|Year : 2021 | Volume
| Issue : 1 | Page : 41-47
Value of mean platelets volume in children with familial mediterranean fever: A case–control prospective study from Sulaymaniyah, Kurdistan Region, Iraq
Hayder Fakhir Mohammad
Department of Pediatrics, College of Medicine, University of Sulaimani, Sulaymaniyah, Region of Kurdistan, Iraq
|Date of Submission||03-Nov-2020|
|Date of Acceptance||06-Jan-2021|
|Date of Web Publication||21-Jun-2021|
Dr Hayder Fakhir Mohammad
Department of Pediatrics/College of Medicine/University of Sulaymaniyah, Sulaymaniyah Kurdistan Regional Government
Source of Support: None, Conflict of Interest: None
BACKGROUND: Familial Mediterranean fever (FMF) is characterized by a rise in acute phase reactants (APRs) during the attacks and occasionally in between the attacks. Although mean platelet volume (MPV) is generally not changed, low MPV could be used as an inflammatory marker in FMF and as an indicator of other diseases. This prospective case–control study was carried out in Sulaymaniyah, Iraq, to assess MPV in Kurdish children with different FMF mutations during and in-between the attacks versus healthy controls.
PATIENTS AND METHODS: From 2011 to 2020, 56 gene-positive FMF patients (Group I) and 60 healthy controls (Group II) were enrolled. Besides the routine APRs, MPV was measured in both groups and categorized into low (<7 fl), normal (7–11 fl) and high (>11 fl). Informed consents from all participants and ethical institutional approval were obtained.
RESULTS: Group I age range was 23 months to 16 years with a male to female ratio of 1.8:1 while Group II age ranged from 21 months to 15 years with a male to female ratio of 1.4:1. MPV was normal in (n = 44, 78.6%) of Group I versus (n = 44, 73.3%) of Group II (P = 0.05); low in (n = 8, 14.3%) of Group I versus (n = 4, 6.7%) of Group II (P = 0.05) and high in (n = 4, 7.1%) of Group I versus (n = 4, 6.7%) of Group II (P = 0.05). Low MPV values were relatively more frequent among the homozygotes (n = 4, 50%) and complex heterozygotes (n = 2, 25%) (P = 0.003).
CONCLUSION: The current study showed that MPV was not statistically different between FMF patients and controls, while abnormal MPVs were associated with specific genotypes that may indicate coexistent problems.
Keywords: Familial Mediterranean fever, genotypes, inflammatory markers, mean platelets volume
|How to cite this article:|
Mohammad HF. Value of mean platelets volume in children with familial mediterranean fever: A case–control prospective study from Sulaymaniyah, Kurdistan Region, Iraq. Iraqi J Hematol 2021;10:41-7
|How to cite this URL:|
Mohammad HF. Value of mean platelets volume in children with familial mediterranean fever: A case–control prospective study from Sulaymaniyah, Kurdistan Region, Iraq. Iraqi J Hematol [serial online] 2021 [cited 2021 Dec 6];10:41-7. Available from: https://www.ijhonline.org/text.asp?2021/10/1/41/318774
| Introduction|| |
Platelets play an important role in inflammatory responses. Different inflammatory factors like coagulants and cytokines are released by platelets. The mean platelets volume (MPV) which is a measure of the average size of the platelets varies according to platelets function and activity. In the last years many articles reported that MPV may be used as an inflammatory marker in different diseases., Some reports mentioned an increase in MPV in high altitude and in diseases such as myocardial infarction, cerebrovascular accidents, atherosclerosis, Vitamin D deficiency, thyroid disorders, and cancers. In contrast, chemotherapy and other diseases such as rheumatoid arthritis, ankylosing spondylitis, impaired bone marrow function, ulcerative colitis were associated with a decrease in MPV. Genetic disorders may cause either an increase or a decrease in MPV.,,,
Familial Mediterranean fever (FMF) is an inflammatory disorder inherited by autosomal recessive gene characterized by recurrent episodes of febrile polyserositis. The disease is especially prevalent in individuals of Mediterranean descent. Due to its non-specific manifestations, FMF may mimic other disorders such as infections, cholecystitis, appendicitis, and arthritis leading to a delay in diagnosis for a long time and predisposing the patients to extensive evaluations and even unnecessary surgery. Patients who do not receive treatment or receive the treatment late in the course of the disease are liable to serious complications such as end stage renal disease and malabsorption secondary to amyloidosis besides failure to thrive in children and infertility in adults. Nevertheless, both acute episodic attacks and late sequelae are quite preventable by treatment with oral colchicine therapy.,,
This prospective case–control study was carried out in Sulaymaniyah Pediatric Teaching Hospital in order to (1) Compare the MPV in children with genetically proved FMV versus healthy controls, (2) Correlate the MPV with different patients' genotypes, and (3) Compare the MPV in patients with FMF during the attacks and in between the attacks.
| Patients and Methods|| |
This prospective case–control study was conducted over 9 years (2011–2020) in Sulaymaniyah, Region of Kurdistan, Iraq. The study enrolled 56 Kurdish children with FMF (Group I) and 60 healthy control children (Group II). Patients in Group I were clinically diagnosed according to Tel-Hashomer criteria and all were gene positive. According to Tel-Hashomer, the major diagnostic criteria are recurrent febrile episodes with serositis (peritonitis, synovitis or pleuritis), amyloidosis of AA type without a predisposing disease and favorable response to regular colchicine treatment while recurrent febrile episodes, erysipelas-like erythema and FMF in a first degree relative are the minor criteria. Two or more major or one major plus two minor findings are sufficient for FMF diagnosis.
After full history and thorough clinical examination, patients and healthy controls were sent for laboratory investigations including complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum iron, total iron binding capacity, serum ferritin, Vitamin D, MPV. Moreover, genetic testing was performed for the patients (Group I) in order to prove the diagnosis, and it was in our plan for all patients from the beginning.
Patients in Group I had laboratory investigations at 2 occasions: during the attack (Group I A; n = 56) and during the attack-free period (Group I B; n = 56). Patients with incomplete information in term of history, clinical examination or investigation were excluded from the study (n = 8; with missing data during attack-free period).
The inclusion criteria for the controls (Group II) included the following: Kurdish nationality, age between 1 and 17-year-old, have relatively same male to female ratio, had no fever at time of test, no history of acute nor chronic problem, had normal white blood cell (WBC), ESR and CRP and were coming just for evaluation.
The MPV was recorded in both patients and controls. The MPV was measured in two private laboratories in femtoliter (fl). In this study MPV values were divided into three categories; low MPV considered when <7 fl, normal MPV between 7 and 11 fl, and large MPV when the measurement >11 fl.,,,,
Prior to 2016, genetic studies were done abroad as they were not available in Sulaymaniyah but thereafter, 2 private laboratories began to perform these studies. Each patient was genetically rechecked by the same laboratory during the follow-up period and was excluded from the study if a different genetic profile was obtained. Peripheral blood samples in vacutainers containing ethylenediaminetetraacetic acid as anticoagulant were used for genomic DNA extraction by using real prep DNA extraction kit from promega-USA. The MEFV gene variants were genotyped by multiplex real time polymerase chain reaction method detecting 18 common pathogenic variants (Centogene–Turkey). The variants were M694V, M694I, M680I, V726A, E148Q, P369S, A744S, E84K, G304R, E148V, F479L, E167D, T267I, L110P, P283L, K695R, R761H, and E230K/Q.
All were treated with colchicine therapy in a dose 0.5 mg/day for children below 5; 1–2 mg/day for 6–16 years old children and up to 3 mg/day for old children with uncontrolled FMF attacks.
All patients' parents were told that their children will be included in this study and they gave their agreement, and study had been proved by the Ethical Committee in the College of Medicine/University of Sulaimani.
The statistical analysis was performed using the SPSS program(Statistical Package for Social Sciences) version 23 (IBM SPSS) (Armonk, NY, IBM Corp, USA). Chi-square tests were used for correlation between variables. P < 0.05 was considered statistically significant.
| Results|| |
The age range of patients with FMF was between 23 months and 16 years old with a mean of 8.02 ± 3.91 and a male to female ratio of 1.8:1 while in the control group, age ranged from 21 months to 15 years with a mean of 7.77 ± 3.72 and a male to female ratio of 1.4:1. The other demographic characteristics are shown in [Table 1].
|Table 1: Demographic characteristics of patients with familial mediterranean fever and control group|
Click here to view
The triggering factors for attacks in our patients are: Flue and upper respiratory tract infections (46%), Urinary tract infections (31.6%), emotional and physical stresses (12.3%), gastrointestinal infections (8.2%), and others (1.9%).
WBC, ESR, and CRP all had significant statistical association between Group IA and IB while MPV and serum ferritin had no significant statistical correlations as shown in [Table 2]:
The mean ± standard deviation of MPV in control group (Group II) was 8.05 ± 1.07 fl, for patients in Group IA was 8.01 ± 1.31 fl and for Group IB was 8.25 ± 1.28 fl, respectively. The correlation was statistically not significant (P = 0.493) as shown in [Table 3].
|Table 3: Correlation of mean platelet volume between Groups IA, IB and II|
Click here to view
Normal MPV seems to appear more frequent in heterozygote and compound heterozygote, while low MPV values were relatively more frequent among the complex heterozygote and homozygote, and the correlation was statistically significant (P = 0.003), these MPV values were taken during attack period (Group AI) as shown in [Table 4].
The gene (M680I) was associated with abnormal MPV in all types of mutations (whether heterozygote, homozygote, compound heterozygote or complex heterozygote) followed by E148Q relatively, these findings during attack period (Group IA) as shown in [Table 5].
| Discussion|| |
FMF is a chronic auto-inflammatory disease, and like other inflammatory disorders, the patients are prone to some complications. Hence, it is important to identify the accurate markers of inflammation or additional markers that can detect disease activity and the predisposed individual to complications and/or other associated diseases before their appearance.
MPV is reported as an inflammatory marker of disease activity in many connective tissue diseases such as juvenile idiopathic rheumatoid arthritis and ankylosing spondylitis., On the other hand, an increase in MPV is considered a predictor of atherothrombotic events. This study took these findings in consideration to identify the significance of MPV in FMF during the attacks and in attack-free period in comparison with healthy controls group and if there was a significance association of MPV values with genotypes of FMF.
All patients in this study were Muslims and from Kurdish nationality, and they were tested gen positive. Their male to female ratio was 1.8:1 with an age range of 23 months to 16 years (mean = 8.02 ± 3.91 year). These age and gender characteristics were similar to those of Fayadh et al., Tunca et al., and Montazeri et al.,,, to the best of my knowledge, there were few previous studies describing FMF in Kurdish nationality.
In the current study, there were high WBC counts during the attacks and mostly of neutrophil type (71.8% of total WBC) and correlation with WBC counts in the attack-free periods was statistically significant (P = 0.013). Uslu et al., Colak et al., Heydari et al. and Kucuk et al. reported increased WBC counts during the attacks. Moreover, they have considered the neutrophil/lymphocytes ration a useful marker even in the attack-free period.,,, On the other hand, Aslan reported leukopenia in 15 patients with FMF. The leukocytosis observed in this study particularly the neutrophilia could be related to FMF disease itself or may be related to bacterial infections triggering FMF attacks.
The ESR and CRP were elevated in our patients especially in attack periods with statistically significant correlation with the attack-free periods (P = 0.012 and 0.013 respectively) and can be used as markers of inflammation in FMF. However, serum ferritin had neither significant elevation nor correlation. Most studies about inflammatory markers in FMF reached similar results in regard to CRP and ESR as acute phase reactants (APRs). Serum ferritin, on the other hand, was not part of APRs in the short lived attacks of FMF according to Yorulmaz et al., Basaran et al., Korkmaz et al., Talaat et al. and Stojanovic et al.,,,,
In the current study, the MPV during the attacks was not statistically different from that in the attack-free periods (P = 0.667). Likewise, it was not different from that of the healthy controls (P = 0.493). Marzouk et al., Akdeniz et al. and Arica et al. reported the use of the MPV as a useful marker in subclinical inflammation together with splenomegaly. Furthermore, they suggested that an increase in the MPV can be an indicator of future atherosclerotic diseases.,, Only one patient in this series had splenomegaly but the MPV was normal. This was not enough for statistical correlation.
According to Üstün et al., Karakurt Ö et al., Uluca et al. and Makay et al., regular and early colchicine therapy in children with FMF may mask the significance of MPV as inflammatory marker and as predictor of atherosclerotic disease.,,, All patients in this series received colchicine therapy soon after diagnosis. Most of them took colchicine regularly and had an excellent response. On the other hand, Sahin et al. observed that MPV deceases in attack and attack-free period in comparison with healthy controls and they attributed the lowered MPV level to secondary thrombocytosis in FMF patients. No patient during the time of this study developed amyloidosis.
It is worthy to mention that FMF may be associated with different diseases that are characterized by low MPV such as vasculitis, juvenile rheumatoid arthritis, inflammatory bowel disease, sacroiliitis, rheumatic fever, systemic lupus erythematous, and Behcet disease. Jae Kim et al. suggested the use of increasing in MPV as a marker of improvement in vasculitis, because during active stage the patients have low MPV. Patients with FMF and low MPV in this study deserve further investigations to rule out possible association with the aforementioned diseases.
In this study, patients whose MPV was low (n = 8) were double the patients with large MPV (n = 4). This may be associated with a low risk of future atherothrombotic events.,,, Although a good follow-up is needed. The small percentage of patients with low MPV could be due to colchicine therapy which was started immediately after diagnosis.
When low MPV was correlated with genotypes, there was a significant statistical association (P = 0.003) with homozygote and complex heterozygote unlike other genotypes (the heterozygote and compound heterozygote). It was quite clear that some genes were associated with abnormal MPV (whether small or large) like M680I gene which was associated with low MPV in homozygote, compound heterozygote and complex heterozygote but not in simple heterozygote, while it was associated with large MPV in simple heterozygote (1 patient) and compound heterozygote. Another gene had the same presentation but with less extent was E148Q gene.
Rabinovich et al. reported on 98 patients with rheumatoid arthritis, twelve of them were severe cases and had E148Q mutation while few patients had M694V and V726A mutations. Ben-Chetrit et al. concluded that genes of FMF could be associated with other autoimmune disease (s), whose correct early diagnosis is crucial for better outcome. Ekinci et al. stated that concomitant diseases particularly juvenile rheumatoid arthritis influence FMF severity, therefore, it may be beneficial to focus on diagnosis and treatment of such diseases, which, if missed, may worsen the course of FMF. A case report by Yurdakul et al. and a research paper by Tutar et al. showed that some specific FMF mutations had a significant association with rheumatic heart disease particularly M680I mutation., In the current study, the most frequent mutation associated with low MPV was M680I mutation, but no patient had clinical evidence of rheumatic heart disease or an autoimmune condition.
| Conclusion|| |
The current study showed that MPV was not statistically different between FMF patients and controls and, therefore; MPV could be of little value in FMF if compared with APRs such as the ESR and CRP. On the other hand, abnormal MPV could be associated with specific genotypes that may indicate an associated problem(s) and required further investigations.
The Ethics Committee of Sulaimani University/School of Medicine approved the study.
I would like to thank Prof. Dr. Abdulsalam Y Taha MBChB, FICMS (Cardiothoracic and Vascular Surgeon), University of Sulaimani College of Medicine, Sulaymaniyah, Region of Kurdistan, Iraq ([email protected]) for providing language help, writing assistance and proof reading the article, also great thanks to Dr. Salim Rahma Shanon MBChB, CABP; Consultant Pediatrician and former Professor, College of Medicine, AlNahrain University, Baghdad, Iraq ([email protected]) for his advises and guidance in writing the paper.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tekin M, Toplu Y, Kahramaner Z, Erdemir A, Gulyuz A, Konca C, et al
. The mean platelet volume levels in children with PFAPA syndrome. Int J Pediatr Otorhinolaryngol 2014;78:850-53.
Lokeshwar M, Changlani D, Vijayaraghavan A. Immune thrombocytopenic purpura-diagnosis and management. In: Lokeshwar M, Shah N, Agarwa B, Manglani M, Sachdeva A, Pillai A, editors. Textbook of Pediatric Hematology and Oncology. 1st
ed.., Vol. 1. Daryaganj: Jaypee Brothers Medical Publishers; 2016. p. 317-30.
Safak S, Uslu AU, Serdal K, Turker T, Soner S, Lutfi A. Association between mean platelet volume levels and inflammation in SLE patients presented with arthritis. Afr Health Sci 2014;14:919-24.
Kisacik B, Tufan A, Kalyoncu U, Karadag O, Akdogan A, Ozturk M, et al
. Mean platelet volume (MPV) as an inflammatory marker in ankylosing spondylitis and rheumatoid arthritis. Revue du rhumatisme. Joint Bone Spine 2008;75:291-4.
Yüksel O, Helvaci K, Başar O, Köklü S, Caner S, Helvaci N, et al
. An overlooked indicator of disease activity in ulcerative colitis: Mean platelet volume. Platelets 2009;20:277-81.
Choi D, Kang S, Song H. Mean platelet volume: A potential biomarker of the risk and prognosis of heart disease. Korean J Intern Med 2016;31:1009-17.
Zadeh N, Getzug T, Grody WW. Diagnosis and management of familial Mediterranean fever: Integrating medical genetics in a dedicated interdisciplinary clinic. Genet Med 2011;13:263-9.
Amanda K, Daniel L. Hereditary periodic fever syndrome and other systemic autoinflammatory diseases. In: Robert M. Klingemann, Bonita F, Joseph W, Nina F, editors. Nelson Textbook of Pediatrics. 20th
ed., Vol. 1. Philadelphia: Elsevier; 2016. p. 1193-204.
Sara bay G, Touitou I. Genetics of familial Mediterranean fever. In: Gatton M, editor. Familial Mediterranean Fever. 1st
ed., Vol. 1. Switzerland: Springer; 2015. p. 1-9.
Sarı İ, Birlik M, Kasifoğlu T. Familial Mediterranean fever: An updated review. Eur J Rheumatol 2014;1:21-33.
Güneş A, Ece A, Şen V, Uluca Ü, Aktar F, Tan I, et al
. Correlation of mean platelet volume, neutrophil-to-lymphocyte ratio, and disease activity in children with juvenile ıdiopathic arthritis. Int J Clin Exp Med 2015;8:11337-41.
Khodashahi M, Nayyereh S, Rezaieyazdi Z, Sahebari M, Saremi Z. Evaluation of mean platelets volume in patients with rheumatoid arthritis and its relation with the severity of disease. Rheumatol Res J 2019;4:121-26.
Chu S, Becker R, Berger B, Bahatt L, Eikelboom J, Konkle B, et al
. Mean platelet volume as a predictor of cardiovascular risk: A systematic review and meta-analysis. J Thromb Haemost 2010;8:148-56.
Fayadh M, Abdul Nabi S, Muhsen J, Askir B, Al-Akashi R. Familial Mediterranean fever (FMF) a study of thirty Iraqi patients. IJGE 2005;1:44-8.
Tunca M, Akar S, Onen F. Familial Mediterranean fever (FMF) in Turkey: Results of a nationwide multicenter study. Medicine (Baltimore) 2005;84:1-11.
Montazeri A, Pahlavanazdeh H. Familial Mediterranean fever: A study of 32 cases. Med J Islamic Repub Iran 1991;5:97-100.
Saulaiman D, Mohammad J, Sulaiman S, Eissa A. The spectrum of MEFV gene mutations among Kurdish patients suspected to have familial Mediterranean fever from Duhok/Iraq. J Univ Duhok 2016;19:78-82.
Uslu A, Deveci K, Korkmaz S, Aydin B, Senel S, Sancakdar E, et al
. Is neutrophil/lymphocyte ratio associated with subclinical inflammation and amyloidosis in patients with familial Mediterranean fever? Biomed Res Int 2013;2013:185317.
Colak B, Gurlek B, Yegin ZA, Deger SM, Elbek S, Pasaoglu H, et al.
The relationship between the MEFV genotype, clinical features, and cytokine-inflammatory activities in patients with familial Mediterranean fever. Ren Fail 2008;30:187-91.
Heydari S, Namdar H, Behzadnia M. Familial Mediterranean fever (FMF): Mysterious presentations and challenging points from diagnosis to management in acute care settings; A literature review. Int J Travel Med Glob Health 2019;7:118-22.
Kucuk A, Erol M, Senel S, Eroler E, Yumun H, Uslu A, et al
. The role of neutrophil lymphocyte ratio to leverage the differential diagnosis of familial Mediterranean fever attack and acute appendicitis. Korean J Intern Med 2016;31:386-91.
Aslan D. Leukopenia in familial Mediterranean fever: Case series and literature review with special emphasis on pathogenesis. Pediatr Hematol Oncol. 2014;31:120-8. doi: 10.3109/088 80018.2013. 782082).
Yorulmaz A, Akbulut H, Adeviye S, Tıraş M, Yahya I, Peru H. Evaluation of hematological parameters in children with FMF. Clin Rheumatol 2018;18:433-39.
Basaran O, Uncu N, Celikel BA, Aydın F, Cakar N. Assessment of neutrophil to lymphocyte ratio and mean platelet volume in pediatric familial Mediterranean fever patients. J Res Med Sci 2017;22:35.
] [Full text]
Korkmaz C, Ozdogan H, Kasapçopur O, Yazici H. Acute phase response in familial Mediterranean fever. Ann Rheum Dis 2002;61:79-81.
Talaat H, Sheba M, Mohammed R, Ibrahim M. Markers for subclinical inflammation in Egyptian children with familial Mediterranean fever: Splenomegaly and mean platelet volume. Rheumatol Currt Res 2020;10:1-8.
Stankovic Stojanovic K, Hentgen V, Fellahi S, Georgin-Lavialle S, Amselem S, Grateau G, et al
. Concordance between CRP and SAA in familial Mediterranean fever during attack-free period: A study of 218 patients. Clin Biochem 2017;50:206-9.
Marzouk H, Lotfy H, Farag Y, Rashed L, El-Garf K. Mean platelet volume and splenomegaly as useful markers of subclinical activity in Egyptian children with familial Mediterranean fever: A cross-sectional study. Int J Chron Dis 2015;2015:152616.
Akdeniz A, Olgularda A, Trombosit O, Artış H, Riski A, Bir A, et al
. Increased mean platelet volume in patients with familial Mediterranean fever may not be a marker of atherosclerosis risk. Anadolu Kardiyol Derg 2013;13:606-20.
Arıca S, Ozer C, Arıca V, Karakuş A, Celik T, Güneşaçar R. Evaluation of the mean platelet volume in children with familial Mediterranean fever. Rheumatol Int 2012;32:3559-63.
Üstün N, Ulaşlı A, Çelik T, Yula E, Turhanoğlu D. Mean platelet volume in children with familial Mediterranean fever and the relationship with attack status, colchicine treatment and gene mutation. Eur J Gen Med 2014;11:169-73.
Karakurt Arıtürk Ö, Üreten K, Sarı M, Yazıhan N, Ermiş E, Ergüder İ. Relationship of paraoxonase-1, malondialdehyde and mean platelet volume with markers of atherosclerosis in familial Mediterranean fever: An observational study. Anadolu Kardiyol Derg 2013;13:357-62.
Uluca Ü, Ece A, Şen V, Karabel D, Yel S, Güneş A, et al
. Usefulness of mean platelet volume and neutrophil-to-lymphocyte ratio for evaluation of children with Familial Mediterranean fever. Med Sci Monit 2014;20:1578-82.
Makay B, Türkyilmaz Z, Unsal E. Mean platelet volume in children with familial Mediterranean fever. Clin Rheumatol 2009;28:975-8.
Sahin S, Senel S, Ataseven H, Yalcin I. Does mean platelet volume influence the attack or attack-free period in the patients with familial Mediterranean fever? Platelets 2013;24:320-3.
Özçakar ZB, Çakar N, Uncu N, Çelikel BA, Yalçinkaya F. Familial Mediterranean fever-associated diseases in children. QJM 2017;110:287-90.
Kim HJ, Jung SM, Song JJ, Park YB, Lee SW. Mean platelet volume can estimate the current vasculitis activity of microscopic polyangiitis. Rheumatol Int 2018;38:1095-101.
Rabinovich E, Livneh A, Langevitz P, Brezniak N, Shinar E, Pras M, et al
. Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene. Ann Rheum Dis 2005;64:1009-14.
Ben-Chetrit E, Peleg H, Aamar S, Heyman SN. The spectrum of MEFV clinical presentations--is it familial Mediterranean fever only? Rheumatology (Oxford) 2009;48:1455-9.
Kişla Ekinci RM, Balci S, Ufuk Altintaş D, Yilmaz M. The influence of concomitant disorders on disease severity of familial Mediterranean fever in children. Arch Rheumatol 2018;33:282-7.
Yurdakul F, Caliskan A, Bodur U, Bodur H. Rheumatic heart disease and M680I mutation in two atypical FMF patients: More than an incidental coexistence? Surg Case Rep Rev 2018;2:1-3.
Tutar E, Akar N, Atalay S, Yilmaz E, Akar E, Yalçinkaya F. Familial Mediterranean fever gene (MEFV) mutations in patients with rheumatic heart disease. Heart 2002;87:568-9.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]