This cross-sectional study was approved by the Ethics Committee of Kunming yan’an Hospital, which waived the requirement for informed consent, as this research involved only data analysis without identifiable personal information. Data on prevalence and standardized disease definitions for KS in children aged 0–19 years were retrieved using the Global Health Data Exchange query tool developed by GBD collaborators. The GBD database is widely recognized as one of the most comprehensive and systematic global epidemiological frameworks, spearheaded by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington (GBD, 2021 Causes of Death Collaborators et al., 2024). The primary aim of the GBD initiative is to quantify health losses attributable to various diseases, injuries, and risk factors globally.

The GBD approach facilitates comparative evaluations of prevalence and DALYs across countries, regions, and globally. Within this framework, disease burden is quantified through two principal metrics: prevalence and DALYs. DALYs represent the cumulative measure of health loss, calculated as the sum of Years of Life Lost (YLL) due to premature death and Years Lived with Disability (YLD). The respective formulas applied are: YLL = Number of deaths × Standard life expectancy at the age of death YLD = Prevalence of the condition × Disability weight

Disability weights, derived from expert consensus, range from 0 (perfect health) to 1 (equivalent to death). This robust methodological approach enables a scientifically rigorous understanding of global disease and injury burdens (GBD, 2021 Causes of Death Collaborators et al., 2024). However, these weights are not specific to pediatric KS; rather, they are adapted from generic health states (such as developmental delay, learning disability, hypogonadism, or infertility) that are considered analogous to the sequelae of KS. This methodological choice may underestimate or misclassify the unique disability burden of KS in children and adolescents. While DALYs provide a robust comparative metric, they may underestimate certain aspects of chronic disability and quality-of-life impairment relevant to KS.

The prevalence and DALYs of KS were estimated using the GBD standard tool DisMod-MR 2.1 (a Bayesian meta-regression model). This model integrates global epidemiological data and adjusts for diagnostic bias through covariates such as the Socio-demographic Index (SDI) and Healthcare Access and Quality (HAQ) Index. For regions with sparse data (e.g., low-SDI countries), spatiotemporal extrapolation was employed to generate estimates, while Markov chain Monte Carlo (MCMC) sampling was used to quantify uncertainty (reported as 95% uncertainty intervals [UIs]). Model validation adhered to the GBD cross-validation protocol (GBD, 2019 Diseases and Injuries Collaborators, 2020).

Data on KS prevalence and DALYs among children aged 0–19 years from 1990 to 2021 were extracted from the GBD database (https://vizhub.healthdata.org/gbd-results/; data accessed on 20 March 2025). Analyses incorporated multiple demographic dimensions, including sex, age groups (categorized as <1 year, 2–4 years, 5–9 years, 10–14 years, and 15–19 years), and geographical regions. However, analyses based on race or ethnicity were not performed due to the absence of relevant parameters in the GBD database. This study strictly adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (von Elm et al., 2007).

The SDI is a composite measure reflecting the socioeconomic development level of a nation or region, encompassing economic structure and size, education level, standard of living, and social welfare and protection, among other factors (Li et al., 2024). The SDI ranges from 0 to 1, with higher scores indicating better socioeconomic status. The GBD classifies countries and regions into five categories based on SDI: low, low-middle, middle, high-middle, and high. This classification facilitates the examination of the influence of socioeconomic and geographical disparities on the burden of KS among children.

Prevalence and DALYs per 100,000 population, along with 95% UIs, were calculated according to GBD statistical methods (GBD, 2019 Hearing Loss Collaborators, 2021). Joinpoint regression models were employed to determine annual percentage changes (APC) and associated 95% confidence intervals (CI), providing granular insights into annual trends within each distinct period (Lv et al., 2024). Additionally, log-transformed linear regression models calculated the estimated annual percentage change (EAPC) and corresponding 95% CI to evaluate temporal trends in prevalence and DALYs from 1990 to 2021. The EAPC is particularly valuable for assessing long-term trends, independent of short-term fluctuations (Zi et al., 2024). An EAPC value with a lower bound of the 95% CI above 0 indicates a rising trend, whereas an EAPC with an upper bound of the 95% CI below 0 indicates a declining trend. Curve-fitting analyses were conducted to investigate associations between disease burden indicators and SDI. All analyses were performed using R version 4.3.3, with statistical significance set at P < 0.05.

Funders played no role in study design, data collection, analysis, interpretation, or manuscript preparation. All authors had unrestricted access to the study data and assumed full responsibility for the decision to submit the manuscript for publication.

This comprehensive analysis provides the first global estimate of KS burden in children and adolescents, revealing significant yet underappreciated impacts on population health. Previous study estimates a global birth prevalence of KS around 21.9 per 100,000 (approximately 0.022%) (Shen et al., 2024). This figure is markedly lower than the 0.1%–0.2% (1 in 500–1,000) prevalence suggested by neonatal cytogenetic surveys (Bojesen et al., 2003), underscoring that most KS cases remain unidentified in childhood. Such pervasive underdiagnosis means the true burden is substantially higher than reported, limiting our ability to address the needs of this population. Nevertheless, the cases that are captured in this study already amount to a considerable global pediatric burden of chronic health issues. Although KS contributed relatively low DALY rates (well under 1 per 100,000 globally), its importance lies in life-long impacts on quality of life rather than acute mortality. Children with KS often face neurodevelopmental challenges – language delays, learning disabilities, and psychosocial difficulties – that can hinder educational attainment and social integration (Boks et al., 2007). Without early recognition and support, these challenges can translate into significant cumulative disability. Thus, the finding that the recorded pediatric prevalence and DALY burden of KS have remained low globally should not be misconstrued as indicating that KS is negligible. Rather, this pattern likely reflects persistent under-detection and the historical neglect of this common chromosomal disorder in global health assessments. In a broader context, our results bring KS into the spotlight as a global health concern – albeit one that has been “hidden” in plain sight – affecting an estimated 1 in 600 males worldwide. By quantifying its prevalence and health loss among those under 20, this study fills a critical gap in the epidemiology of pediatric genetic disorders and establishes a baseline for tracking improvements in early diagnosis and care.

In this study, the “M-shaped” curve from 2000 to 2006 may partly reflect enhanced cytogenetic reporting, the adoption of new newborn screening protocols, and increased awareness of KS in high-resource settings. Improved diagnostic capabilities, such as more widespread karyotyping, contributed to transient spikes in case ascertainment. Notably, the “rise then fall” DALY trend was not uniform across SDI levels; regional analyses show this pattern was most pronounced in high-SDI and some upper-middle SDI regions, likely reflecting improved detection followed by stabilization as diagnostic practices plateaued. In low-SDI settings, DALY rates increased gradually, potentially due to persistent underdiagnosis and limited care access. The highest EAPCs for prevalence (0.10; 95% CI: 0.04–0.15) and DALYs (0.18; 95% CI: 0.12–0.25) occurred in high-SDI regions (Tables 1, 2), likely attributable to greater healthcare resources, comprehensive screening, and heightened clinical awareness enabling higher detection. Conversely, underdiagnosis in low-SDI regions may stem from limited karyotyping access, reduced clinician awareness, and sociocultural stigma. Strategies to enhance detection include expanded newborn screening, professional education, and improved registry infrastructure.

When viewed alongside the literature, our findings reinforce a crucial point: the global health significance of KS lies not in early mortality or dramatic disability, but in its chronic, often unaddressed effects on health and wellbeing across the lifespan. Prior research has established that men with KS face elevated risks of numerous comorbidities, including metabolic syndrome (Zitzmann et al., 2021), type 2 diabetes (Gravholt et al., 2011), thromboembolism (Liang et al., 2022), osteoporosis (Willems et al., 2023), autoimmune disorders (Lucas-Herald et al., 2025), and certain malignancies (Win et al., 2020), contributing to a reduction in life expectancy by an estimated 2–6 years (Bojesen et al., 2011). These risks are already germinating in adolescence. For instance, adolescents with KS have higher rates of obesity and insulin resistance than their peers, as well as a propensity for psychiatric conditions such as anxiety and depression (Bojesen et al., 2010). The Million Veteran Program study in the US recently demonstrated that even men carrying an extra X or Y chromosome who were never clinically diagnosed showed significantly greater odds of cardiometabolic disease and neuropsychiatric issues compared to controls (Davis, 2024a). Notably, that large cohort genetic screening found a combined prevalence of X/Y aneuploidy around 1 in 370 men (0.27%) – higher than traditional newborn estimates – yet very few of those individuals had a documented KS diagnosis in medical records (Davis et al., 2024b). They were essentially “hidden” patients suffering the consequences without tailored care. This observation aligns with findings from Danish registry studies demonstrating that KS confers an increased standardized mortality risk, predominantly attributable to these comorbid conditions (Cho et al., 2020). Our study, focusing on those under 20, did not directly measure long-term outcomes like mortality; however, it quantifies the precursor state: the number of youths who, if left undiagnosed, are likely to fall through the cracks until perhaps presenting with infertility or severe disease decades later. In that sense, our work complements and extends prior studies by illuminating the pediatric segment of the KS population – a segment that previous global burden assessments had essentially omitted (Bai et al., 2024). By doing so, we contextualize KS within health systems: as a prevalent condition where the failure to integrate genetic diagnosis into primary care and pediatrics has led to preventable morbidity. The disparities we observed can be viewed as a barometer of health system capacity for genetic disorders. High detection rates in places like Northern Europe (e.g., Denmark, which achieved near-complete ascertainment of KS through past newborn studies (Herlihy et al., 2011)) show what is possible when proactive screening is in place. On the other hand, the near-absence of diagnosed cases in many low-income countries reflects systemic barriers – lack of trained specialists, limited access to karyotyping or chromosomal microarray tests, and low awareness among frontline providers (Wojcik et al., 2023). These deficiencies are not unique to KS; they apply to many rare pediatric conditions. Yet KS is among the most common congenital disorders (far more common than, for example, cystic fibrosis or phenylketonuria, which do receive newborn screening in many locales). Thus, the neglect of KS detection speaks to a broader policy blind spot in pediatric genetics and endocrinology. Our findings serve as a call to action to integrate genomic medicine equity into child health frameworks: every country should be capable of diagnosing a condition as frequent as KS. Closing these gaps is feasible – KS diagnosis requires a relatively simple chromosome analysis – but it demands political will and investment to ensure such tests and specialist consultations are accessible beyond tertiary centers in wealthy cities.

Timely, multidisciplinary intervention can substantially improve the long-term outcomes of individuals with KS.

Endocrine management: Early androgen therapy (for example, low-dose oxandrolone) has shown benefit for muscle tone, bone health, and selected neurocognitive domains.

Developmental support: Early referral to speech, occupational, and physical therapy can address developmental delays, supporting academic and social success.

Long-term care: Establishment of multidisciplinary KS clinics—combining endocrinology, psychology, genetics, and education specialists—should be prioritized. In low-resource regions, telemedicine or periodic outreach clinics may help bridge the gap in specialist access.

Universal newborn screening for KS is not yet standard practice globally, due in part to the variable natural history, potential psychosocial harms, and resource constraints. While feasibility studies support the technical implementation of screening, rigorous cost-benefit analyses and outcome studies are needed before broad adoption (Tassone, 2014). Short-term pilot programs in high-prevalence settings, coupled with strong genetic counseling, may offer a pragmatic step forward.

Prenatal and early diagnosis of KS, particularly via non-invasive prenatal testing (NIPT), raises important ethical questions. Parents must receive balanced counseling about the typically mild, manageable nature of KS, and the broad range of possible phenotypes. Avoiding unnecessary pregnancy termination due to misperceptions or stigma is an ethical imperative. In cases of prenatal or neonatal diagnosis, early linkage to multidisciplinary care is recommended to maximize developmental outcomes.

In conclusion, this study presents a novel global perspective on KS in children and adolescents, revealing a condition of significant prevalence that remains largely under-recognized.

This study has several important limitations. First, the analysis relies heavily on data from the GBD database, whose accuracy is constrained by the availability and quality of national registry data, a substantial number of undiagnosed pediatric KS cases, and the lack of detailed information on risk factors specific to childhood KS. Second, due to the clinical complexity of KS, missed diagnoses and misdiagnoses contribute significantly to underreporting, particularly in developing countries where diagnostic capabilities and awareness may be limited. Third, the GBD study’s estimates of the prevalence and DALYs for KS rely heavily on statistical modeling, particularly in countries with low SDI. Although the models adjust for diagnostic bias through covariates (e.g., SDI and healthcare accessibility), the uncertainty of estimates in regions lacking empirical data is substantially amplified.