Table of Contents
Overview of Sex Chromosome Aneuploidies in Pediatrics
Sex chromosome aneuploidies (SCAs) represent a significant category of chromosomal abnormalities that affect approximately 1 in 500 live births. Among these, Turner syndrome (TS) and Klinefelter syndrome (KS) are the most frequently observed. TS is characterized by a complete or partial absence of one X chromosome, leading to a range of clinical manifestations such as short stature, ovarian insufficiency, and cardiovascular anomalies. Conversely, KS, defined by the presence of an extra X chromosome (47,XXY), is associated with features such as hypogonadism, gynecomastia, and learning difficulties. The variability in phenotypic presentation is influenced by the specific aneuploidy, the degree of mosaicism, and the dosage effects of sex chromosome-linked genes.
Recent advances in diagnostics have improved the detection and management of SCAs, yet the underlying pathophysiological mechanisms continue to be a topic of active research. Oxidative stress, defined as an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, has been implicated in the progression of SCAs, contributing to various comorbidities such as metabolic syndrome, cardiovascular disease, and neurodevelopmental disorders (Paparella et al., 2025). Understanding the role of oxidative stress in SCAs can illuminate potential therapeutic strategies aimed at mitigating the impact of these chromosomal disorders on pediatric patients.
Mechanisms of Oxidative Stress in Turner and Klinefelter Syndromes
The role of oxidative stress in SCAs is multifaceted. In TS, the absence of one X chromosome correlates with a decreased capacity for antioxidant defense, leading to elevated oxidative stress markers such as lipid peroxidation and reduced levels of glutathione. The lack of sufficient estrogen, which has protective antioxidant properties, exacerbates these effects. Estrogen is known to upregulate the expression of various antioxidant enzymes, including superoxide dismutase (SOD) and catalase, which are crucial for maintaining redox balance in cells (Paparella et al., 2025).
In KS, the presence of an extra X chromosome can lead to increased ROS production due to the higher expression of specific genes on the X chromosome that are implicated in redox regulation. The imbalance in gene dosage affects the metabolic pathways involved in oxidative stress responses, resulting in an overall increase in oxidative damage within tissues (Paparella et al., 2025).
The following table summarizes the key findings related to oxidative stress in TS and KS:
Karyotype | Key Findings on Oxidative Stress |
---|---|
45,X (Turner Syndrome) | Reduced antioxidant capacity, increased oxidative stress markers (e.g., lipid peroxidation, reduced glutathione levels). |
47,XXY (Klinefelter Syndrome) | Increased levels of oxidative stress biomarkers; associated with metabolic syndrome, which exacerbates oxidative stress. |
Role of Antioxidants in Mitigating Oxidative Damage
Antioxidants play a crucial role in countering oxidative stress in pediatric patients with SCAs. Various dietary and pharmacological antioxidants have been studied for their potential therapeutic benefits. Key antioxidants include vitamin C, vitamin E, glutathione precursors, polyphenols, and melatonin. These compounds can help restore redox balance and mitigate systemic complications associated with SCAs (Paparella et al., 2025).
Research indicates that combining antioxidant therapies with hormone replacement therapies, such as estrogen in TS and testosterone in KS, may yield synergistic effects in improving outcomes for affected individuals. For instance, estrogen replacement therapy has been shown to enhance the expression of antioxidant enzymes while simultaneously providing hormonal benefits crucial for development and metabolic health (Paparella et al., 2025).
Clinical Implications of Oxidative Stress in Pediatric Populations
The clinical implications of oxidative stress in pediatric populations with SCAs are profound. Increased oxidative stress is associated with various health complications, including cardiovascular issues, metabolic disorders, and neurocognitive deficits. In TS, oxidative stress contributes to endothelial dysfunction, increasing the risk for hypertension and cardiovascular disease. Additionally, the oxidative burden may impair neurodevelopment, leading to cognitive and behavioral challenges.
In KS, the oxidative stress linked to the extra X chromosome can exacerbate the risk of metabolic syndrome, characterized by obesity, insulin resistance, and dyslipidemia. This highlights the importance of early recognition and intervention strategies targeting oxidative stress, which could significantly improve the quality of life and long-term health outcomes for affected children (Paparella et al., 2025).
Future Directions for Research on SCAs and Oxidative Stress
Despite growing evidence linking oxidative stress to the pathophysiology of SCAs, significant gaps remain in our understanding of this relationship. Future research should focus on elucidating the precise mechanisms by which oxidative stress contributes to the clinical manifestations of TS and KS. Additionally, studies should investigate the efficacy of specific antioxidant interventions and their potential to improve health outcomes in pediatric populations with SCAs.
Furthermore, large-scale clinical trials are needed to establish standardized protocols for the use of antioxidants in conjunction with hormone therapies in managing SCAs. These studies should also explore the role of lifestyle modifications and dietary interventions in reducing oxidative stress levels in affected individuals. Ultimately, a comprehensive approach integrating genetic, metabolic, and environmental factors will be essential for developing effective strategies to manage SCAs and their associated oxidative stress.
FAQ
What are sex chromosome aneuploidies?
Sex chromosome aneuploidies (SCAs) are genetic disorders caused by an abnormal number of sex chromosomes, leading to conditions like Turner syndrome (45,X) and Klinefelter syndrome (47,XXY).
How does oxidative stress affect children with SCAs?
Oxidative stress, an imbalance between ROS production and antioxidant defenses, can lead to various health issues in children with SCAs, including cardiovascular problems, metabolic disorders, and neurodevelopmental challenges.
What role do antioxidants play in managing SCAs?
Antioxidants can help mitigate oxidative damage by restoring redox balance in pediatric patients with SCAs. They may also enhance the effects of hormone replacement therapies, improving overall health outcomes.
What are the future research directions in SCAs and oxidative stress?
Future research should aim to clarify the mechanisms linking oxidative stress to SCAs, evaluate the effectiveness of antioxidant therapies, and develop standardized treatment protocols for affected pediatric populations.
References
-
Paparella, R., Panvino, F., Tarani, F., D’Agostino, B., Leonardi, L., Ferraguti, G., Venditti, S., & Tarani, L. (2025). An Overview of Oxidative Stress in Sex Chromosome Aneuploidies in Pediatric Populations. Antioxidants, 14(5), 531
-
Lewis, N., Lagopoulos, J., & Villani, A. (2025). Gut–Brain Inflammatory Pathways in Attention-Deficit/Hyperactivity Disorder: The Role and Therapeutic Potential of Diet. Metabolites, 15(5), 335
-
Abdullahi, F., Dieli, F., & Tarani, L. (2025). Tumor-Associated Macrophages: Polarization, Immunoregulation, and Immunotherapy. Cells, 14(10), 741
-
Payne, R., Kirk, U. B., Nymberg, V. M., Sandal, N., Huibers, L., & Hvidt, E. A. (2025). Primary care video consulting: a view from Northern Europe. British Journal of General Practice, 75(755), 281-292
-
Mudgal, M., Balaji, S., Gajendiran, A. P., Subramanya, A., Murugan, S., Gondhi, V., Bhatnagar, A. R., & Gunasekaran, K. (2025). Connective Tissue Disorder-Induced Diffuse Alveolar Hemorrhage: A Comprehensive Review with an Emphasis on Airway and Respiratory Management. Life, 15(5), 793
-
Chhabra, K. R., Gupta, A. S., & Iyer, S. S. (2025). Correlations of dietary energy and protein intakes with renal function impairment in chronic kidney disease patients with or without diabetes. Clinical Nutrition, 15(5), 307. https://doi.org/10.1016/j.clnu.2024.01.003