Monogenic systemic autoinflammatory diseases (SAIDs) are driven by innate immune dysregulation, often due to aberrant inflammasome activation. Inflammasomopathies, those involving NLRP3, MEFV, MVK, and TNFRSF1A mutations, constitute a subgroup marked by sterile inflammation and overlapping symptoms like fever, serositis, rash, and arthritis. However, diagnostic complexity from phenotypic variability and incomplete penetrance makes genetic and immunological confirmation essential. This study aimed to characterize the clinical, biochemical, immunological, and genetic profiles of pediatric patients with confirmed or suspected inflammasomopathies at a tertiary care center.
Data were obtained from a monogenic SAID registry. Genetic analysis was performed using panel-based exome sequencing, and inflammatory biomarkers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], MRP8/14) were evaluated.
Over a 10-year period, 36 patients were assessed, of whom 13 (36%) had definitive diagnoses. Median age at symptom onset was 18 months, while diagnosis occurred at a mean age of 99 months, highlighting diagnostic delay. Predominant symptoms included fever (25%), ocular inflammation (12.5%), rash, arthritis, and aphthous ulcers (9% each). Despite identical NLRP3 mutations, phenotypic variation suggested roles for modifier genes or environmental factors. All patients showed laboratory signs of systemic inflammation—elevated ESR, CRP, MRP8/14, leukocytosis, and thrombocytosis—with absence of autoantibodies, consistent with autoinflammatory etiology. Overall variants were classified according to the ACMG (American College of Medical Genetics and Genomics) in inflammasome-related genes. Tailored to treatment strategies included IL-1 and TNF inhibitors.
This cohort reinforces the pivotal role of the inflammasome in monogenic autoinflammatory diseases. Clinical heterogeneity, even among patients with identical mutations, underscores the need for individualized evaluation. Early integration of clinical, immunological, and genetic data guiding targeted cytokine therapies that can mitigate innate immune dysregulation improving outcomes in children.
