BACKGROUND:Differences in the clinical manifestation of pediatric coronavirus disease 2019 (COVID-19) across Omicron variants in emergency departments (EDs) remain unclear. PATIENTS AND METHODS:This retrospective observational study characterized the clinical features of pediatric patients with COVID-19 for each variant period at a primary ED in Kobe City, Japan. The variant-dominant periods comprised BA.1/BA.2 (sixth wave, January-June 2022), BA.5/BQ.1 (seventh-eighth waves, July 2022-March 2023), and XBB (ninth wave, April-December 2023). COVID-19 was diagnosed by rapid antigen testing. RESULTS:Among the 46,719 pediatric ED visits, 4085 were COVID-19 cases; 599 (9.0%), 2943 (15.4%) and 543 (2.6%) cases were diagnosed in the sixth, seventh-eighth, and ninth waves, respectively. During the XBB period, cough was significantly more frequent than in other periods and nasal discharge was more common compared with the BA.5/BQ.1 period. Vomiting occurred more frequently in the BA.5/BQ.1 period than in the BA.1/BA.2 period. Among children aged <1 year, vomiting was significantly more common during the XBB period. No significant differences were observed between patients aged 1-4 years. Dyspnea was more common in the BA.1/BA.2 than in the BA.5/BQ.1 period. In adolescents, fever occurred more frequently during the BA.5/BQ.1 period. CONCLUSION:This study compared pediatric COVID-19 cases across the BA.1/BA.2, BA.5/BQ.1, and XBB waves. Although evidence for the XBB wave remains limited, upper respiratory symptoms such as nasal discharge and cough were observed more frequently during this period. Distinct differences in clinical presentations according to variant type and age group were identified.

Anti-GD2 immunotherapy has improved outcomes in high-risk neuroblastoma; however, therapeutic responses remain heterogeneous. Although GD2 is generally assumed to be uniformly expressed in neuroblastoma, its spatial distribution within clinical tumors has not been systematically characterized. We therefore investigated intratumoral GD2 heterogeneity using whole-slide immunohistochemistry and explored its molecular regulation. GD2 expression was evaluated in 45 FFPE neuroblastoma tumors using standardized whole-slide immunohistochemistry and independently assessed by two pathologists. GD2 surface expression was analyzed by flow cytometry in 12 neuroblastoma cell lines. Functional roles of ganglioside biosynthetic enzymes were evaluated using siRNA-mediated knockdown. Whole-slide immunohistochemistry demonstrated frequent intratumoral GD2 heterogeneity. Fourteen tumors (31

A 63-year-old woman presented with numerous small cysts in both kidneys and the liver. The kidneys were not enlarged. Her serum creatine level was 1.34 mg/dL, estimated glomerular filtration rate 32 mL/min/m2, and urinary protein 0.6 g/g creatinine. A kidney biopsy was performed. Light microscopy showed small cysts derived from the proximal tubules and severe tubulointerstitial fibrosis; the remaining glomeruli were intact. Fluorescence imaging showed no immunoglobulin or complement deposition. In the glomerular basement membrane (GBM), electron microscopy revealed not only widespread thinning (180-200 nm) but also partial irregular thickening with subendothelial edema. The patient’s mother had a history of asymptomatic hematuria, so genetic testing was performed. Testing revealed a missense heterozygous variant in exon 2 of ALG5, NM_013338.5:c.236G>A, p.(Arg79Gln). Recently, a collection of European cases has led to an increasing focus on this ALG5 variant as a rare cause of autosomal dominant polycystic kidney disease. In the present case, the clinical picture was similar to that of previously reported cases, but the presence of cysts in the liver and thinning of the glomerular basement membrane were unique findings. Electron microscopy revealed abnormal GBM, and genetic testing identified a novel heterozygous mutation in exon 40 of the COL4A4 gene. A diagnosis of autosomal dominant Alport syndrome was made.

Introduction PTEN hamartoma tumor syndrome (PHTS) is a hereditary tumor syndrome characterized by macrocephaly, neurodevelopmental disorders, mucocutaneous lesions, and predisposition to tumors. In childhood, the characteristic mucocutaneous and tumor-related manifestations may not yet be apparent; hence, diagnosis is often difficult. Therefore, genetic tools, such as whole-exome sequencing (WES) and transcript analysis may be useful for accurate diagnosis. We report a child presenting with macrocephaly and developmental delay who was diagnosed with PHTS using WES and transcript analysis. Case report A three-year-old girl presented with macrocephaly and a mild developmental delay. NSD1 testing and chromosomal microarray analysis were unremarkable. However, WES revealed a heterozygous splice-site variant of PTEN (NM_000314.8:c.802-1G>A). Further transcript analysis using reverse transcription-polymerase chain reaction, TA cloning, and Sanger sequencing revealed an aberrant transcript lacking the first nucleotide at the 5′ end of exon 8. Based on these molecular findings, the patient was diagnosed with PHTS. Subsequently, genetic counseling was provided, and tumor surveillance was planned. Discussion The aberrant splicing identified in this patient supports the loss-of-function effect of PTEN. This splicing pattern differs from that previously observed for variants at the same splice acceptor site (c.802-2A>G and c.802-2A>T). Thus, transcript analysis may be useful for evaluating variant-specific effects. In addition, early diagnosis of PHTS in this patient was crucial for planning tumor surveillance and providing genetic counseling. This case highlights the utility of comprehensive genetic analysis in children with macrocephaly and neurodevelopmental disorders and emphasizes the value of transcript analysis for interpreting splice-site variants.

INTRODUCTION:While calcineurin inhibitors (CNIs) reduce proteinuria in a subgroup of children with genetic podocytopathies, previous reports suggest that the response is short-lived and of no benefit to long-term outcomes. Here, we assess CNI response sustainability and the association between different patterns of response preservation and kidney survival. METHODS:We performed a retrospective cohort study of patients aged 0-18 years with genetic podocytopathies treated with CNIs for at least three months from 34 pediatric nephrology centers worldwide. Response status was defined in accordance with International Pediatric Nephrology Association Clinical Practice Recommendations. RESULTS:We analyzed 136 patients with genetic podocytopathies over a median follow-up period of 42.1 months (between CNI initiation and last follow-up or commencement of kidney replacement therapy, whichever occurred first). At least partial response was attained in 28% and 22% of patients at six months post-CNI initiation and last follow-up, respectively. Compared to no response group, patients with at least partial response at six months had significantly lower urine protein-to-creatinine ratios across various time points post-CNIs. 71%, 11% and 18% exhibited no response, non-sustained and sustained response, respectively, throughout the observation period. Both sustained and non-sustained responses were significantly associated with superior kidney survival compared to no response. Importantly, no patients with sustained response developed kidney failure over a follow-up period of 42 (interquartile range 19-62) months. Patients with non-sustained response had a 92% lower risk of kidney failure compared to non-responders. CONCLUSIONS:A subset of children with genetic podocytopathies experienced a sustained response to CNIs, and none developed kidney failure. Children with non-sustained response still demonstrated superior kidney survival compared to non-responders. Our findings may support a trial of CNIs in genetic podocytopathies, and continuing therapy among those showing clinical response.

Background Congenital cytomegalovirus (CMV) infection is a leading cause of neurodevelopmental disabilities. Although oral valganciclovir (VGCV) treatment has shown short-term benefits, long-term outcomes beyond 3 years remain unclear. Objective To evaluate 4-year neurodevelopmental outcomes in infants with symptomatic congenital CMV (SCCMV) disease treated with VGCV and identify predictors of adverse outcomes. Methods This prospective follow-up study (VGCV-2) included 24 infants with SCCMV disease who received oral VGCV (16 mg/kg, twice daily for 6 months). Neurodevelopmental assessments were performed at 1, 2, 3, and 4 years of age using the Kyoto Scale of Psychological Development (KSPD). The primary outcome was developmental delay (developmental quotient [DQ] < 70) at 4 years. Secondary outcomes included diagnoses of neurodevelopmental disorders and results of autism spectrum disorder (ASD) screening. Results Twenty-one participants (87.5%) completed the 4-year follow-up. Developmental delay was evident in 28.6% (6/21) of patients at 4 years. Neurodevelopmental disorders, including intellectual disability (28.6%), ASD (19.0%), and cerebral palsy (14.3%), were diagnosed in 42.9% (9/21) of patients. A poorer best-ear hearing assessment at baseline was a significant predictor of developmental delay. Shorter body length, smaller head circumference at birth, and poorer baseline hearing were significantly associated with the diagnosis of neurodevelopmental disorders. Early positive Modified Checklist for Autism in Toddlers screening at 2 and 3 years strongly predicted the diagnosis of neurodevelopmental disorders. Conclusion Despite VGCV treatment, substantial neurodevelopmental impairment persisted for 4 years in children with SCCMV disease. Early clinical markers can help identify high-risk infants who require intensive developmental support. (Clinical trial registration: jRCT2051190075).

Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder caused by GATA-binding protein 3 (GATA3) haploinsufficiency. Although the clinical triad is well recognized, the phenotype is often incomplete, making clinical diagnosis challenging. This study aimed to elucidate the clinical and genetic characteristics of HDR syndrome in a kidney disease cohort. We retrospectively analyzed patients with absent or mild urinary abnormalities who underwent genetic testing for chronic kidney disease (CKD) between 2010 and 2025. Targeted next-generation sequencing–based kidney disease panels were used, and copy number variations were assessed using array comparative genomic hybridization. Among 1254 families with CKD, pathogenic or likely pathogenic GATA3 variants were identified in 10 patients (seven families). One additional patient with a clinically compatible phenotype carried a missense variant of uncertain significance. The median age at diagnosis was 5 years (IQR, 2–23; range, 0.7–44 years). GATA3 variants included missense (n = 3, including one variant of uncertain significance), nonsense (n = 2), short insertion/deletion (n = 2), and a whole-gene deletion (n = 1). Regarding the classical triad, hypoparathyroidism, deafness, and renal anomalies were observed in 45, 100, and 90

The mutant glycine amidinotransferase (GATM) protein polymerizes into a characteristic crystal, resulting in mitochondrial dysfunction in proximal tubules and Fanconi syndrome with progressive kidney failure. We identified a novel hereditary Fanconi syndrome characterized by mutant GATM proteins in a Japanese family, the first in Asia. Kidney biopsies exhibited typical histological features, confirmed by immunofluorescent staining with anti-GATM and anti-ATP synthase β subunit (ATPB) antibodies and electron microscopy. Quantitative immunofluorescence analysis showed a significant correlation between ATPB and GATM-ATPB colocalization, suggesting mitochondrial pathogenicity of the mutant. Previously reported GATM mutations, clustered in the fourth of 5 β-sheets of the GATM protein, are assumed to have increased adhesive properties, changing the β-sheet from its original dimeric form to a unique polymerization. Targeted panel sequencing showed a novel mutation (Q268E) in the GATM gene (NM_001482.3: c.802C>G), distinct from this sheet. Because conventional methods failed to detect the significance, we employed an advanced molecular dynamics approach-hypersound-perturbed molecular dynamics simulations. This analysis effectively demonstrated that the Q268E mutation enhanced conformational flexibility of region-spanning residues that are spatially positioned between the mutated site and the sheet, leading to the pathological polymerization of the mutant protein. This simulation offers valuable insights into the pathological mechanisms of abnormal protein conformation.

Townes-Brocks syndrome (TBS) is an autosomal dominant hereditary disorder caused by SALL1 variants, characterized by auricular malformations, anal anomalies, and limb deformities, often accompanied by kidney dysfunction. We describe a case of TBS, which was suspected after birth, in a 27-year-old man presenting with progressive kidney dysfunction and obesity. At age 16, school urinalysis revealed proteinuria and impaired kidney function. A kidney biopsy at that time showed a perihilar variant focal segmental glomerulosclerosis (FSGS) lesion, and the patient was treated with angiotensin II receptor blocker and sodium/glucose cotransporter 2 inhibitor. Kidney function gradually declined, prompting a second biopsy at age 27, which revealed progressive FSGS lesions and interstitial fibrosis/tubular atrophy. Genetic analysis identified a pathogenic SALL1 variant, confirming the diagnosis. This case demonstrates the mechanistic link between SALL1 variants, congenital renal hypoplasia, impaired podocyte repair, and obesity-related hyperfiltration, culminating in rapid development of FSGS. Longitudinal histopathological analysis through repeated biopsy was essential for understanding this progression. The integration of sequential renal biopsies and genetic analysis provided unique pathophysiological insight and diagnostic clarity in TBS-associated kidney disease. In patients with TBS and congenital nephron reduction, weight control is particularly important to mitigate obesity-related hyperfiltration injury.