Unraveling the Pediatric Hyperinflammatory Continuum: A Comparative Clinical and Genomic Analysis of Kawasaki Disease and MIS-C (Multisystem Inflammatory Syndrome in Children)

Kawasaki Disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) represent two major hyperinflammatory disorders of childhood that share significant clinical and pathogenic similarities. Despite extensive research, it remains unclear whether they are distinct entities or part of a single continuum of pediatric hyperinflammation triggered by infectious agents in genetically predisposed individuals. This study aimed to elucidate the relationship between KD and MIS-C through a dual clinical and genomic approach. The clinical analysis compared two large multicenter cohorts of patients diagnosed with either KD (KIWI registry, collecting patients between 2015 and 2023) or MIS-C (the HyperPed-COVID registry, which retrospectively collected MIS-C patients from 2020), assessing demographic, clinical, laboratory, and instrumental parameters. Comparisons were performed using Student's t-test or Mann–Whitney U test for continuous data, and χ² or Fisher's exact tests for categorical data. A multivariable logistic regression model was developed to identify the most discriminative clinical and laboratory predictors, alongside age-stratified analyses (<1 year, 1–4 years, 4–8 years) to assess phenotypic overlap across age groups. The genetic component of the study employed whole-genome sequencing (WGS). Following rigorous quality control (QC), approximately 10 million variants per cohort were retained. Three analytical approaches were applied: (1) in silico panel analysis of 134 candidate genes; (2) genome-wide and targeted Transmission Disequilibrium Test (TDT) performed separately for each disease; (3) combined genome-wide Sibship TDT (S-TDT) under the hypothesis of a shared genetic background. Results. 1,701 patients (722 KD, 979 MIS-C) were included in the clinical study. KD patients were significantly younger (3.2 ± 2.6 years vs. 7.9 ± 4.6 years, p<0.0001). Mucocutaneous manifestations were nearly universal in KD (99.7%), but also highly prevalent in MIS-C (82.1%). Gastrointestinal involvement — particularly abdominal pain — was the strongest distinguishing marker for MIS-C (62.6% vs. 15.1%; Cramér's V 0.48). Coronary abnormalities, especially aneurysms (33.9% KD vs. 7.7% MIS-C), were strongly associated with KD, whereas myocarditis (39.5% vs. 9.8%) and pericarditis (24.3% vs. 10.2%) were more frequent in MIS-C. The final multivariable model demonstrated excellent discriminative performance (AUC = 0.912; Pseudo-R² = 0.46). The strongest independent predictors of KD were coronary aneurysm (OR 7.36), cheilitis (OR 3.93), and cervical lymphadenopathy (OR 2.22); the strongest predictors of MIS-C were abdominal pain (OR 0.20), myocarditis (OR 0.33), and older age (OR 0.33 per SD). Age-stratified analysis revealed a significant drop in diagnostic performance in children aged 1–4 years (AUC = 0.805), a range in which phenotypic overlap is greatest and laboratory markers are least discriminating. WGS was performed on 86 pediatric patients (38 KD and 48 MIS-C) and 16 asymptomatic siblings who contracted SARS-CoV-2 without hyperinflammatory complications. In silico panel analysis identified the presence of rare variants in genes implicated in cytokine signaling, vascular integrity, immune regulation, and pathogen sensing pathways, without significant differences between the two groups of patients. Targeted TDT using a literature-derived panel of 850 genes revealed the presence of a common variant in SLC8A1 — a gene involved in calcium ion exchange — as nominally significant in both diseases. Comparison of effect size distributions across cohorts showed that variants with concordant direction of effect were enriched in genes related to calcium signaling, mucocutaneous, and vascular pathways. Combined S-TDT analysis identified six variants exceeding the suggestive threshold, with CNTN1 (contactin-1, two independent variants) and RBFOX1 emerging as the most notable candidate genes, both with roles in neuronal and glial signaling. Conclusions. Despite notable clinical differences that allowed the development of a multivariable model with high accuracy, KD and MIS-C present a clear overlap in younger children. Moreover, the genetic analyses provide preliminary evidence of shared genetic susceptibility. Taken together, these data suggest that KD and MIS-C may represent two expressions of the same hyperinflammatory continuum.