Genotype–phenotype correlations in pediatric CAPS with predominantly low-penetrance NLRP3 variants among Turkish patients in Germany and Turkey: beyond borders

Abstract Background The phenotypic heterogeneity and variable disease course of CAPS cannot be explained solely by NLRP3 mutations, suggesting additional environmental or modifying factors. This study aimed to characterize the phenotypic and genotypic features of Turkish-origin pediatric CAPS patients residing in Turkey (Turkish cohort) and Germany (German cohort). Methods This multicenter, retrospective study included Turkish-origin pediatric patients meeting CAPS criteria from centers in Germany and Turkey. Demographic, genetic, clinical, and treatment data were collected, and disease activity was assessed using PGA and PPGA. Results The study included 51 Turkish-origin pediatric CAPS patients (living in Turkey: 23; Germany: 28) with a median age of disease onset at 1 year and diagnosis at 4 years. The Turkish cohort had more pathogenic mutations and more severe phenotypes, while the German cohort predominantly carried VUS/Q703K variants with a mild phenotype. Diagnostic delay and attack duration were longer in the Turkish cohort; urticarial rash, fatigue, thoracic pain, fever, and aphthous ulcers were more frequent, whereas diarrhea, lymphadenopathy, and infection-triggered attacks predominated in the German cohort. Baseline disease activity was higher in the Turkish cohort, and most patients achieved remission at last visit under therapy—mainly above-standard doses of Canakinumab—whereas over half of the German cohort reached remission without treatment. VUS and Q703K subgroup: Among patients with similar genotypes (VUS/Q703K), the Turkish cohort presented with older age at diagnosis, longer diagnostic delay, more moderate phenotypes, and higher baseline disease activity, whereas the German cohort exhibited milder phenotypes, infection-triggered attacks, and gastrointestinal involvement. The Turkish cohort received Canakinumab or Anakinra more frequently, often with dose adjustments and above-standard doses, achieving complete remission frequently under therapy at last visit, while the German cohort more often reached remission without treatment. Non-remission and partial remission were observed exclusively in the Turkish cohort. Conclusion These findings suggest that Turkish-origin pediatric CAPS patients living in Turkey, including those with similar VUS/Q703K genotypes, may experience higher disease activity and greater treatment dependence than their German counterparts. However, as most patients in our cohort carried low-penetrance VUS variants, these observations are not directly generalizable to individuals with clearly pathogenic NLRP3 genotypes. Overall, this supports the notion that factors beyond genetics, potentially including environmental or modifying influences, contribute to CAPS severity and warrant further investigation.