Beyond genotype: clustering analysis highlights clinical heterogeneity in paediatric familial Mediterranean fever

BACKGROUND: gene. Despite therapeutic advances with colchicine and interleukin-1 (IL-1) inhibitors, FMF shows marked interindividual variability, including among symptomatic heterozygotes, challenging genotype-phenotype correlations. OBJECTIVES: To identify clinically meaningful subgroups of paediatric patients with FMF using a clustering approach and to characterise their clinical features and disease trajectories. METHODS: We conducted a monocentric retrospective study including 185 paediatric patients diagnosed with FMF between 2004 and 2025 according to Eurofever criteria. Patients were stratified as genetically confirmed FMF (homozygous, compound heterozygous) or symptomatic heterozygotes. Demographic, clinical, laboratory and treatment data were collected longitudinally. Clustering analysis was used to identify clinically meaningful subgroups. RESULTS: The median age at onset was 2.5 years and the median diagnostic delay was 24 months. Ninety-three (50%) patients were symptomatic heterozygotes. Compared with genetically confirmed FMF, heterozygotes had milder disease, lower colchicine doses and less frequent IL-1 inhibitor use. Cluster analysis identified five distinct subgroups, ranging from asymptomatic or mild heterozygotes without treatment to early-onset homozygous patients with severe disease requiring higher-dose colchicine and IL-1 inhibitors. Not all heterozygous patients had a mild disease course. Sex, age at onset, genotype, attack frequency and inflammatory markers contributed to cluster differentiation. Severe phenotypes were enriched in female patients with early-onset M694V homozygosity. CONCLUSION: Cluster analysis identified heterogeneous patterns of disease expression, suggesting that the genotype alone does not fully explain clinical variability in FMF. These findings highlight the value of multidimensional approaches to better characterise disease heterogeneity.