Search Results (205)

Background: In childhood acute lymphoblastic leukemia (ALL), in addition to classical chromosomal abnormalities, loss of heterozygosity (LOH), including copy-neutral LOH, is also observed. While LOH has been described in the literature, its clinical relevance in pediatric ALL remains unclear. The aim of this study is to identify and analyze patterns of LOH, assess their frequency, and evaluate their association with clinical characteristics and early treatment response during the induction phase of the ALL protocol. Methods: The study included 853 pediatric ALL patients, of whom 120 had B-ALL LOH+ and 58 had T-ALL LOH+. LOH was analyzed using CytoScan HD SNP microarrays. Patients were stratified using multiple correspondence analysis (MCA) and hierarchical clustering on principal components (HCPC), which identified three genetically and clinically distinct clusters. Results: In B-ALL, two clusters with extensive LOH—particularly involving chromosome 9—were associated with poor prognosis and suboptimal response to therapy. In contrast, Cluster 2, characterized by CDKN2A duplication and rare LOH, showed a favorable clinical course. In T-ALL, Cluster 1 had LOH in CDKN2A but favorable outcomes; Cluster 2 exhibited biallelic CDKN2A deletion and aggressive disease; Cluster 3 lacked CDKN2A alterations and showed a genetically stable profile. LOH was common on chromosomes not typically affected by trisomy and rare on those gained. Conclusions: Our study indicates that LOH profiling can positively influence patient stratification by identifying high-risk subgroups, inform prognosis by highlighting unfavorable genetic alterations, and help predict poor treatment response in specific clinical profiles. Full article

Genetic dystonias are a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions that cause repetitive movements and abnormal postures. Often beginning in childhood, they can significantly affect quality of life. Although individually rare, genetic causes are collectively relevant in pediatric dystonias, with over 250 associated genes. Among these, TOR1A, SGCE, and KMT2B are the most frequently reported in pediatric forms. Diagnosis is challenging due to the wide clinical and genetic variability. Recent advances in genetic testing, including whole-exome and whole-genome sequencing, have improved the early identification of causative variants. Functional data on selected mutations are helping to refine genotype–phenotype correlations. Management typically requires a multidisciplinary approach. Symptomatic treatments include anticholinergics, benzodiazepines, and botulinum toxin, while deep brain stimulation can be effective in refractory cases, especially in patients with TOR1A variants. Disease-modifying therapies are also emerging, such as gene therapy for AADC deficiency, highlighting the potential of precision medicine. This review provides an updated overview of pediatric genetic dystonias, with a focus on differential diagnosis and treatment strategies. Early and accurate diagnosis, together with personalized care, is key to improving outcomes in affected children. Full article

Background: Primary ciliary dyskinesia (PCD) is a rare hereditary disorder caused by defective motile cilia, predominantly affecting the respiratory system. Conductive hearing loss (CHL) due to chronic otitis media with effusion (OME) is a typical feature of PCD, particularly in childhood. However, the underlying mechanisms contributing to sensorineural hearing loss (SNHL) in patients with PCD remain unclear. Methods: We present the case of a 52-year-old male with a clinical diagnosis of PCD, confirmed by the presence of situs inversus, chronic respiratory symptoms, and ultrastructural ciliary defects. Results: Despite a history of recurrent acute otitis media (AOM), the patient developed severe bilateral SNHL, a relatively uncommon and poorly understood manifestation of PCD. Genetic testing revealed a pathogenic SH3TC2 variant, a gene classically associated with Charcot–Marie–Tooth disease type 4C (CMT4C), raising the possibility of an alternative or contributory genetic etiology for the patient’s auditory dysfunction. Conclusions: This case highlights the importance of comprehensive audiological and genetic evaluations in PCD patients, particularly those presenting with progressive or atypical HL. The presence of a pathogenic SH3TC2 mutation suggests a potential neuropathic component to the patient’s HL, underscoring the need for further research into the intersection between ciliary dysfunction and genetic neuropathies. Early identification and intervention are critical to optimizing auditory outcomes and quality of life in affected individuals. Full article

Background/Objectives: Glycogen storage disease type IX (GSD IX) is a group of inherited metabolic disorders caused by phosphorylase kinase deficiency affecting the liver or muscle. Despite being relatively common among GSDs, GSD IX remains underexplored. Methods: A systematic review of GSD IX was conducted per PRISMA guidelines using SCOPUS and PubMed, registered with PROSPERO. Inclusion focused on human clinical studies published up to 31 December 2024. Results: A total of 400 patients with GSD IX were analyzed: 274 IXa (mean age at diagnosis 5.1 years), 72 IXc (mean age at diagnosis 4.9 years), 39 IXb (mean age at diagnosis 4.2 years), and 15 IXd (mean age at diagnosis 44.9 years). Hepatomegaly was commonly reported in types IXa, IXb, and especially IXc (91.7%), but was rare in IXd. Elevated transaminases were frequently observed in types IXa, IXb, and particularly IXc, while uncommon in IXd. Fasting hypoglycemia was occasionally observed in types IXa and IXb, more frequently in IXc (52.7%), and was not reported in IXd. Growth delay or short stature was observed in a substantial proportion of patients with types IXa (43.8%), IXb, and IXc, but was rare in IXd. Muscle involvement was prominent in IXd, with all patients showing elevated CPK (mean 1011 U/L). Neurological involvement was infrequently reported in types IXa and IXc. Conclusions: This systematic review includes the most extensive clinical case history of GSD IX described in the literature. The clinical spectrum of GSD IX varies widely among subtypes, with IXc being the most aggressive. While liver forms are generally present in early childhood, muscle-type IXd shows delayed onset and milder symptoms, often leading to diagnostic delays. For diagnosis, it is essential not to underestimate key clinical features such as hepatic involvement and hypoglycemia in a child under 5 years of age. Other manifestations, including the as-yet unexplored systemic involvement of bone and kidney, remain insufficiently understood and require further investigation. Next-generation sequencing has improved diagnostic precision over traditional biopsy. Dietary management, including uncooked cornstarch, Glycosade^®, and high-protein intake, remains the cornerstone of treatment. However, there is a paucity of well-designed, evidence-based studies to determine the most effective therapeutic approach. Despite its historically perceived benign course, the broad phenotypic variability of GSD IX, including progressive liver involvement and potential neurological complications, highlights its substantial clinical relevance and underscores the need for accurate diagnostic classification and long-term multidisciplinary follow-up. Full article

Rotavirus (RV) is the most common cause of severe acute gastroenteritis (AGE) in children under five years of age. This review summarizes current knowledge on RV infections, with a particular focus on viral structure, pathophysiological mechanisms, and age-dependent clinical presentation. Special attention is given to systemic manifestations, including central nervous system involvement, autoimmune responses such as type 1 diabetes and celiac disease, and rare associations with biliary atresia. The mechanisms of RV-induced diarrhea and vomiting are discussed in detail. Clinical severity scoring systems—such as the Vesikari and Clark scales—and dehydration assessment tools—the Clinical Dehydration Scale (CDS) and the Dehydration: Assessing Kids Accurately (DHAKA) score—are compared. The review highlights differences in disease course between children under and over five years, emphasizing that RV is not limited to early childhood. A major section addresses the global effectiveness of vaccination programs, their role in reducing disease burden, coverage challenges, and decreased efficacy in low-income countries. Particular focus is placed on high-risk groups, including preterm and immunocompromised infants. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that first develops in early childhood and is characterized by restricted interests, activities, and behaviors, as well as difficulties with social interactions and communication. ASD arises from a complex interaction between environmental factors and genetic inheritance, influenced by epigenetic mechanisms. With an estimated heritability of 70–90%, ASD is highly familial, indicating that genetic factors play a significant role in its development. This shows how hundreds of genetic variants contribute to ASD, whose risk effects are highly variable and are often related to other conditions; these genetic alterations are at different levels, which include single gene mutations, monogenic disorders, genomic variants, and chromosomal abnormalities. Copy number variants (CNVs) appear to contribute significantly to understanding the pathogenesis of this complex disease. In some cases, single CNVs in genomic DNA are pathogenic and causative, supporting the hypothesis that some sporadic cases of ASD may result from rare mutations with significant clinical impact. However, in many cases, there are common genomic variants that increase the risk of developing ASD but are insufficient by themselves to determine an ASD phenotype, and rare genomic variants, of various sizes, inherited from a parent or de novo, that can be associated with the ASD phenotype. Therefore, the aim of this review is to deepen the concept of ASD inheritance through the two-hit theory of CNVs, in which the concomitant presence of two alterations could determine the clinical phenotypes, the concept of incomplete penetrance for inherited CNVs with pathogenic clinical significance, and the presence of compound heterozygosity. These aspects represent important mechanisms underlying the pathogenesis of autism, contributing to a better elucidation for the understanding of the genetic contribution to the ASD phenotype. Full article

Introduction: Craniopharyngiomas are rare sellar embryonic malformational tumors of low-grade histological malignancy. Despite high overall survival rates (92%), quality of life is frequently reduced due to adverse late effects caused by hypothalamic obesity. It is well known that morbid hypothalamic obesity is associated with the grade of hypothalamic damage. Accordingly, craniopharyngioma should be considered a paradigmatic disease, reflecting challenges in the diagnosis and treatment of acquired hypothalamic obesity. Methods: A narrative review was performed after searching the MEDLINE/PubMed, Embase, and Web of Science databases for initial identifying articles. The search terms childhood-onset craniopharyngioma and hypothalamic obesity were used. Results: Despite the availability of promising therapeutic approaches, such as medication with central stimulating agents, antidiabetic drugs, glucagon-like peptide 1 (GLP1) receptor agonists, and Setmelanotide, it must be emphasized that there is currently no pharmaceutical treatment for hypothalamic obesity in craniopharyngioma proven to be effective in randomized controlled trials. For Setmelanotide, a prospective blinded randomized trial over a 12-month treatment period is ongoing. Bariatric interventions are effective, but non-reversible procedures such as bypass operations are controversial in the pediatric age group due to legal and ethical concerns. Recently, a treatment algorithm was introduced to improve the management of hypothalamic syndrome/obesity by offering more personalized treatment. Decisions on treatment strategies focusing on the preservation of visual, neuroendocrine, and hypothalamic integrity should be made by experienced multidisciplinary teams. Conclusions: Treatment approaches for hypothalamic obesity are limited. Further research on novel treatment approaches for hypothalamic obesity is warranted to improve the quality of life after childhood-onset craniopharyngioma. Full article

Introduction: Epidermolysis bullosa acquisita (EBA) is a rare autoimmune disease causing subepithelial blistering due to autoantibodies against type VII collagen. While mechanobullous EBA predominantly affects adults, our report presents an exceedingly rare case in an 11-year-old football player. Case Report: The patient reported a one-year history of blistering and scarring on the knees and scrotum. The diagnosis was established with direct immunofluorescence (DIF), mosaic indirect immunofluorescence (IIF) showing IgG antibodies reacting with the dermal side of salt-split primate skin, and multiplex ELISA revealing an elevated level of IgG antibodies against type VII collagen. Treatment with a superpotent topical glucocorticosteroid and activity modifications improved his condition. Review: This case highlights the importance of considering EBA in differential diagnoses of pediatric blistering diseases and suggests that conservative management may be effective in mild cases. We also review clinical and laboratory considerations on the topic of childhood EBA. Conclusions: Further studies are essential to develop evidence-based guidelines for pediatric EBA. Full article

Introduction: Sleep is a fundamental biological function critical for physical and mental health. Chronic sleep disturbances can significantly impair cognitive, emotional, and social functioning, leading to deficits in attention, alertness, and executive function, alongside increased irritability, anxiety, and depression. For pediatric patients, such disturbances pose additional concerns, potentially disrupting developmental processes and quality of life for both children and their families. Objectives: Emerging evidence suggests a correlation between neurofibromatosis type 1 (NF1) and an increased prevalence of sleep disorders in children. NF1, a genetic condition affecting multiple body systems, including the nervous system, may predispose children to sleep disturbances due to its neurodevelopmental and behavioral impacts. This observational case–control study aimed to explore the association between NF1 and sleep disorders in pediatric patients, comparing the prevalence and patterns of sleep disturbances between NF1 patients and healthy controls. Patients and Methods: The study included 100 children aged 2–12 years, divided into two groups: 50 with NF1 (case group) and 50 children belonging to the control group. NF1 patients were recruited from the Unit of Rare Diseases of the Nervous System in Childhood at the Policlinico “G. Rodolico—San Marco” University Hospital in Catania. Data were collected using a questionnaire completed by parents, assessing parasomnias, breathing-related sleep disorders, and other behavioral and physiological disturbances; these data were compared to a sleep assessment performed using an Apple Watch Ultra. Results: NF1 patients exhibited a significantly higher prevalence of sleep disorders than controls. Notable differences included increased nocturnal hyperhidrosis (48% vs. 10%), bruxism (48% vs. 28%), restless legs syndrome (22% vs. 4%), frequent nighttime awakenings (22% vs. 8%), and sleep paralysis (12% vs. 0%). A finding of poorer sleep quality also emerged from the results of sleep analysis using an Apple Watch Ultra. Conclusions: These findings confirm an elevated risk of sleep disorders in children with NF1, emphasizing the importance of early identification and management to improve quality of life and mitigate cognitive and behavioral impacts. Further research is essential to understand the mechanisms underlying these associations and develop targeted interventions for this population. Full article

Background: While the HTA community appears well-equipped to assess preventive and diagnostic technologies, certain limitations persist in evaluating technologies designed for rare diseases, including those based on Artificial Intelligence (AI). In Europe, the EUnetHTA Core Model^® serves as a reference for assessing preventive and diagnostic technologies. This study aims to identify key ethical, legal, and social issues related to AI-based technologies for the prevention and diagnosis of rare diseases, proposing enhancements to the Core Model. Methods: An exploratory sequential mixed methods approach was used, integrating a PICO-guided literature review and a focus group. The review analyzed six peer-reviewed articles and compared the findings with a prior study on childhood melanoma published in this journal (Healthcare), retaining only newly identified issues. A focus group composed of experts in ethical, legal, and social domains provided qualitative insights. Results: Thirteen additional issues and their corresponding questions were identified. Ethical concerns related to rare diseases included insufficient disease history knowledge, lack of robust clinical data, absence of validated efficacy tools, overdiagnosis/underdiagnosis risks, and unknown ICER thresholds. Defensive medicine was identified as a legal issue. For AI-based technologies, concerns included discriminatory outcomes, explicability, and environmental impact (ethical); accountability and reimbursement (legal); and patient involvement and job losses (social). Conclusions: Integrating these findings into the Core Model enables a comprehensive HTA of AI-based rare disease technologies. Beyond the Core Model, these issues may inform broader assessment frameworks, ensuring rigorous and ethically responsible evaluations. Full article

Objectives: The aim of this study was to establish the etiology of uveitis and to examine its relationship with anatomical localization, age, and gender. Methods: A prospective study on patients with uveitis was conducted over a 13-year period at the Department of Ophthalmology, University Hospital “St. George”, Plovdiv, Bulgaria. Each case was diagnosed based on a comprehensive eye examination, a review of the systems, and additional laboratory and specialized examination methods. Patients were categorized into four groups based on the location of inflammation: anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis. Results: A total of 606 patients with uveitis were included in the study. The mean age of the study group was 46.5 ± 18.6 years. There was no statistically significant difference in gender distribution (p = 0.329). Anterior uveitis was the most dominant anatomical localization (p < 0.001). Cases with clarified etiology were significantly prevalent (p < 0.001). The most frequently identified etiology was HLA B27-associated uveitis (32.5%), followed by viral uveitis (16.8%). A significant correlation between etiology and anatomical localization was found (p < 0.001). The highest proportion (93%) of cases with clarified etiology was associated with posterior uveitis, while the lowest (39.7%) was linked to intermediate uveitis. Conclusions: We found that anterior uveitis was the most common anatomical localization, followed by intermediate uveitis. The disease is rare in childhood, while in elderly patients, there is an increase in idiopathic and viral uveitis cases. Our results provide valuable information about the most common etiologies of uveitis among the Bulgarian population. Full article

Prader-Willi syndrome (PWS) is a rare genetic disorder. The main characteristics are muscular hypotonia, failure to thrive and feeding problems in infancy, which switch to hyperphagia in early childhood and continue into adulthood. Due to hyperphagia, the risk of developing morbid obesity is high without treatment. PWS is considered a hypothalamic disease, and within the hypothalamus the arcuate nucleus (AC) is of central importance for controlling metabolism, hunger, and satiety. The AC has been studied in several animal models as well as in humans, including PWS. The function of AC is regulated by several neuropeptides and proteins produced within the central nervous system such as oxytocin, orexin, tachykinins as well as the hypothalamic hormones, regulating the adeno-hypophyseal hormones, also acting as neurotransmitters. Additionally, there are many peripheral hormones among which insulin, leptin, adiponectin, ghrelin, and glucagon-like peptide (GLP-1) are the most important. High levels of adiponectin and ghrelin have consistently been reported in PWS, but dysregulation and deviating levels of many other factors and hormones have also been demonstrated in both individuals with PWS and in animal models. In this review, we focus on the role of AC and peptides and proteins produced within the central nervous system in the regulation of hunger and satiety in PWS. Full article

Pineoblastoma (PB) is a rare yet lethal pediatric brain cancer of the pineal gland, a small endocrine organ that secretes melatonin to regulate the circadian rhythm. For PB patients ≤5 years of age, the overall survival rate is approximately 15%; metastatic PB is incurable. Standard treatment, including surgical resection, radiation, and systemic chemotherapy, improves survival but compromises neurocognitive function. A better understanding of the disease and the generation of preclinical models may enable re-evaluation of previous clinical trials, development of precision therapeutic strategies and improve patient outcome. Over the past 5 years, PB has been recognized to include several major subtypes driven by (i) loss of microRNA processing factors DICER and DROSHA characterized by a relatively good prognosis; (ii) loss of the retinoblastoma tumor suppressor RB1; and (iii) amplification or induction of the cMYC protooncogene, with the latter two subtypes exhibiting exceedingly poor prognosis. Recently, mouse models for the major PB subtypes (RB1-, DICER1- and DROSHA-) except MYC- have been established. This progress, including better understanding of the disease, cell of origin, tumor progression, role of autophagy, and targetable vulnerabilities, holds promise for novel therapeutic strategies to combat each subtype of this lethal childhood malignancy. Full article

Background: The registry-based collection of detailed cancer and late effect (LE) data in childhood and adolescent cancer (CAC) is rarely explored. Aim: We aimed to provide an overview of CAC registration practices in Europe and share a Slovenian example. Methods: We distributed a questionnaire among European cancer registries on disease, treatment and LE registration and present the system at the Slovenian Cancer Registry along with an example of retrospectively collected LE data from a cohort of central nervous system tumour survivors from 1983 to 2000. Kaplan–Meier and Cox regression were used to calculate the LE incidence. Results: Out of 27 responding registries, over 80% registered cancer type, vital status, death and second primary cancer data. Less than 20% registered cumulative doses of radiation and systemic therapy or progressions. Only three registered LEs. The obstacles in setting up LE collection in registries are a lack of standardization in the variable sets, definitions and methods of collection. In the retrospective cohort, neurological and endocrine LEs were most common. Females had a higher risk of endocrine LEs (HR of 1.89; 95% CI of 1.08–3.31), while patients treated with radiotherapy had higher risks of endocrine (3.47; 1.80–6.69), musculoskeletal and skin LEs (3.16; 1.60–6.26) and second primary cancers (2.85; 1.18–6.75). Conclusions: Standardization and harmonization are necessary to promote detailed CAC and LE registration. Full article

Background: Bickerstaff brainstem encephalitis (BBE) is a rare autoimmune disease and approximately 74 cases have been reported in the literature, mostly in childhood. Methods: We reported this case report according to the CARE guidelines. Results: A 13-year-old female presented with a 4-day history of persistent fever and hallucinations. She rapidly developed nystagmus associated with blurred vision with ataxic gait. She also developed altered mental status, blepharoptosis, diplopia and extrinsic ocular motility. An EEG showed asymmetric brain electrical activity with slow and spiky abnormalities in the left cerebral hemisphere. Lumbar puncture showed mild pleocytosis with lymphocytic predominance, elevated protein, with normal glucose. Anti-GM1 and anti-GM2 antibodies were positive. She was administered intravenous immunoglobulin therapy due to a suspicion of BBE, showing rapid improvement in mental status. Conclusions: BBE is a diagnosis of exclusion and should be considered especially in pediatric age. Full article