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
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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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