The effect of gene dosage and age at the disease onset on the severity of familial Mediterranean fever.

Objective: To compare the demographic and clinical characteristics of familial Mediterranean fever (FMF) patients according to age at disease onset and evaluate the dose effect of the number of pathogenic or likely pathogenic exon 10 mutations of the MEFV gene on disease severity.

Methods: This medical record review study was performed on 485 pediatric FMF patients with uni- or biallelic exon 10 mutations of the MEFV gene (M694V, M694I, M680I, V726A, R761H, T267I). Patients were grouped according to age at disease onset (Group 1:<6 years; Group 2:6-11 years; and Group 3:>11 years). Disease severity was assessed by the international severity scoring system for FMF (ISSF).

Results: Of the patients, 294 (60.6%) were classified in Group 1, 152 (31.4%) in Group 2 and 39 (8%) in Group 3. The mean elapsed time to diagnosis was 26.7 ± 27.4 months in Group 1 and was higher than the other groups (p < 0.001). During the attack, fever was higher in Group 1, arthritis in Group 2, and chest pain in Group 3 (p < 0.001). The median ISSF score was similar in patients with uni- or biallelic mutations in Group 1 and 3 (p = 0.086, p = 0.35, respectively) but lower in heterozygous patients in Group 2 (p < 0.001). In Groups 1 and 2, mild disease severity was higher in heterozygotes, while moderate disease severity was higher in homozygotes (p = 0.034, p = 0.001, respectively).

Conclusion: The presence of pathogenic or likely pathogenic homozygous or compound heterozygous mutations in exon 10 of the MEFV gene in patients with early-onset disease is associated with a more severe disease course compared to patients with heterozygous mutations. The gene dose effect of the number of mutations on disease severity is more common in children aged 6-11 years.