Mehmet BÜLBÜL, Semanur ÖZDEL, Esra BAĞLAN

PFAPA Sendromunda Mefv Gen Mutasyonlarının Hastalık Üzerine Etkisi

Amaç: Kalıtsal olmayan otoinflamatuvar hastalıklardan biri olarak sınıflandırılan PFAPA (Periodic fever, apthous stomatitis,pharyngitis and cervical adenitis) sendromu; periyodik ateş, farenjit, servikal lenfadenit ve stomatit ile seyretmektedir.Altta yatan hematolojik bozukluk ve/veya üst solunum yolu enfeksiyonlarının olmaması, PFAPA sendromu tanısınındoğrulanması için zorunludur. Hastalığa tanı koydurucu özgül bir laboratuvar belirteci bulunmamaktadır. Ülkemiz 1/5taşıyıcılık oranı ile dünya üzerinde ailesel Akdeniz ateşi taşıyıcılığının en fazla olduğu toplumlardan birisidir. Bu yüksektaşıyıcılığın romatoid artrit, ankilozan spondilit, PFAPA sendromu gibi çeşitli romatizmal hastalıkların şiddetini arttırdığıiyi bilinmektedir. Bu çalışmada ailesel Akdeniz ateşi taşıyıcılığının PFAPA sendromlu çocuklarda klinik ve laboratuvarbulguları, hastalık seyri ve şiddeti üzerindeki etkisini araştırmak amaçlanmıştır.Gereç ve Yöntemler: Çalışmaya PFAPA sendromu tanısı konulmuş ve MEFV gen analizi gönderilmiş 70 hasta dahiledilmiştir. Hastaların demografik verileri, klinik bulguları, atak sayısı ve şiddeti, atakta laboratuvar değerleri (lökosit sayısı,eritrosit sedimentasyon hızı, C reaktif protein), MEFV gen analiz sonuçları önceden hazırlanmış formlara kaydedilmiştir.MEFV gen mutasyonu pozitif olan 33 hasta ile MEFV gen mutasyonu negatif olan 37 hasta demografik veriler, kliniközellikler ve hastalık seyri açısından karşılaştırılmıştır.Bulgular: MEFV gen mutasyonu taşıyan PFAPA’lı hastalarda atak süresi ve sıklığı mutasyon taşımayan hastalara göredaha fazlaydı (p

The Effect of Mefv Gene Mutatıons in Patients With PFAPA Syndrome

Objective: The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a condition characterized by recurrent episodes of fever accompanied by aphthous stomatitis, cervical adenitis, and pharyngitis. The absence of underlying hematological disorder and/or upper respiratory tract infections is mandatory for confirmation of PFAPA syndrome diagnosis. There is no specific laboratory test confirming a diagnosis of PFAPA syndrome. Our country is one of the communities with the highest number of familial Mediterranean fever carriers worldwide, with a rate of 1/5. It is well known that this high carriage increases the severity of various rheumatic diseases such as rheumatoid arthritis, ankylosing spondylitis, PFAPA syndrome. In this study, it was aimed to investigate the effect of familial Mediterranean fever carriage on clinical and laboratory findings, disease course and severity in children with PFAPA syndrome. Material and Methods: The cohort consisted of 70 children with PFAPA syndrome who were tested for MEFV gene mutations. Demographic data, clinical findings, attack frequency and duration, laboratory values (leukocyte count, erythrocyte sedimentation rate, C reactive protein), MEFV gene analysis results were recorded to pre-prepared forms. Demographic variables, clinical characteristics, and disease course of 33 PFAPA patients with and 37 without MEFV gene mutations were compared. Results: The duration and frequency of attacks were more frequently in patients with PFAPA carrying the MEFV gene mutation compared to the patients without mutation (p

PDF

___

1. Marshall GS, Edwards KM, Lawton AR. PFAPA syndrome. Pediatr Infect Dis J 1989; 8:658-9.
2. Theodoropoulou K, Vanoni F, Hofer M. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome: a Review of the Pathogenesis. Curr Rheumatol Rep 2016;18:18.
3. Adrovic A, Sahin S, Barut K, Kasapcopur O. Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. Rheumatol Int 2019; 39:29–36.
4. Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, Migdal A, Pras M, Passwell JH. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr 1999; 135:98–101.
5. Hofer M, Pillet P, Cochard MM, Berg S, Krol P, Kone-Paut I, Rigante D, et al. International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients. Rheumatology (Oxford) 2014; 53:1125–9.
6. Pehlivan E, Adrovic A, Sahin S, Barut K, Kul Cinar O, Kasapcopur O. PFAPA syndrome in a population with endemic familial Mediterranean fever. J Pediatr 2018; 192:253–5.
7. Barut K, Sahin S, Adrovic A, Sinoplu AB, Yucel G, Pamuk G, et al. Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int 2018; 38:67–74.
8. Özen S, Batu ED, Demir S. Familial Mediterranean fever: recent developments in pathogenesis and new recommendations for management. Front Immunol 2017; 8:253.
9. Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, et al. Familial Mediterranean fever (FMF) in Turkey: Results of a nationwide multicenter study. Medicine (Baltimore) 2005; 84: 1-11.
10. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17: 25-31.
11. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1997; 90: 797-807.
12. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL, et al. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood 2008; 112:1794-803.
13. Berkun Y, Ben-Chetrit E. Pyrin and cryopyrin—similar domain sequence but opposite inflammatory consequence. Clin Exp Rheumatol 2007;25(4 Suppl 45): S6-8.
14. 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.
15. Fidder H, Chowers Y, Ackerman Z, Pollak RD, Crusius JB, Livneh A, et al. The familial Mediterranean fever (MEVF) gene as a modifier of Crohn’s disease. Am J Gastroenterol 2005;100: 338-43.
16. Shinar Y, Livneh A, Villa Y, Pinhasov A, Zeitoun I, Kogan A, et al. Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients. Genes Immun 2003; 4:197-203.
17. Yaşar Bilge Ş, Sarı İ, Solmaz D, Şenel S, Emmungil H, Kılıç L, et al. The distribution of MEFV mutations in Turkish FMF patients: multicenter study representing results of Anatolia. Turk J Med Sci 2019; 49:472-7.
18. Thomas KT, Feder HM Jr, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr 1999; 135:15–21.
19. Harel L, Hashkes PJ, Lapidus S, Edwards KM, Padeh S, Gattorno M, et al. The first international conference on periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome. J Pediatr 2018; 193:265–74.
20. Berkun Y, Levy R, Hurwitz A, Meir-Harel M, Lidar M, Livneh A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arhritis Rheum 2011; 40:467-2.
21. Adachi M, Watanabe A, Nishiyama A, Oyazato Y, Kamioka I, Murase M, et al. Familial cases of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr 2011; 158:155-9.
22. Akelma AZ, Cizmeci MN, Kanburoglu MK, Mete E, Bozkaya D, Tufan N, et al. Is PFAPA syndrome really a sporadic disorder or is it genetic? Med Hypotheses 2013; 81:279-81.
23. Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R. MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int 2010: 30: 633–6.
24. Taniuchi S, Nishikomori R, Iharada A, Tuji S, Heike T, Kaneko K. MEFV Variants in Patients with PFAPA Syndrome in Japan. Open Rheumatol J 2013: 7: 22–5.
25. Gunes M, Cekic S, Kılıc SS. Is colchicine more effective to prevent periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis episodes in Mediterranean fever gene variants? Pediatr Int 2017; 59:655-60.
26. Celiksoy MH, Ogur G, Yaman E, Abur U, Fazla S, Sancak R, et al. Could familial Mediterranean fever gene mutations be related to PFAPA syndrome? Pediatr Allergy Immunol 2016; 27:78-82.
27. Batu ED, Kara Eroğlu F, Tsoukas P, Hausmann JS, Bilginer Y, Kenna MA, et al. Periodic Fever, Aphthosis, Pharyngitis, and Adenitis Syndrome: Analysis of patients from two geographis ares. Arthritis Care Res (Hoboken) 2016; 68:1859-65.
28. Tasher D, Stein M, Dalal I, Somekh E. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr 2008; 97:1090-2.
29. Thomas KT, Feder HM Jr, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr 1999; 135: 15-21
30. Peridis S, Pilgrim G, Koudoumnakis E, Athanasopoulos I, Houlakis M, Parpounas K. PFAPA syndrome in children: a meta-analysis on surgical versus medical treatment. Int J Pediatr Otorhinolaryngol 2020; 74: 1203–8.
31. Manthiram K, Li SC, Hausmann JS, Amarilyo G, Barron K, Kim H, et al. Physicians’ perspectives on the diagnosis and management of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Rheumatol Int 2017; 37: 883-9.
32. Dusser P, Hentgen V, Neven B, Kone-Paut I. Is colchicine an effective treatment in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome? Jt Bone Spine 2016; 83: 406- 11.
33. Butbul Aviel Y, Tatour S, Gershoni Baruch R, Brik R. Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Semin Arthritis Rheum 2016; 45:471-4.
34. Taskiran EZ, Cetinkaya A, Balci-Peynircioglu B, Akkaya YZ, Yilmaz E. The effect of colchicine on pyrin and pyrin interacting proteins. J Cell Biochem 2012; 113: 3536–46.
35. Balci-Peynircioglu B, Akkaya-Ulum YZ, Avci E, Batu ED, Purali N, Ozen S, Yilmaz E. Potential role of pyrin, the protein mutated in familial Mediterranean fever, during inflammatory cell migration. Clin Exp Rheumatol 2018; 36 Suppl 115:116-24.
36. Batu ED. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: main features and an algorithm for clinical practice. Rheumatol Int 2019; 39: 957-70