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Published on: June 21, 2018
Beyond genotype: clustering analysis highlights clinical heterogeneity in paediatric familial Mediterranean fever
Isild Mahé1,2,3, Claire Billard4, Federica Anselmi1,2,3
1Paediatric Rheumatology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux universitaires Paris-Sud - Hôpital Bicêtre, Paris, France.
Background:
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in the MEFV 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.
Insights
Familial Mediterranean fever (FMF) shows varied severity, even in heterozygotes. Clustering identified five patient subgroups, revealing that genotype alone doesn't predict disease course, highlighting the need for comprehensive assessment.
Area of Science:
- Genetics
- Immunology
- Pediatrics
Background:
- Familial Mediterranean fever (FMF) is an autoinflammatory disorder linked to MEFV gene mutations.
- Existing treatments like colchicine and IL-1 inhibitors show variable efficacy, with significant inter-individual differences in disease presentation.
- The clinical variability, even in symptomatic heterozygotes, complicates genotype-phenotype correlations.
Purpose of the Study:
- To identify distinct clinical subgroups among pediatric FMF patients using clustering.
- To characterize the clinical features and disease trajectories of these identified subgroups.
- To investigate factors contributing to disease heterogeneity in FMF.
Main Methods:
- A retrospective monocentric study of 185 pediatric FMF patients (2004-2025) diagnosed via Eurofever criteria.
- Patients were classified as genetically confirmed (homozygous/compound heterozygous) or symptomatic heterozygotes.
- Longitudinal data on demographics, clinical presentation, labs, and treatment were analyzed using clustering techniques.
Main Results:
- The study identified five distinct patient subgroups, ranging from mild heterozygotes to severe early-onset homozygous FMF.
- Symptomatic heterozygotes generally exhibited milder disease, requiring less colchicine and fewer IL-1 inhibitors compared to genetically confirmed FMF.
- Disease severity was influenced by sex, age at onset, genotype (M694V homozygosity linked to severe phenotypes in females), attack frequency, and inflammatory markers.
- Crucially, not all heterozygous patients presented with mild disease courses.
Conclusions:
- Clustering analysis revealed significant heterogeneity in FMF disease expression, underscoring that MEFV genotype alone is insufficient to predict clinical variability.
- Multidimensional approaches are essential for accurately characterizing FMF heterogeneity and guiding personalized treatment strategies.
- These findings emphasize the complex interplay of genetic and clinical factors in FMF pathogenesis.
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