatment, and outcomes in Japanese BRIC patients. Methods: We recruited patients with BRIC type 1 (BRIC-1) or 2 (BRIC-2) treated at four pediatric centers and one adult center between April 2007 and March 2022. Demographics, clinical course, laboratory results, molecular genetic findings concerning ATP8B1 and ABCB11 genes, histopathology, and treatment response were examined retrospectively. Results: Seven Japanese patients with BRIC were enrolled (four male, three female; four BRIC-1 and three BRIC-2). The median age at onset for BRIC-1 was 12 years; for BRIC-2, it was 1 month. Intermittent cholestatic attacks numbered from one to eight during the 11 years of median follow-up. Six patients received a mainstream education; only one patient attended special education. None developed cirrhosis. Three with BRIC-1 showed compound heterozygosity for a variant ATP8B1 gene, while one was heterozygous; two BRIC-2 patients showed compound heterozygosity in ABCB11 and one was heterozygous. Liver biopsy specimens obtained during cholestatic attacks showed fibrosis varying from none to moderate; inflammation was absent or mild. Rifampicin administered to three patients for cholestatic attacks was effective in all, as was cholestyramine in two of three. Conclusions: To our knowledge, this is the first East Asian multicenter study of BRIC patients. Onset age and number of cholestatic attacks varied. Rifampicin and cholestyramine were effective against attacks. No patient developed cirrhosis; most had normal growth and development. The long-term outcomes were satisfactory. Full article