Long-term clinical course of pediatric familial Mediterranean fever with heterozygous pathogenic MEFV exon 10 variants.

UNLABELLED: Familial Mediterranean fever (FMF) is classically inherited as an autosomal recessive disease, yet some clinically diagnosed patients are heterozygous for pathogenic MEFV variants. We evaluated long-term clinical course, cumulative damage, and colchicine outcomes in children with FMF and heterozygous pathogenic MEFV exon 10 variants. Of 3187 patients screened, 274 with heterozygous pathogenic MEFV exon 10 variants fulfilling Yalçınkaya-Özen or EUROFEVER/PRINTO criteria and ≥ 5 years of follow-up were included. Clinical phenotype, disease severity, renal findings, ADDI-defined damage, and colchicine course were assessed. Median follow-up was 86 months. Clinical features included abdominal pain in 89.4% (n = 245/274), fever in 86.9% (n = 238/274), arthralgia in 66.1% (n = 181/274), myalgia in 54.4% (n = 149/274), acute arthritis in 20.8% (n = 57/274), and erysipelas-like erythema in 6.6% (n = 18/274). PRAS severity was mild in 35.4% (n = 97/274), and moderate in 64.6% (n = 177/274); ISSF severity was mild in 43.8% (n = 120/274), moderate in 55.1% (n = 151/274), and severe in 1.1% (n = 3/274). Persistent unexplained non-nephrotic proteinuria occurred in 2.2% (n = 6/274), and cumulative damage in 8.0% (n = 22/274). Among 92 patients who discontinued colchicine, 66.3% (n = 61/92) required re-initiation, whereas 33.7% (n = 31/92) remained off treatment. Patients with cumulative damage had higher annual attack frequency.

CONCLUSION: Children with FMF and heterozygous pathogenic MEFV exon 10 variants may exhibit a persistent, clinically meaningful phenotype with measurable cumulative damage. These findings support structured surveillance and individualized colchicine decisions integrating genotype with longitudinal clinical course.

WHAT IS KNOWN: • FMF is classically inherited as an autosomal recessive disease, although clinically diagnosed patients may be heterozygous for a pathogenic MEFV variant. • Long-term outcomes and the need for sustained colchicine treatment in this subgroup remain insufficiently defined.

WHAT IS NEW: • Children with heterozygous pathogenic MEFV exon 10 variants may show persistent clinical activity and continued colchicine requirement during long-term follow-up. • Cumulative damage occurred in a subset, supporting structured long-term surveillance and individualized treatment decisions.