Heterozygous E148Q Mutation in an Indian Family with a Milder Form of Familial Mediterranean Fever

Abstract

Dear Editor, Familial Mediterranean fever (FMF, OMIM no. 249100) is an inherited autoinflammatory disorder resulting from MEFV gene mutations. A 15-year-old girl from Kerala, South India, born of a nonconsanguineous union presented with recurrent fever, diffuse abdominal pain, and left knee joint pain for 1 year. She had fever for 3 days every week associated with left knee arthritis. Some of the episodes were associated with diffuse abdominal pain, oral ulcers, and an erythematous facial rash. She also had right hip and ankle pain with swelling on a few occasions. On examination, she had swollen and warm left knee joint. Her 12-year-old sibling also had similar problems (recurrent fever, diffuse abdominal pain, and joint pain) for 10 months. Both the parents were asymptomatic. Blood tests showed neutrophilic leukocytosis, high erythrocyte sedimentation rate, and C-reactive protein. Ultrasonography of the abdomen showed mild ascites. Immunological testing showed normal C3 complement and the absence of rheumatoid factor, antinuclear, anti-double-stranded DNA, and anti-neutrophilic cytoplasmic antibodies. The periodicity of symptoms and positive family history made us consider inherited autoinflammatory disorder. Targeted mutational analysis showed the MEFV variant E148Q in the heterozygous state in both siblings. No pathogenic variants were identified in the MEFV exon, TNFRSF1A, and MVK genes [Table 1]. The patient and her younger sister were managed with colchicine (1.0 mg daily), and on follow-up up to 1 year, the patients were asymptomatic. Genetic counseling was given to the patient family.Table 1: The results of targeted mutational analysis of the MEFV, TNFRSF1A, and MVK genes in the two siblingsFMF is common among certain ethnic groups of the Eastern Mediterranean region. More than 300 different mutations of the MEFV gene related to FMF have been identified, although only a few are pathogenic.[1] Previous studies testing the pathogenicity of E148Q alteration showed conflicting results. In a study of 646 FMF patients by Tirosh et al., 1% had a heterozygous E148Q variant with a milder clinical phenotype compared with patients having M694V homozygosity.[2] A Turkish FMF cohort of 153 patients had 33 (21.6%) patients with E148Q variant and 34 compound heterozygous patients (with E148Q and exon 10 mutations).[3] E148Q allele frequency among FMF patients was found to be 25% in Jewish, Arab, and Druze patients living in Israel, 20% in Turkish, 34% in Japanese, 17% in Azeri Turk patients living in Iran, and 2% in Armenian patients.[3] Several studies noted that the E148Q mutation was associated with a milder FMF phenotype. However, there was no significant difference in the frequency of clinical findings among the Turkish cohort.[3] Two patients from a South Indian family with recurrent fever, diffuse abdominal pain, and left knee joint pain for 1 year were found to have the MEFV variant E148Q in the heterozygous state. Both of them responded well to colchicine. The diagnosis of a milder phenotype of FMF was thus confirmed. Even though autoinflammatory disorders were reported from the Indian subcontinent,[4,5] we do not have data regarding the E148Q allele frequency and other mutations causing FMF. We report FMF in two members of a family with E148Q mutation which was not previously reported from the Indian subcontinent. This case reminds the readers to consider hereditary periodic fever syndromes when evaluating recurrent fever and the importance of E148Q mutation in the Indian population. Ethics approval All procedures performed in studies involving human participants were by the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Declaration of patient consent The authors certify that informed consent was taken from the father of both patients and assent was obtained from the children for participating in the study. The informed consent from the father and assent from the children were also obtained for using the clinical information to be reported in the journal. The patients and parents understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.