Search Results (649)

Background/Objectives: Severe unstable hemoglobinopathies may cause transfusion dependence from early childhood, and allogeneic hematopoietic cell transplantation (allo-HCT) is the only established curative option. Pediatric experience with allo-HCT for unstable hemoglobinopathies is limited to isolated reports, and long-term outcomes remain poorly characterized. The objective of this study was to characterize the clinical and molecular features, transplant approaches, and long-term outcomes of two Brazilian patients with unstable hemoglobinopathies, in the context of the published pediatric literature. Methods: We performed a retrospective analysis of two children with unstable hemoglobinopathies who underwent allo-HCT at a Brazilian center. PubMed/MEDLINE and Scopus were searched for pediatric cases published between 2002 and 2025 using terms related to unstable hemoglobin variants and hematopoietic transplantation. Published cases were combined with the Brazilian patients to form an aggregated cohort. Clinical, molecular, transplant, and follow-up data were analyzed descriptively. Results: The aggregated cohort included 13 patients and 15 allo-HCT procedures, using matched sibling, haploidentical, and other alternative donors. All patients were transfusion-dependent before transplantation. Two patients required retransplantation after graft failure. At last follow-up, the nine published patients with available outcome data and both Brazilian patients were alive and transfusion independent. The Brazilian patients maintained complete donor chimerism and transfusion independence for 8 and 9 years, the longest follow-up reported in this population. One remained transfusion independent after retransplantation for secondary graft failure. Conclusions: Allo-HCT may achieve durable transfusion independence in children with severe unstable hemoglobinopathies, but the small number of reported cases limits the interpretation of these findings. Our series adds long-term follow-up data supporting this approach and highlights the need for larger, prospective studies to guide donor selection and conditioning strategies in this rare population. Full article

Background: Serum α-tocopherol depends on lipids, so absolute concentrations misclassify vitamin E status in children with chronic liver disease (CLD). The CALIPER program defined lipid-adjusted E:cholesterol (E:C) and E:triglyceride (E:TG) ratios, but their application in mixed-etiology pediatric CLD using immunoassay has not been reported. Methods: Exploratory single-center cross-sectional study of 66 children (observed age range 4 months–17.9 years) with mixed-etiology CLD. Retinol and total vitamin E were measured by ELISA, whereas the CALIPER reference intervals applied here were established for α-tocopherol measured by HPLC; the two platforms are not interchangeable, so every classification reported is an exploratory application of those cutoffs. Vitamin E status was classified by absolute concentration, E:C (<3.7) and E:TG (<8.5). Cholestatic (n = 15), non-cholestatic (n = 45) and post-transplant (n = 6) groups were compared. Results: Vitamin A was largely preserved (5.2% below WHO). Vitamin E was low in 45.3% by absolute concentration, 62.5% by E:C and 43.8% by E:TG. Of 35 children with a normal absolute vitamin E concentration, 11 (31.4%) were reclassified as low by E:C. Low E:C differed across groups (cholestatic 78.6%, non-cholestatic 63.6%, post-transplant 16.7%; p = 0.030). E:TG was inversely correlated with 25(OH)D (rho = −0.45; p < 0.001). Conclusions: Lipid-adjusted interpretation reclassified a substantial proportion of children whose absolute vitamin E concentration appeared adequate, and the prevalence of a low E:C ratio was lower among post-transplant participants than in the other two groups. In this exploratory cohort, the E:C ratio showed greater potential than the E:TG ratio for lipid-adjusted interpretation of vitamin E status; prospective validation against HPLC-based measurements and established functional indices is required before routine clinical adoption. Full article

Early extubation after pediatric liver transplantation (PLTx) is increasingly incorporated into enhanced-recovery pathways, yet definitions, selection criteria, and outcome reporting remain inconsistent. This narrative review synthesizes evidence identified through PubMed/MEDLINE (January 2000 through August 2026), citation screening, and supplementary screening of recent reports. Immediate extubation denotes tracheal extubation in the operating room, whereas early extubation has been defined through 24 postoperative hours; delayed extubation and prolonged mechanical ventilation are similarly heterogeneous. The available evidence informs a dynamic framework in which preoperative characteristics define baseline vulnerability, the intraoperative course reflects whether that vulnerability has been overcome or amplified, and the early postoperative course validates the decision. Young age, low body weight, growth failure, or higher disease-severity scores may increase risk but should not function as absolute exclusions; conversely, low scores may underestimate disease-specific risk in metabolic disorders. Direct readiness indicators include effective ventilation, neurological and quantitative neuromuscular recovery, normothermia, stable hemodynamics without escalating vasoactive support, controlled bleeding, satisfactory abdominal closure, and improving acid–base status and lactate clearance. Early extubation is associated with shorter intensive-care and hospital stays in selected cohorts, but causality remains uncertain because evidence is predominantly retrospective and single-center. Standardized definitions and prospective multicenter validation are required. Full article

Background: Recurrent acute liver failure (RALF) is a rare phenotype with heterogeneous inherited causes. Methods: We conducted a PRISMA 2020 systematic review of PubMed/MEDLINE and Web of Science Core Collection. Reports were classified into two non-combinable evidence sets: strict RALF, requiring at least two documented pediatric acute liver failure episodes with recovery of liver synthetic function between episodes, and contextual disease-specific evidence used only to inform broader natural history, treatment, or transplantation. Results: The searches identified 128 records; 30 duplicates were removed, and 98 records were screened. Forty-eight full texts were assessed, and 44 publications representing 41 study or cohort units were retained across both evidence sets. The evidence consisted predominantly of case reports, small case series, and retrospective cohorts, with inconsistent RALF definitions and incompletely reported follow-up. The five-group framework is a pragmatic organization of reported qualifying disorders rather than an exhaustive genetic classification. Conclusions: Genomic testing during a first unexplained severe episode is proposed to avoid waiting for recurrence, but most disorder-specific treatment and transplantation conclusions remain based on limited observational evidence and expert practice. Full article

Pleural and thoracic air-leak complications after hematopoietic cell transplantation (HCT) are clinically important but underrepresented in broad post-transplant pulmonary reviews. Direct evidence is concentrated in adult allogeneic HCT. In a cohort of 618 adults, clinically significant pleural effusion had a 1-year cumulative incidence of 9.9% (95% confidence interval, 7.7–12.5%). A separate computed tomography-based cohort of 178 first allogeneic HCT recipients reported a day-100 cumulative incidence of 41.0%; these estimates are not directly comparable because the populations, ascertainment methods, endpoints, and follow-up differed. In 50 HCT recipients undergoing thoracentesis, a specific diagnosis was established in 26%, with 5 pneumothoraces and 0 hemothoraces. Thoracic air-leak syndrome is uncommon but carries poor outcomes in reported adult and pediatric series. This focused narrative review distinguishes direct HCT evidence from data extrapolated from hematologic malignancy, general pleural practice, critical care, interventional radiology, and cellular therapy. We organize evaluation by urgency, transplant phase, and radiographic pattern; define chronic graft-versus-host disease serositis as a diagnosis of exclusion; summarize chylothorax and pleural infection management; and provide procedure-specific safety considerations for thoracentesis, small-bore drainage, indwelling pleural catheters, intrapleural enzyme therapy, and pleural biopsy. No prospective HCT-specific trials validate these procedural pathways. Clinicians should therefore use ultrasound or image guidance; apply procedure-specific rather than uniform hemostatic thresholds; and integrate infection risk, platelet trajectory, anticoagulant exposure, oxygenation, operator setting, and expected benefit. The two clinical frameworks presented are proposed and non-validated. Full article

Background/Objectives: Although minimally invasive laparoscopic donor nephrectomy (LDN) has been established as the standard method for donor nephrectomy for adult recipients in recent years, there might still be a role for conventional open donor nephrectomy (ODN) in pediatric kidney transplantation (KTx). To investigate this, we compared the outcomes of LDN with those of ODN in pediatric patients. Methods: A systematic literature search was conducted in Web of Science and Medline (via PubMed) databases, focusing on intraoperative data in donors and short-term postoperative outcomes in pediatric recipients following ODN and LDN. We used a subgroup analysis to compare these outcomes in recipients aged five years or younger. Results: Fifteen datasets comprising 1926 pediatric kidney transplant recipients (1036 ODN and 890 LDN) were included in the quantitative synthesis. There were no significant differences in operation time, warm ischemia time, or blood loss among donors (p > 0.05). There were also no significant differences in the rates of acute graft rejection, delayed graft function, or one-year graft survival between pediatric recipients undergoing ODN and LDN. In the subgroup analysis, the rates of delayed graft function and acute graft rejection were significantly lower in recipients aged ≤5 years in the ODN group compared with the LDN group (Odds ratio (OR), 0.26; p = 0.041 and OR, 0.29; p = 0.016, respectively). The certainty of evidence was very low across all outcomes according to the GRADE assessment. Conclusions: Our findings suggest that outcomes following ODN and LDN appear broadly comparable in pediatric kidney transplantation. However, as the available comparative evidence is derived primarily from studies conducted during the early adoption era of laparoscopic donor nephrectomy, these findings should be interpreted cautiously and mainly in a historical context. The overall certainty of evidence was rated as very low according to GRADE. Contemporary data from high-volume transplant centers are needed to better define outcomes in very young pediatric recipients. Full article

Cultured epithelial autografts (CEAs) have been used for more than 40 years in the setting of extensive total body surface area (TBSA) burns. The development and clinical implementation of cultured epidermal autografts and, subsequently, combined cultured dermo-epidermal autografts (CDEAs) have provided an essential adjunctive treatment option. Over the past five decades, numerous studies have reported on their clinical application. CEAs are manufactured from autologous epidermal cells that are expanded in vitro and assembled into sheet grafts suitable for transplantation. While substantial literature exists regarding their clinical use, data specifically addressing treatment-related complications remain scarce. This systematic review aims to comprehensively synthesize the available evidence on sheet-type CEA/CDEA use in burn patients, with a particular focus on complications, tumorigenicity, and mortality. A systematic literature search was conducted in 2023 across five electronic databases (Cochrane on 31 May 2023, Embase on 31 May 2023, Ovid Medline on 31 May 2023, Scopus on 1 June 2023, and Web of Science on 1 June 2023) to identify studies reporting on the use of CEAs in burn patients. Search terms included combinations of “cultured,” “epithelial,” “autografts,” “take rate,” “mortality,” and “skin cancer.” Eligible studies were human clinical studies involving burn patients treated with sheet-type CEA or CDEA, published in English, French, or German. Exclusion criteria comprised studies involving allogeneic materials, in vitro or animal studies, and commentaries and editorials. Efficacy endpoints included complications, tumorigenicity, and mortality outcomes in CEA-treated patients. Risk of bias was assessed for each included study using the modified Downs and Black checklist and graded according to Hooper et al. Seventy studies contributing 72 patient cohorts published between 1984 and 2023 met inclusion criteria, encompassing a total of 2091 patients from all five continents. The mean graft take rate was 64% in adults and 70% in pediatric patients. Complication events and mortality data are described in the corresponding tables. This systematic review represents the first comprehensive synthesis specifically addressing complications, tumorigenicity, and mortality in burn patients treated with CEAs. The reported adverse events must be interpreted within the context of the high morbidity associated with extensive burn injuries. The observed mortality and number of complications appear primarily related to burn severity rather than to CEA use itself. No adverse events were identified that could be specifically attributed to CEAs. Interpretation of these findings is limited by the clinical and methodological heterogeneity of the included studies. In patients with extensive burn injuries, the use of CEAs is associated with a relatively low number of complications and appears to be a safe and clinically justified treatment option. This study received no internal or external funding. This study is referenced in the PROSPERO Database for systematic reviews under the number CRD420251040971. Full article

Background: Short bowel syndrome (SBS) secondary to intestinal resection is the most common cause of intestinal failure (IF) in children and is associated with prolonged parenteral support (PS), impaired growth, and substantial morbidity. SBS outcomes have improved dramatically over the past ten years due to advancements in intestinal rehabilitation programs, nutritional approaches, pharmaceutical treatments, and surgical restoration. Objective: With an emphasis on surgical decision-making, intestinal rehabilitation, nutritional optimization, pharmacologic advancements and predictors of enteral autonomy, the goal is to thoroughly review and synthesize the most recent data on managing pediatric SBS after intestinal resection. Methods: This systematic review was conducted in accordance with the PRISMA 2020 statement using PubMed and Embase. Eligible primary clinical studies evaluated management strategies or clinically relevant outcomes in pediatric patients with SBS secondary to intestinal resection. Secondary evidence sources, including review articles and evidence-based position papers, were considered separately and were used to contextualize the primary findings and contemporary clinical recommendations. The methodological quality and risk of bias of primary studies were assessed using design-appropriate critical appraisal tools. Owing to substantial clinical and methodological heterogeneity, the evidence was synthesized qualitatively. Results: Multidisciplinary intestinal rehabilitation programs have become the mainstay of therapy, increasing the rates of enteral autonomy and improving survival. While optimal PS administration reduces intestinal failure–associated liver disease (IFALD) and catheter-related bloodstream infections (CRBSIs), early, organized enteral feeding encourages intestinal adaptation. Significant advances in decreasing PS requirements have been achieved by pharmacological therapies such as glucagon-like peptide-2 (GLP-2) analogs. Advances in multidisciplinary intestinal rehabilitation have reduced the need for intestinal transplantation and have refined patient selection for autologous bowel reconstruction. Consequently, procedures such as Serial Transverse Enteroplasty (STEP) and Longitudinal Intestinal Lengthening and Tailoring (LILT) are now reserved for highly selected patients with persistent bowel dilatation, dysmotility, and inadequate intestinal adaptation despite optimized nutritional and medical therapy. Conclusions: Following intestinal resection, pediatric SBS is now managed through multidisciplinary, protocol-driven intestinal rehabilitation. Outcomes have improved through the integration of nutritional, pharmacological, and surgical strategies tailored to each patient’s residual anatomy and adaptive potential. Future prospective pediatric studies are needed to standardize outcome measures and clarify the optimal timing and sequencing of nutritional, pharmacological, and surgical interventions during intestinal rehabilitation. Full article

Central nervous system (CNS) relapse remains a major cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL). Repeated isolated CNS relapse is particularly rare and associated with poor prognosis, while optimal therapeutic strategies remain insufficiently defined. Intensified CNS-directed therapy may improve disease control but is also associated with substantial long-term neurotoxicity and survivorship burden. We present the case of a boy with favorable-risk B-cell ALL who developed two isolated CNS relapses despite a good initial response to frontline therapy and absence of classical CNS relapse risk factors. The second relapse was associated with extensive meningeal involvement and optic nerve infiltration. The patient underwent intensive multimodal CNS-directed therapy, including repeated intrathecal chemotherapy, liposomal cytarabine administered according to the IntReALL 2010 protocol, cranial irradiation, and allogeneic hematopoietic stem cell transplantation (alloHSCT) from a matched sibling donor. Durable long-term remission was achieved despite the extremely unfavorable prognosis that is associated with a second isolated CNS relapse. A twenty-year follow-up extending into early adulthood revealed substantial late complications, including epilepsy, transient ischemic attack, optic nerve injury, endocrinopathies, obesity, secondary thyroid malignancy, neurocognitive difficulties, and depression requiring long-term psychiatric and psychological support. The present case illustrates the complex balance between effective CNS disease control and cumulative treatment-related neurotoxicity in pediatric ALL survivors. It also highlights the cumulative CNS injury and long-term survivorship burden that is associated with repeated CNS relapse and multimodal CNS-directed therapy. Full article

Background/Objectives: Busulfan is a cornerstone conditioning agent for pediatric hematopoietic stem cell transplantation (HSCT), yet its narrow therapeutic index and substantial pharmacokinetic (PK) variability complicate dosing. This review synthesizes current evidence on pediatric busulfan PK, exposure-guided dosing, and the transition from conventional therapeutic drug monitoring (TDM) to model-informed precision dosing (MIPD). Methods: We conducted a focused narrative search of PubMed, Web of Science, and ScienceDirect from database inception to August 2026 and synthesized relevant literature on pediatric busulfan PK, exposure–response relationships, TDM, population PK modeling, Bayesian methods, and emerging quantitative approaches. Results: Body size is the primary determinant of busulfan clearance in children, while maturation, underlying disease, concomitant medications, and pharmacogenetic variation may contribute additional variability, although their effects are inconsistent across populations. Busulfan exposure is associated with HSCT outcomes and toxicity; however, reported targets differ by dosing regimen, conditioning intensity, disease category, and exposure metric. Reliable exposure estimation requires accurate sampling records and validated bioanalysis, while limited sampling strategies may improve clinical feasibility. Integrating population PK models with Bayesian estimation enables individualized dose adjustment, although routine implementation requires external validation and compatibility with local workflows. Emerging approaches, including physiologically based PK, PK/PD, and machine learning models, show promise but lack sufficient clinical validation for routine use. Conclusions: TDM remains the foundation of pediatric busulfan precision dosing, while MIPD provides a framework for integrating patient characteristics, measured concentrations, and validated models. Standardized workflows, population-appropriate exposure targets, prospective validation, and evidence of improved clinical outcomes are essential for broader implementation. Full article

Background/Objectives: Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive combined immunodeficiency and an actin cytoskeleton-related inborn error of immunity characterized by severe atopy, recurrent infections, and broad immune dysregulation. We aimed to describe the clinical, immunological, genetic, treatment-related, and outcome features of children with genetically confirmed DOCK8 deficiency, emphasizing immune dysregulation and systemic involvement. Methods: We retrospectively reviewed 17 pediatric patients from 14 unrelated kindreds with genetically confirmed DOCK8 deficiency followed at a tertiary pediatric immunology center between 2005 and 2026. Demographic data, infectious and allergic manifestations, autoimmune and hematological findings, organ involvement, malignancy, laboratory parameters, genetic findings, hematopoietic stem cell transplantation (HSCT) status, and survival outcomes were analyzed descriptively. Results: Twelve patients were male (70.6%), and parental consanguinity was present in 13 patients (76.5%). The median age at symptom onset was 5 months (IQR, 3–10), whereas the median age at diagnosis was 44 months (IQR, 23–56). A history of eczema was documented in all patients. Recurrent skin infections occurred in 16 patients (94.1%), recurrent pneumonia in 13 (76.5%), mucocutaneous candidiasis in 10 (58.8%), and cytomegalovirus infection in four (23.5%). Confirmed autoimmune manifestations were documented in two patients, including autoimmune hepatitis and autoimmune hemolytic anemia. Malignancy occurred in two patients: gastrointestinal stromal tumor and cutaneous squamous cell carcinoma. Additional uncommon systemic manifestations included sclerosing cholangitis, giant aortic aneurysm, and chronic pancreatitis. HSCT was performed in 12 patients (70.6%); complete clinical recovery was achieved in 11, whereas one patient died after transplantation. Four of five non-transplanted patients died during follow-up. Conclusions: Pediatric DOCK8 deficiency showed an early-onset, severe, multisystem phenotype. Beyond infections and atopy, immune dysregulation-related and systemic manifestations were clinically important. Favorable HSCT outcomes were consistent with previous evidence supporting early molecular diagnosis and timely transplant evaluation. Full article

Non-cirrhotic portal hypertension (NCPHT) is defined as portal hypertension (PHT) occurring in the absence of cirrhosis. Major etiological causes of NCPHT include immunological disorders, chronic infections, exposure to medications or toxins, prothrombotic conditions, and several genetic syndromes, highlighting that NCPHT is not a single disease but a shared phenotype arising from diverse underlying pathways. NCPHT is frequently misdiagnosed, largely due to inconsistent nomenclature and limited scientific literature. The broader term non-cirrhotic portal fibrosis (NCPF) or porto-sinusoidal vascular disease (PSVD) includes patients in a preclinical stage who demonstrate histological features similar to NCPHT but lack clinical evidence of PHT. Early detection is linked to a favorable prognosis and improved clinical outcomes. Management strategies in pediatrics continue to rely on extrapolations from adult practice, with sparse evidence to guide pediatric care. Liver biopsy remains the cornerstone of diagnosis, demonstrating nodular regenerative hyperplasia, obliterative portal venopathy, or incomplete septal fibrosis. Management focuses on prophylactic and symptomatic care, with endoscopic therapy for controlling variceal bleeding. Porto-systemic shunts and, ultimately, liver transplantation therapies may be needed for advanced stages. A pressing need exists for standardized diagnostic criteria and multicenter studies to define natural history, refine risk stratification, and evaluate therapeutic approaches in the pediatric population. This review provides an overview of the pediatric causes of NCPHT, outlines the current understanding of pathophysiology, and discusses the clinical presentations and management strategies, while highlighting existing research gaps. Full article

Pediatric nephrology is shifting from broad phenotype-based labels toward molecularly defined, genotype-guided diagnosis and management. Childhood kidney disorders are enriched for monogenic causes, yet persistent microscopic hematuria, bilateral kidney cysts, steroid-resistant nephrotic syndrome, and thrombotic microangiopathy may represent shared endpoints of biologically distinct mechanisms. Using these four scenarios, this narrative review illustrates how structured phenotyping, pedigree analysis, biochemical evaluation, and appropriately selected genomic testing can establish etiology, revise diagnoses, and guide clinical decision-making. Molecular diagnosis may support early nephroprotection, prevent ineffective immunosuppression, reveal tumor or extrarenal risks, enable mechanism-based therapy, and optimize transplantation planning. It also enables cascade testing, reproductive counseling, presymptomatic evaluation of relatives, and safer assessment of living-related donors. Genomic findings, however, require clinical context. Variants must be evaluated against gene–disease validity, inheritance, segregation, molecular mechanism, and phenotype, while variants of uncertain significance should not independently determine treatment or donor eligibility. Negative or inconclusive findings should prompt phenotypic reassessment, evaluation of analytical limitations, targeted studies, and periodic genomic reanalysis. Emerging genome and long-read sequencing, multiomics, artificial intelligence, and RNA-based therapeutics may further expand precision care, but rigorous interpretation, equitable access, appropriate counseling, and multidisciplinary collaboration remain essential. Precision nephrology derives value not from identifying variants alone, but from converting molecular etiology into safer, anticipatory, and individualized care. Full article

Pediatric chronic kidney disease (CKD) is traditionally viewed as a disorder of impaired renal function, yet its effects extend far beyond the kidneys. Growing evidence indicates that CKD may disrupt brain development through interconnected biological, vascular, inflammatory, and psychosocial mechanisms, with lasting consequences for cognition, mental health, and educational attainment. In this perspective, we propose the kidney-brain axis as a neuro-renal framework for understanding these neurological consequences of pediatric CKD. We discuss current evidence linking CKD with neurocognitive impairment, structural brain abnormalities, psychosocial burden, and adverse educational outcomes, while examining the biological mechanisms that may underlie these associations. We also consider the role of kidney transplantation, emphasizing that restoration of renal function does not necessarily restore normal neurodevelopmental trajectories. Finally, we outline the clinical implications of integrating routine neurodevelopmental assessment into pediatric nephrology care and highlight priorities for future research. Recognizing neurodevelopment as a core component of pediatric CKD may help redefine disease burden and support more comprehensive, lifelong care for affected children. Full article

Bardet–Biedl syndrome (BBS) is a genetically heterogeneous ciliopathy associated with hyperphagic obesity and kidney disease. Evidence on setmelanotide after pediatric kidney transplantation is limited. We evaluated two children with BBS treated with setmelanotide after kidney transplantation, collecting anthropometric, hunger, metabolic, graft-function, cyclosporine and genetic data. Patient 1, a 17-year-old boy with a homozygous pathogenic SDCCAG8 exon deletion, improved over 12 months: weight 55.6 to 48.0 kg, BMI 26.6 to 23.0 kg/m², BMI-for-age z-score +1.60 to +0.43, maximal-hunger score 8/10 to 5/10, and HbA1c 6.5% to 5.1%. Patient 2, an 8-year-old girl with a homozygous likely pathogenic BBS5 splice-site variant and a heterozygous PCSK1 N221D variant, showed reduced hunger and an initial z-score fall from +6.10 to +5.69 by month 2.5, meeting the 0.2-point threshold for clinically meaningful change; this was not sustained, and BMI rose from 38.0 to 42.7 kg/m² by eight months despite a dose of 3 mg/day. Graft function and cyclosporine trough concentrations remained stable, and skin hyperpigmentation was the only treatment-related adverse effect. In these two patients, setmelanotide was not associated with graft deterioration or altered cyclosporine trough concentrations, although two cases cannot establish safety. The divergent trajectories highlight interindividual variability; the role of PCSK1 N221D remains uncertain, and these observations are hypothesis-generating. Full article