Clinical and Demographic Evaluation According to MEFV Genes in Patients with Familial Mediterranean Fever

Abstract

The present study examined the relationship between clinical findings and mutation analyses in children with Familial Mediterranean Fever (FMF) in the inner Black Sea region of Turkey. This retrospective, cross-sectional study included patients with FMF who were evaluated between 2007 and 2015. FMF was diagnosed according to the Tel Hashomer criteria. FMF mutations were analyzed using a Real-time PCR System (Roche Diagnostics, Mannheim, Germany), and patients were classified into three groups according to allele status. The most common symptom was abdominal pain (99%, n = 197). The most frequent mutations were M694V and R202Q. Chest pain was reported more often in patients homozygous for M694V (61.4%). Although fever, abdominal pain, and arthritis were more commonly observed with the M694V mutation, chest pain was the most common symptom in R202Q carriers (n = 10, 32.3%). Proteinuria was observed in 42 (21.2%) patients, frequently accompanied by the M694V mutation (28.6%). The most common mutations in children with FMF in Turkey were M694V and R202Q. Recurrent abdominal pain and arthritis/arthralgia were commonly observed in patients with M694V and R202Q mutations. Moreover, chest pain was commonly seen with the R202Q mutation. Thus, R202Q might be a disease-causing mutation in FMF patients.

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Vol.:(0123456789)
Biochemical Genetics (2019) 57:289–300
https://doi.org/10.1007/s10528-018-9889-y
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ORIGINAL ARTICLE
Clinical andDemographic Evaluation According toMEFV
Genes inPatients withFamilial Mediterranean Fever
ErgünSönmezgöz1· SametÖzer1· AliGül1· ResulYılmaz1· TubaKasap1·
ŞahinTakcı1· RüveydaGümüşer1· OsmanDemir2
Received: 4 August 2017 / Accepted: 25 September 2018 / Published online: 3 October 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
The present study examined the relationship between clinical findings and mutation
analyses in children with Familial Mediterranean Fever (FMF) in the inner Black
Sea region of Turkey. This retrospective, cross-sectional study included patients with
FMF who were evaluated between 2007 and 2015. FMF was diagnosed according to
the Tel Hashomer criteria. FMF mutations were analyzed using a Real-time PCR
System (Roche Diagnostics, Mannheim, Germany), and patients were classified into
three groups according to allele status. The most common symptom was abdominal
pain (99%, n = 197). The most frequent mutations were M694V and R202Q. Chest
pain was reported more often in patients homozygous for M694V (61.4%). Although
fever, abdominal pain, and arthritis were more commonly observed with the M694V
mutation, chest pain was the most common symptom in R202Q carriers (n = 10,
32.3%). Proteinuria was observed in 42 (21.2%) patients, frequently accompanied by
the M694V mutation (28.6%). The most common mutations in children with FMF in
Turkey were M694V and R202Q. Recurrent abdominal pain and arthritis/arthralgia
were commonly observed in patients with M694V and R202Q mutations. Moreover,
chest pain was commonly seen with the R202Q mutation. Thus, R202Q might be a
disease-causing mutation in FMF patients.
Keywords Clinical features· Familial Mediterranean Fever· MEFV gene· R202Q
* Ergün Sönmezgöz
esonmezgoz@gmail.com
1 Department ofPediatrics, Gaziosmanpasa University School ofMedicine, 60250Tokat, Turkey
2 Department ofBiostatistics, Gaziosmanpasa University School ofMedicine, 60250Tokat,
Turkey

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Introduction
Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammtory
disease characterized by self-limiting recurrent short-term attacks of fever and
serosal inflammation (Bakkaloglu 2003). Although it is observed around the
world, FMF is more common among Turkish, Armenian, Arabic, and Sephardic
Jewish peoples residing in the eastern Mediterranean zone (Ben-Chetrit and Levy
1998). In Turkey, the estimated prevalence of FMF is 1/1000, and the carrier rate
is approximately 1:5 (Tunca etal. 2005). Clinical manifestations or symptoms of
FMF usually begin during the first decade of life (Berkun etal. 2012); therefore,
FMF is usually diagnosed in childhood.
The primary signs and symptoms of the disease in many patients are fever,
abdominal pain, chest pain, and arthritis/arthralgia. Serum amyloid A (SAA), an
acute-phase reactant produced in the liver, is quite elevated, especially during
attacks. The diagnosis of FMF relies on clinical criteria; Tel Hashomer criteria
are widely used for this purpose (Livneh etal. 1997). Genetic analyses may sup-
port the clinical diagnosis in suspicious cases (Shohat and Halpern 2011).
The Mediterranean fever (MEFV) gene, which is responsible for FMF, is
located on chromosome 16p13.3. This gene has ten exons and encodes the pyrin
protein, which regulates neutrophil activity. The most common mutations have
been identified in exons 2 and 10 (Aksentijevich etal. 1997). A total of 314 gene
mutations have thus far been identified in the MEFV gene. The most common
mutations, located in exon 10 of the MEFV gene, are M694V, M680I, E148Q,
V726A, and M694I; these account for 85% of disease cases (The International F.
M. F. C. 1997, Yalcinkaya etal. 2000, Touitou 2001). These mutations are seen
at different frequencies among the affected ethnic groups and in the population at
large (Caglayan etal. 2010). Many studies have been conducted in recent years
investigating the effects of MEFV gene mutations on clinical findings.
In this study, we investigated the relationship between genetic mutations
accompanying symptoms and clinical findings in 199 pediatric patients who were
admitted with complaints of recurrent fever, abdominal pain, and arthritis/arthral-
gia and who were diagnosed with FMF. In addition, the relationship between pro-
teinuria rate and genetic mutations, as well as the effect of colchicine treatment
on SAA, were investigated.
Methods
This study was conducted as a retrospective, cross-sectional study. The data were
transferred from the file records of 199 FMF patients who were followed between
January 2009 and December 2015 in the Department of Pediatrics at Gaziosmanpaşa
University Faculty of Medicine. All of the patients were of Turkish origin, from
the inner Black Sea region of Turkey. Only one individual from each family was
included in the study. All patients with FMF were under treatment with colchicines.

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The clinical and demographic data of the patients (e.g., fever, abdominal
pain, arthritis, erysipelas-like rash, family history, age at disease onset, and age
at diagnosis) were obtained from patient files and individual interviews with the
patients’ parents. FMF was diagnosed according to the Tel Hashomer criteria, and
mutations in the MEFV gene were identified (Shohat and Halpern 2011). Using
the Tel Hashomer criteria, two major criteria or one major and two minor criteria
are required for a definitive diagnosis, and one major and one minor criteria for
a likely diagnosis (Table1). The severity of the disease was determined accord-
ing to previously published criteria (Pras etal. 1998). MEFV gene analysis was
performed on all patients; the results are summarized in Table2. Patients were
divided into three groups based on MEFV genotypes: homozygous, compound
heterozygous, and heterozygous.
Gene/mutation Analysis
Blood specimens were drawn into EDTA-containing tubes, and genomic DNA
samples were extracted from the peripheral leukocytes of the collected venous
blood using a High Pure PCR Template Preparation Kit (Roche Molecular Bio-
chemicals, Mannheim, Germany) according to the manufacturer’s instructions.
For MEFV single nucleotide polymorphisms (SNPs), genotyping was performed
using commercial kits (TIB MOLBIOL GmbH, Berlin, Germany) and the Light-
Cycler 480 II Real-Time PCR System (Roche Diagnostics, Mannheim, Germany)
according to the manufacturers’ protocols.
Investigated mutations included p.E148Q (c.442G>C) and p.R202Q
(c.605G>A) in exon 2; p.P369S (c.1105C>T) in exon 3; p.F479L (c.1437C>G)
in exon 5; and p.M680I (c.2040G>C), p.M680I (c.2040G>A), I692del
(c.2076>2078del), p.M694V (c.2080A>G), p.M694I (c.2082G>A), p.K695R
(c.2084A>G), p.V726A (c.2177T>C), p.A744S (c.2230G>T), and p.R761H
(c.2282G>A) in exon 10.
Table 1 Tel-Hashomer
diagnosis criteria for FMF Major criteria:
1. Recurrent febrile episodes accompanied by peritonitis, pleuritis or
synovitis
2. Amyloidosis of AA-type without a predisposing disease
3. Favorable response to colchicine therapy
Minor criteria:
4. Recurrent febrile episodes
5. Erysipelas-like erythema
6. Familial Mediterranean Fever in first degree relative
Definitive diagnosis: 2 major or 1 major and 2 minor
Probable diadnosis:1 major and 1 minor

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Statistical Analysis
Chi-square tests were used to evaluate categorical variables; the results are
expressed as numbers and percentages. Continuous variables are expressed as the
mean (M) and standard deviation (SD). Pearson correlation coefficients were calcu-
lated to determine correlations between variables. P values < 0.05 were considered
to indicate statistically significant results. Calculations were performed with avail-
able statistics software (SPSS Statistics 19; IBM Corp., Armonk, NY). The Ethics
Committee for Clinical Research of the Gaziosmanpasa University School of Medi-
cine approved this study. All procedures were conducted in accordance with the dec-
laration of Helsinki principles after obtaining informed consent from patients and/
or their parents.
Results
The study population consisted of 199 patients diagnosed with FMF (103
males, 96 females; male/female ratio 1.07/1) whose average age at diagno-
sis was 11.69 ± 4.12 years (range: 4–17years). The average age at disease onset
was 8 ± 3.0 years. The average period between disease onset and diagnosis was
Table 2 Genotype distribution
of the patients n (%)
M694V 46 (23)
R202Q 26 (13)
E148Q 17 (8.5)
V726A 6 (3)
M680I 6 (3)
K695R 3 (1.5)
A744S 3 (1.5)
P369S 1 (0,5)
R761H 1 (0.5)
M694V-R202Q 34 (14)
E148Q-R202Q 9 (4.5)
M680I-M694V 8 (4)
E148Q-V726A 6 (3)
E148Q-M694V 5 (2.5)
M694V-V726A 5 (2.5)
R202Q-V726A 2 (1)
M680I-V726A 2 (1)
P369S-M694V 2 (1)
T681I-M680I 1 (0.5)
M694V-R761H 1 (0.5)
No detected mutation 15 (7.5)

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42months. Yearly attacks prior to treatment decreased significantly with colchicine
treatment. Detailed clinical and demographic data are shown in Table3.
The correlations of genetic mutations with symptoms were as follows. Com-
mon symptoms in our patients were, in order, abdominal pain (99%, n = 17), fever
(72.9%, n = 145), arthritis (30.7%, n = 61), chest pain (15.6%, n = 31), and erysipe-
las-like rash (6%, n = 12). These symptoms were most commonly accompanied by
the M694V mutation (43.7%). Other mutations commonly seen with clinical signs
were the compound heterozygous mutation M694V–R202Q (23.3%) and R202Q
(13.3%).
While fever, abdominal pain, and arthritis were more commonly observed with
the M694V mutation, chest pain was the most common symptom associated with
the R202Q mutation (n = 10, 32.3%). Although chest pain was more common in
compound heterozygotes, there was no statistically significant difference in the fre-
quency of chest pain among MEFV genotypes (p = 0.064). Erysipelas-like rash was
the most prominent symptom associated with the M694V–R202Q (n = 3, 25%) com-
pound heterozygous mutation.
Table 3 Demographic, clinical
and mutation characters of FMF
patients
Data are shown as mean ± standard deviation n (%)
Variables Statistics
Age at onset (years) 8.15 ± 3.50
Age at diagnosis (years) 11.69 ± 4.12
Sex
Male 96 (48.2)
Female 103 (51.8)
Medical history
FMF in familial history 102 (51.5)
Apendectomy history 32 (16.1)
Clinical findings
Fever 145 (72.9)
Severity score 6.3 ± 2.3
Abdominal pain 197 (99)
Artrhralgia/arthritis 61 (30.7)
Chest pain 31 (15.6)
Skin eruption 12 (6)
Proteinuria 42 (21.2)
Response to Colchicine
Complete 187 (94)
Non-response 12 (6)
Type of mutation
Heterozygote 81 (40.75)
Homozygote 28 (14.07)
Compound heterozygote 75 (37.68)
Wild type 15 (7.53)

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Proteinuria was observed in 42 (21.2%) patients and was frequently accompanied
by the M694V mutation (28.6%). Among compound heterozygotes, proteinuria was
most commonly observed with the M694V–R202Q mutation (21.5%). Two patients
in whom amyloidosis was detected histopathologically had the M694V homozy-
gous mutation. Proteinuria was seen at a rate of 35.7% (n = 15) in patients with a
compound heterozygous mutation. There was no statistically significant difference
among MEFV genotypes (p = 0.39).
Thirty-two (16.1%) patients had had an appendectomy prior to diagnosis.
Among allele groups, the compound heterozygote group showed the highest rate
(49.2%, n = 16) of appendectomy (p < 0.05). Appendectomy was commonly seen
in M694V–R202Q compound heterozygotes and M694V homozygotes (18.8% and
15.6%, respectively).
According to disease severity scores, 5% (n = 10) of cases had severe illness. The
disease severity score was higher in those who had had an appendectomy than in
those who had not (p = 0.035), and the average colchicine dose was higher among
these patients (p < 0.001).
The response to colchicine was better in heterozygotes (41.7%). The best response
to colchicine was in the M694V–R202Q and homozygous M694V mutation carriers
(17.4%/33 and 13.4%/25, respectively). Furthermore, the response to colchicine was
better in those who were young at the time of diagnosis (p < 0.001).
A family history of FMF was present in 102 (51.1%) patients, although there was
no statistically significant difference in the distribution of MEFV genotypes between
those with and without such a history. Statistically significant differences in the age
at diagnosis and age at disease onset were found in those with a family history com-
pared to those without (p = 0.022 and 0.002, respectively). Complaints of chest pain
were less frequent in those with a family history (p < 0.001).
12 (6%) were unresponsive. Three patients developed diarrhea during colchicine
treatment. Detailed clinical findings and mutation analysis information are shown in
Table4.
Discussion
In this study, the relationships among MEFV gene mutations, clinical symptoms,
and genotypes/phenotypes were investigated in 199 pediatric patients diagnosed
with FMF in the inner Black Sea region of Turkey. In addition, the relationships
between mutations in the MEFV gene and accompanying clinical symptoms were
evaluated.
FMF is a prototype of the periodic fever syndrome, with fever accompanied by
abdominal pain, chest pain, joint pain, and erythema-like skin lesions. Mutations
in the MEFV gene, located mostly in exons 2 and 10, may vary among peoples and
ethnic groups. Thus, whereas M694V is more common among Jews, Turks, and
Armenians, M680I is commonly seen in Armenians, M694I in Arabs, and E148Q in
European peoples (Ben-Chetrit etal. 2002; Papadopoulos etal. 2010).
Various studies have been carried out in Turkey, and the overall frequencies
of mutations have been reported in the respective regions. These findings have

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Table 4 The correlation of clinical findings and mutation types in patients with FMF
Mutation type Fever, n (%) Abdominal
pain, n (%)
Artritis/
Atralgia, n
(%)
Chest pain, n (%) Skin eruption, n (%) Appendec-
tomy, n (%)
Response to
colchicine, n
(%)
Familial
history, n
(%)
Proteinuria, n (%)
M694V 21 (21.4) 46 (23.4) 13 (21.4) 6 (19.3) 1 (8.3) 9 (28.1) 42 (22.5) 25 (24.5) 12 (28.6)
R202Q 18 (12.5) 26 (13.2) 11 (18) 10 (32.3) 2 (16.7) 3 (9.4) 23 (12.3) 13 (12.8) 5 (11.9)
E148Q 13 (9) 17 (8.6) 6 (9.8) – – 1 (3.1) 17 (9.1) 10 (9.8) –
V726A 6 (4.1) 6 (3) 1 (1.6) 3 (9.27) – 1 (3.1) 6 (3.2) 3 (2.9) 1 (2.4)
M680I 6 (4.2) 6 (3) – – – – 6 (3.2) 4 (3.9) 3 (7.6)
K695R 3 (2.1) 3 (1.5) – – – – 3 (1.6) 1 (1) 1 (2.4)
A744S 3 (2.1) 3 (1.5) 1 (1.6) – – – 3 (1.6) 2 (2) –
P369S – 1 (0.5) – – – – 1 (0.5) – –
R761H – 1 (0.5) – – – – – – –
M694V-202Q 25 (17.2) 8 (17.2) 10 (16.4) 7 (22.6) 3 (25) 6 (18.8) 33 (17.7) 15 (14.8) 9 (21.5)
E148Q -R202Q 5 (5) 9 (4.6) 3 (4.9) 1 (3.2) 1 (8.3) 3 (9.4) 8 (4.3) 5 (4.9) 3 (7.2)
M680I (g/c)-M694V 6 (4.1) 7 (3.6) 1 (1.6 – – 3 (9.4) 8 (4.3) 3 (2.9) –
E148Q-M694V 4 (2.8) 5 (2.5) 3 (4.9) – 2 (16.7) 1 (3.1) 3 (1.6) 2 (2) 1 (2.4)
E148Q-V726A 4 (2.8) 6 (3) 1 (1.6) – – 1 (3.1) 6 (3.2) 4 (3.9) –
M694V- V726A 3 (2.1) 5 (2.5) 1 (1.6) 1 (3.2) 1 (8.3) 1 (3.1) 5 (2.7) 1 (1) 1 (2.4)
R202Q-V726A 1 (0.7) 2 (1) 1 (1.6) – – – 2 (1.1) 1 (1) –
M680I (g/c)-V726A 1 (0.7) 2 (1) 1 (1.6) – – 1 (3.1) 2 (1.1) 2 (2) 1 (2.4)
P369S-694V 2 (1.4) 2 (1) – – – – 2 (1.1) 2 (2) –
T681I-M680I (g/c) 1 (0.7) 1 (0.5) 1 (1.6) 1 (3.2) – – 1 (0.5) –
M694V -V 761H – – – – – – 1 (0.5) –

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demonstrated regional differences and similarities in the frequencies of MEFV muta-
tions. According to the Turkish FMF study group, the most common MEFV muta-
tions were M694V (51.4%), M680I (14.4%), and V726A (8.6%) (Tunca etal. 2005).
In a study that showed the carrier rate in the healthy Turkish population to be 20%,
the frequencies of mutations in the diseased group were M694V, 51.55%; M680I,
9.22%; and V726A, 2.88% (Yilmaz etal. 2001). The most common mutations in 147
pediatric patients in the southeastern region of Turkey were E148Q (30.7%), M694V
(26.0%), R761H (13.5%), M680I (13.0%), V726A (10.5%), and P369S (6.3%) (Ece
etal. 2014). In another study, the most common mutations in 1058 FMF patients
from the eastern region of Turkey were M694V (36.50%), E148Q (32.77%), V726A
(14.09), and M694I (4.41%) (Coskun etal. 2015). The most common mutations in
1330 Iranian FMF patients were M594V, E148Q, V726A, M680I, and M694I (42%,
21%, 19%, 14%, and 2%, respectively). In a recent study, the distribution of MEFV
mutations M694V, M680I, V726A, K695R, and E148Q was 32.7%, 13.7%, 6%,
6.3%, and 3.4%, respectively. In addition, the G138G and A165A polymorphisms
were found to be more common in the FMF group than in the control group (Oksuz
etal. 2017).
In our study, M694V (23.3%), R202Q (13.1%), and E148Q (8.5%) were the most
common mutations. Thus, the R202Q mutation was the second most common muta-
tion found in our study.
It has been noted that the vast majorty of FMF-associated mutations are clustered
around the pyrin B30.2 domain (Arakelov etal. 2018). To date, 28 disease‐caus-
ing mutations have been identified in the B30.2 region of the human pyrin crystal
structure (Weinert etal. 2009). In our study, MEFV SNP genotyping was performed
using commercial kits.
The main symptoms of FMF are fever (96%), peritonitis (91%), pleurisy (57%),
arthritis/arthralgia (45%), and erysipelas-like erythema (1.3%) (Samuels et al.
1998). The form of these clinical symptoms may vary among ethnic groups and
communities (Dusunsel etal. 2008). Recent studies of the Turkish population have
shown abdominal pain to be the most prominent symptom, followed by fever, arthri-
tis, pleuritis, and erysipelas-like erythema (Ureten etal. 2010; Ozalkaya etal. 2011).
In the present study, the most common symptom was abdominal pain (99%). Other
common symptoms, in order of the rate of incidence, were fever (72.9%), arthri-
tis/arthralgia (30.7%), chest pain (15.6%), and erysipelas-like rash (6%). Similar to
other studies, clinical signs in our patients were most commonly accompanied by the
M694V mutation. In contrast to our results, another study found that fever (97.3%)
was the most common symptom; other symptoms were abdominal pain (96.6%),
arthritis (43.2%), and chest pain (40.7%) (Kilic etal. 2015). As in the present study,
these clinical signs have been shown to be most often accompanied by the M694V
mutation (Ozalkaya etal. 2011; Kilic etal. 2015; Kilinc etal. 2016). In our study,
unlike in other studies, the R202Q mutation was the second most common mutation
accompanying fever, abdominal pain, and arthritis symptoms.
The R202Q polymorphism, which is quite common, is not regarded as a patho-
genic mutation (Bernot etal. 1998; Öztürk etal. 2008). Nonetheless, the R202Q
mutation was the second most common mutation (13.1%) and had a high preva-
lence in clinically diagnosed FMF patients in our study. Our knowledge of the

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clinical features of the R202Q mutation in previous studies is limited. The R202Q
mutation was first identified in exon 2 of the MEFV gene (Bernot etal. 1998). In
the Greek population, R202Q homozygosity and heterozygosity were detected in
14/152 (9.2%) and 48/152 (31.6%) patients, respectively. Other researchers have
emphasized that the presence of the R202Q mutation in its homozygous form can
pose a risk for FMF, particularly in cases where MEFV gene mutations are not
present (Giaglis etal. 2007). A homozygous R202Q genetic change was detected
in 4 of 26 patients diagnosed with FMF who were negative for other mutations
in the MEFV gene, and it was emphasized that R202Q gene changes may be
mutations instead of polymorphisms (Ritis etal. 2004). In addition, R202Q was
found at a higher rate in FMF patients compared to the healthy control group in
recent studies, suggesting that R202Q is a disease-causing mutation. In a previ-
ous study in our region, the R202Q mutation showed a high rate of occurrence
in patients diagnosed with clinical FMF (Yigit etal. 2012). In a study conducted
using sequence analysis in the southeastern Mediterranean region of Turkey,
R202Q (21.35%) was reported to be the most common mutation. The mutations
commonly seen in the Turkish population were seen less often [E148Q (8.85%),
M694V (7.95%), M680I (2.40%), and V726A (1.85%)] (Gunesacar etal. 2014). In
a study conducted in the southwestern Mediterranean region of Turkey, the most
common mutation was R202Q (39.13%). In the present study, the M694V–R202Q
compound heterozygous mutation was seen at a significantly higher rate and fre-
quently accompanied symptoms of fever, abdominal pain, arthritis, and chest pain
(Kilinc etal. 2016). In a comprehensive MEFV gene analysis carried out using
1000 genomic databases, a homozygous p.R202Q mutation was present in five
major populations, providing further evidence that these mutations are signifi-
cantly more common than disease-causing mutations in all populations (Mora-
dian etal. 2017). In recent studies conducted in Turkey, the R202Q mutation has
been reported to be associated with clinical signs. In these studies, the complex
homozygous R202Q–M694V gene mutation was associated with an increase
in the risk of chronic periodontitis and FMF-associated secondary amyloidosis
(Fentoglu etal. 2017). In the present study, the R202Q mutation was the second
most common mutation accompanying these symptoms. While fever, abdominal
pain, and arthritis were more commonly observed with the M694V mutation,
chest pain was the most commonly observed symptom with the R202Q muta-
tion. In addition, the incidence of chest pain accompanying the M694V muta-
tion and the compound heterozygous mutation M694V–R202Q was noteworthy.
Consistent with our study, another study conducted in our country found that the
frequency of the compound heterozygous mutation M694V–R202Q was 24% and
that of the R202Q allele was 24.6% (Gumus 2018).
In our study, E148Q was the third most common mutation, but chest pain and
an erysipelas-like rash were not observed with this mutation. M680I and K695R,
with which only fever and abdominal pain were observed, were rare mutations. The
least common mutations were P369S and R761H, which were only accompanied
by abdominal pain. There was no family history of these two mutations. Both of
our patients who were diagnosed with FMF after Henoch-Schonlein purpura had the
M694V mutation.

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Proteinuria is commonly reported with the M694V mutation and less commonly
with the E148Q mutation (Dundar etal. 2012). Consistent with the literature, pro-
teinuria was most commonly observed with the M694V mutation in our patients.
Proteinuria was not detected with the E148Q mutation, which was present entirely in
the heterozygous form. In several studies showing a genotype–phenotype correlation
in FMF, the M694V mutation has been associated with a worse prognosis and has
been shown to be a risk factor for amyloidosis (Brik etal. 1999; Gershoni-Baruch
etal. 2002; Yilmaz etal. 2009). In the present study, the M694V and compound
heterozygous M694V–R202Q mutations were associated with a higher likelihood of
appendectomy. In addition, the disease severity score was higher in those who had
had an appendectomy compared to those who had not.
Some authors have stated that the frequency of family history was lower in
MEFV mutation-negative FMF patients (Ben-Zvi etal. 2015). In one study, the fam-
ily history associated with FMF was reported as 4% (Yilmaz etal. 2009); in another,
it was 28.7% (Ozturk etal. 2012). In our study, family history of FMF was relatively
high. Although there was no statistically significant difference in the distribution of
MEFV genotypes between those with and without such a history.
The major limitation of this retrospective study was the use of commercial kits
for MEFV gene analysis. In addition, the study group was small. Nonetheless, our
genotype–phenotype correlation results will contribute to the mutation profile of
Turkish FMF patients.
In summary, this was a comprehensive study showing the types and rates of
mutations accompanying the demographic and clinical features of children with
FMF in our study region. The most common mutation was M694V, which was also
the mutation most commonly seen together with clinical symptoms. The high rate of
incidence of the R202Q mutation in this study is remarkable. Chest pain and an ery-
sipelas-like rash were more common with heterozygous mutations and compound
heterozygous mutations accompanied by R202Q, particularly in clinically diagnosed
FMF patients. The high incidence of the R202Q mutation in our region and its fre-
quent association with clinical symptoms indicate a risk for FMF disease.
Acknowledgements The English in this document has been checked by at least two professional editors,
both native speakers of English. For a certificate, please see:
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