Genotype-phenotype divergence in pediatric familial Mediterranean fever across two closely related populations: a Türkiye-Azerbaijan comparison.

BACKGROUND

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and has a high prevalence in Türkiye. Despite shared ethnic ties, pediatric FMF in Azerbaijan remains poorly characterized. This study aimed to systematically compare the clinical, laboratory, and genetic characteristics of pediatric FMF patients from Türkiye and Azerbaijan to determine whether common ancestral origins result in uniform disease expression.

METHODS

This retrospective bicentric study enrolled pediatric FMF patients aged 0-18 years who met the Eurofever/PRINTO criteria and had ≥12 months of follow-up at specialized centers in Türkiye and Azerbaijan. Demographics, clinical features, laboratory findings, Mediterranean FeVer (MEFV) genotypes, severity scores, and treatment data were compared.

RESULTS

The cohort comprised 549 patients: 477 (86.9%) Turkish and 72 (13.1%) Azerbaijani. Azerbaijani patients had earlier symptom onset (30 [IQR 16-67] vs. 48 [IQR: 24-72] months, p=0.044) but a longer diagnostic delay (14 [IQR: 11.4-48.7] vs. 12 [IQR: 6-23] months, p<0.001). Turkish patients showed higher rates of chest pain (22.6% vs. 8.3%, p=0.005), arthralgia (52.6% vs. 32 %, p= 0.001), annual attack frequency (12 [IQR: 6-12] vs. 6 [IQR: 4-8], p<0.001), International Severity Score for Familial Mediterranean Fever (ISSF) scores (2 [IQR: 1-3] vs. 2 [IQR: 1-2], p=0.002), and C-reactive protein (CRP) levels (56 [IQR: 34-96] vs. 17.9 [IQR: 3.2-35.6] mg/L, p<0.001). Confirmatory exon 10 genotypes predominated in Turkish patients (66.7%) whereas unconfirmatory genotypes in Azerbaijani patients (59.7%). M694V was the most common variant in both groups. Within exon 10 homozygotes, Turkish patients had higher ISSF scores (median 3 [IQR: 2-4] vs. 2 [IQR: 1-3], p=0.037) and more arthritis (39% vs 6.3%, p=0.032). Colchicine response was comparable (90.6% vs. 93.1%), but anti-IL-1 use was higher in Turkish patients (11.5% vs. 2.9%, p=0.028).

CONCLUSION

This first systematic Türkiye-Azerbaijan comparison reveals distinct genotype-phenotype correlations in pediatric FMF, with Turkish patients showing a higher burden of confirmatory exon 10 genotypes and more severe disease, highlighting the need for center- and population-aware management strategies.