THE MEFV GENE PATHOGENIC VARIANTS AND PHENOTYPE-GENOTYPE CORRELATION IN CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER IN THE ÇANAKKALE POPULATION
Battal F, Silan F, Topaloğlu N, Aylanç H, Yıldırım Ş, Köksal Binnetoğlu F1, Tekin M1, Kaymaz N1, Ozdemir O,
*Corresponding Author: Assistant Professor Dr. Şule Yıldırım, Department of Pediatrics, Faculty of Medicine, Çanakkale Onsekiz Mart University, Terzioğlu Yerleşkesi Ek Bina, 17100, Çanakkale, Turkey. Tel: +90-286-2180018/2107. Fax: +90- 286-263-59-56. E-mail: sule.yildirim@comu.edu.tr
page: 23

DISCUSSION

We studied the spectrum of MEFV gene distribution and the clinical characteristics of patients who have MEFV gene pathogenic variants. The most common pathogenic variant seen in our country was also prevalent for our region. Of the three patients with a homozygous pathogenic variant, one had arthritis and two had abdominal pain. All the other clinical signs belonged to heterozygous or compound heterozygous pathogenic variant groups. 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 et al. [21], it was reported to be 94.6% and it was more prominent in p.Met694Val gene pathogenic variants. In this study, abdominal pain was found to be more common in the homozygous and compound heterozygous p.Met694Val (eight), p.Met680Ile (six), p.Arg202 Gln (six) and p.Glu148Gln (five) pathogenic variants. 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 et al. [22] showed that in patients initially diagnosed with appendicitis, most had the p.Met694 Val pathogenic variant (19.0%). In our patients there were different pathogenic variants, but the number of patients was few and the geographical region of our study was different. 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 et al. [21], the incidence of arthritis was reported as 39.8%. In this study, it was reported in 14 patients (23.3%) and the most common pathogenic variants in these patients were p.Met694Val (four), p.Met680Ile (three), p.Pro369Ser (three) and p.Arg202 Gln (two). 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 et al. [16] in their multicenter study, reported that the most common pathogenic variant in the Turkish population was p.Met694Val (51.4%), followed by p.Met 680Ile (14.4%) and p.Val726Ala (8.6%). In another multicenter study from Turkey, the p.Met694Val pathogenic variant was again the most common with an incidence of 24.0% [21]. In our study, the incidence of the p.Met694Val pathogenic variant was 20.0% and it was the most common of the pathogenic variants. This demonstrated that our region is similar to the general population of Turkey in terms of FMF pathogenic variants. 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 et al. [25] reported it to be 3.5% in Turkish FMF patients. They also discovered that 12.0% of the healthy population had the p.Glu148Gln pathogenic variant and claimed that this variant causes mild clinical form [25]. In contrast Topaloğlu et al. [26] reported that patients with homozygous p.Glu148Gln pathogenic variants are symptomatic and require treatment. In our study, patients with heterozygous and compound heterozygous p.Glu148 Gln pathogenic variants had arthritis and abdominal pain and they also required treatment. In conclusion, all patients were clinically examined according to the Tell-Hashomer FMF criteria and were screened genetically for the 16 common MEFV pathogenic variants. Various pathogenic variants were detected in all children examined (100.0%). The most frequent pathogenic variant was p.Met694Val followed by p.Glu148Gln, p.Met6801le, p.Arg202Gln, p.Val726Ala, p.Pro369Ser and p.Lys695Arg. These results indicate that the Çanakkale population has a wide range of heterozygous mutation carriers of the MEFV gene and the mutated p.Glu148Gln allele showed a higher incidence when compared to other Mediterranean children. The results indicated that not only clinical characteristics, but also genotyping of the MEFV gene is needed to establish the correct diagnosis of carriers and/or FMF children and other family members. The heterozygous carriers (especially codons p.Met694Val, p.Glu148 Gln and/or compound heterozygotes and compound mutated patients showed the same clinical characteristics as homozygous children in the current report. The results also demonstrated that carriers showed a good response to col-chicine therapy and that this treatment can play a crucial role in heterozygous and compound heterozygous groups as well as in the homozygous group. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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