Familial Mediterranean Fever With Compound Heterozygosity for the Pyrin Variant L110P-E148Q: A Case Report

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder caused by <i>MEFV</i> mutations. Exon 10 variants such as M694V are high-penetrance mutations associated with severe phenotypes, colchicine resistance, and amyloidosis. In contrast, exon 2 variants, particularly E148Q, are modifying alleles that require compound heterozygosity to manifest disease symptoms. Japanese patients frequently present with exon 2-related genotypes, resulting in milder phenotypes and a lower prevalence compared with Mediterranean populations. This report describes the case of a 30-year-old Japanese male with a three-month history of recurrent febrile episodes lasting 5-10 days, accompanied by fatigue and anorexia but no serositis. Elevated C-reactive protein and serum amyloid A levels were observed. The family history included periodic fevers in his mother and maternal grandmother. Genetic analysis revealed compound heterozygosity for <i>MEFV</i> exon 2 variants L110P-E148Q. Colchicine therapy induced complete remission, similar to his mother who also carried the same mutations. FMF is markedly less common in Japan than in Mediterranean regions, reflecting different genetic architectures. FMF can develop with a single exon 10 mutation in Mediterranean patient cohorts, whereas exon 2-exon 10 or exon 2-exon 2 compound heterozygosity is needed in Japanese patients. Owing to the absence of serositis in this patient, the disease could have been misdiagnosed without genetic testing. Thus, recognizing population-specific patterns is essential for appropriate management. This case demonstrates that exon 2 variants, although traditionally considered benign, can cause FMF in compound heterozygous conditions. Accordingly, genetic testing beyond exon 10 is critical for Japanese patients with recurrent fever.