Familial Mediterranean fever (FMF) is an inherited inflammatory disease that primarily affects patients in the Mediterranean and Middle Eastern populations such as Arabs, Jews, Armenians, Cypriots, Italians, Spaniards and Turks [1-7]. The disease is caused by pathogenic variants in the Mediterranean fever (
In this case-control study, the aim was to investigate the type and prevalence of
Peripheral blood samples (collected in vacutainers containing EDTA as anticoagulant) and buccal smears were used for genomic DNA isolation, and this was carried out by the spin-column method (Roche, Mannheim, Germany). The
Alternative mutated frequencies for the
The cohort was composed of 60 FMF children with mean ages of 10.48 ± 4.83 (3-18 years), and a 28 male (46.7%) to 32 female (53.3%) ratio of 1:1.14. Various combinations and point pathogenic variants were detected in all patients. Forty-six (70.0%) were heterozygous, six (10.0%) were homozygous and 12 (20.0%) were compound pathogenic variant profiles (Table 1). The genetic analysis of the current 60 mutated FMF children revealed that p.Met694Val was the most frequent pathogenic variant, followed by p.Glu148Gln, p.Met6801le, p.Arg202Gln, p.Val726Ala, p.Pro369Ser and p.Lys695Arg (Table 2).
Analysis of presenting gender and clinical manifestations of familial Mediterranean fever cases in the current study. FMF: familial Mediterranean fever; Clinical Characteristics FMF Patients ( Mean age (3-18 years) 10.48 ± 4.83 Gender: males 28 (46.7) females 32 (53.3) Pathogenic variant type: heterozygous 42 (70.0) homozygous 6 (10.0) compound 12 (20.0) Appendectomy history: yes 4 (6.7) no 56 (93.3) Parental consanguinity: yes 8 (13.3) no 52 (86.7) Erysipelas-like erythema: yes 3 (5.0) no 57 (95.0) Fever: yes 14 (23.3) no 46 (76.6) Arthritis: yes 14 (23.3) no 46 (76.6) Abdominal pain: yes 32 (53.3) no 28 (46.7) Colchicine therapy (1-2 mg/day): treated 48 (80.0) untreated 12 (20.0)
Frequency of common clinical manifestations related to the 12 pathogenic variant types in the presented cases and gen-otype-phenotype correlation in patients with familial Mediterranean fever according to the method of Mor FMF: familial Mediterranean fever.FMF Patients Clinical Characteristics Erythema Fever Abdominal Pain Arthritis Mutation Type % With Total With Total With Total With Total p.Met694Val 12 20.0 2 66.7 3.3 3 21.4 5.0 6 18.8 10.0 3 21.4 5.0 p.Glu148Gln 8 13.3 0 – – 0 – – 4 12.5 6.7 1 7.1 1.7 p.Met680Ile 7 11.7 0 – – 1 7.1 1.7 4 12.5 6.7 2 14.3 3.3 p.Arg202Gln 7 11.7 0 – – 3 21.4 5.0 5 15.6 8.3 2 14.3 3.3 p.Val726Ala 4 6.7 0 – – 0 – – 2 6.3 3.3 0 – – p.Pro369Ser 3 5.0 1 33.3 1.7 2 14.3 3.3 2 6.3 3.3 3 21.4 5.0 p.Lys695Arg 3 5.0 0 – – 0 – – 1 3.1 1.7 2 14.3 3.3 p.Arg761His 2 3.3 0 – – 1 7.1 1.7 2 6.3 3.3 0 – – IL28B 1 1.7 0 – – 1 7.1 1.7 1 3.1 1.7 0 – – p.Glu244Asp 1 1.7 0 – – 0 – – 0 – – 0 – – p.Met680Ile/p.Met694Val 4 6.7 0 – – 0 – – 2 6.3 3.3 1 7.1 1.7 p.Met694Val/p.Met694Ile 2 3.3 0 – – 0 – – 0 – – 0 – – p.Glu148Gln/p.Met694Val 1 1.7 0 – – 0 – – 0 – – 0 – – p.Met680Leu/p.Glu148Gln 1 1.7 0 – – 2 14.3 3.3 1 3.1 1.7 0 – – p.Arg200Gln/p.Met694Val 1 1.7 0 – – 0 – – 0 – – 0 – – p.Val726Ala/p.Arg202Gln 1 1.7 0 – – 1 7.1 1.7 1 3.1 1.7 0 – – p.Pro369Ser/p.Glu148Gln 1 1.7 0 – – 0 – – 1 3.1 1.7 0 – – p.Lys695Arg/p.Arg202Gln/p.Glu244Asp 1 1.7 0 – – 0 – – 0 – – 0 – – Total 60 3 100.0 5.0 14 100.0 23.4 32 100.0 53.4 14 100.0 23.3
The main clinical features of the patients were as follows: parental consanguinity was detected in eight (13.3%), appendectomy was detected in four (6.7%), abdominal pain was observed in 32 (53.3%), colchicine therapy in 48 (80%), fever in 14 (23.3%), arthritis in 14 (23.3%) and erysipelas-like erythema in three (5.0%). The detected pathogenic variants were mainly located at codons p.Met694Val, p.Glu148Gln, p.Met6801le, p.Arg202Gln, p.Val726Ala, p.Pro369Ser and p.Lys695Arg. The most common pathogenic variant was the p.Met694Val heterozygote (20.0%), followed by the p.Glu148Gln heterozygote (13.3%). The p.Met680Ile, p.Arg202Gln, p.Val726 Ala, p.Pro369Ser and p.Lys695Arg pathogenic variants were 11.7, 11.7, 6.7, 5.0 and 5.0%, respectively.
Table 2 shows the pathogenic variant prevalence as a function of the clinical characteristics in the current FMF cohort. The compound pathogenic variants of p.Met680 Leu and p.Glu148Gln were frequently found in 14.3% of the fever cases. Notably, both the p.Met694Val and p.Met694Ile pathogenic variants were found in 6.3% of the abdominal pain group, and in 7.1% of the arthritis group (Table 2). Phenotype severity was evaluated according to the subsequent genotype (11) in 60 patients (Table 2).
No difference was found when FMF patients carrying two mutated alleles (homozygous or compound heterozygous) were compared with those carrying only one mutated allele (heterozygous) (
Genotype results for 32 children (53.4%) with abdominal pain showed: two homozygotes for p.Met694Val, two homozygotes for p.Met680Ile and 20 heterozygotes for the p.Met694Val, p.Glu148Gln, p.Met680Ile, p.Val726Ala and p.Arg761His codons, and five compound heterozygotes for the codons p.Met680Ile/p.Met694Val, p.Met680 Leu/p.Glu148Gln, p.Val726Ala/p.Arg202Gln and p.Pro 369Ser/p.Glu148Gln (Table 2).
Ten children with fever showed heterozygous pathogenic variants for p.Met694Val (three patients), p.Metl80 Ile (one patient), p.Arg202Gln (three patients), p.Pro369 Ser (two patients) and IL-28β (one patient). Four children with fever showed compound heterozygous pathogenic variants for codons p.Met680Leu/Pro, p.Glu148Gln and p.Val726Ala/p.Arg202Gln (Table 2).
One compound heterozygous pathogenic variant at codons p.Met694Val/p.Met680Ile, one homozygous pathogenic variant at codon p.Met694Val and 12 heterozygous pathogenic variants at codons p.Met694Val, p.Met680Ile, p.Lys695Arg, p.Glu148Gln, p.Arg202Gln, p.Pro396Ser were detected in children with arthritis. Forty-eight FMF children (80.0%) were treated with colchicine (1-2 mg/ per day). One patient was unresponsive to the colchicine therapy (Table 1).
We studied the spectrum of
Abdominal pain is the most common symptom and is seen in 75.0-90.0% of patients. It usually starts suddenly, localized to a quadrant or all quadrants. It has a very broad spectrum ranging from mild abdominal to severe peritonitis. It was also the most common symptom in our study, with an incidence of 53.3% (32 patients). In the study by Kaşifoğlu
Four patients (6.7%) had a history of appendectomy. In the study of the Turkish FMF group it was reported to be 19.0% [16]. Yolbaş
In the case of FMF, the fever generally had a broad spectrum in terms of degree and duration. Afebrile attacks were rarely seen [21]. In our study, 14 (23.3%) patients had febrile attacks. In these patients, the most common pathogenic variants were p.Met694Val (three), p.Arg202 Gln (three) and p.Pro369Ser (two).
Arthritis is another common condition found in FMF [14]. It is generally acute or subacute but in 5.0% of cases it can be chronic. In a multicenter study by Kaşifoğlu
An erysipelas-like rash was seen in 3.0-46.0% of FMF patients [14,16,23]. It was more common in patients with arthritis. In our study, three patients (5.0%) had an erysipelas-like rash. In the case of p.Met694Val and p.Pro369 Ser pathogenic variants, arthritis-rash association was more common.
Tunca
The second most common pathogenic variant in this study was found to be p.Glu148Gln (13.3%), which is similar to the finding of the study by Ülgenalp [24] for the Aegean region. This may be due to the proximity of the two regions. Although the incidence of p.Glu148Gln was not specified in the report of the Turkish FMF Study Group, Yılmaz
In conclusion, all patients were clinically examined according to the Tell-Hashomer FMF criteria and were screened genetically for the 16 common