Abstract
Amaç: Ailevi Akdeniz Ateşi (AAA) (OMIM #249100), genetik mutasyonlardan etkilenebilen ve farklı klinik şiddetle seyreden bir hastalıktır. Bu çalışmada pediatrik AAA hastalarında genotip ile klinik ve hastalık şiddeti arasındaki ilişkiyi değerlendirmektir.
Gereç ve Yöntem: Bu çalışma, 1 Ocak 2016-1 Haziran 2017 tarihleri arasında AAA tanısı ile izlenen 0-18 yaş arası hastaları kapsamaktadır. Retrospektif kesitsel olarak planlanmıştır. Demografik veriler, klinik bulgular, Pras hastalık şiddet puanları ve MEFV gen mutasyonları incelenmiştir. Hastalar genetik analiz sonuçlarına göre dört gruba ayrılmıştır: homozigot, heterozigot, bileşik heterozigot mutasyon saptananlar ve mutasyon tespit edilemeyenler. Klinik özellikler ve hastalık şiddeti gruplar arasında karşılaştırılmıştır.
Bulgular: Toplam 126 AAA hastası çalışmaya dahil edilmiş olup, % 49,2’si kızdı. Medyan semptom başlangıç yaşı 60 (12-168) ay, medyan tanı yaşı 76 (23-180) ay ve tanıda gecikme süresi 12 (0-120) ay olarak bulunmuştur. En sık saptanan semptomlar arasında karın ağrısı (% 98), ateş (% 87,3), artralji (% 60,3) ve miyalji (% 60,3) yer almaktadır. Hastaların medyan Pras şiddet skoru 6 (4-11) olup, % 40,5’i hafif, % 43,7’si orta, % 15,8’i ise şiddetli olarak sınıflandırılmıştır. Genetik analizde hastaların %50’sinde bileşik heterozigot, % 30,2’sinde homozigot, %13,5’inde heterozigot mutasyon saptanmıştır ve % 6,3’ünde ise mutasyon tespit edilmemiştir. Mutasyon grupları arasında klinik özellikler veya hastalık şiddeti açısından anlamlı bir fark bulunmamıştır.
Sonuç: Pediatrik AAA, klinik olarak heterojen bir seyir göstermektedir ve genotip hastalık şiddetini tek başına öngöremez. Tanı ve tedavi için kapsamlı bir klinik yaklaşımın önemi vurgulanmaktadır.
Ethical Statement
İnsan katılımcıların yer aldığı tüm işlemler, Helsinki Bildirgesi ve sonraki değişiklikleriyle belirlenen etik standartlara uygun olarak gerçekleştirilmiştir. Etik onay, 13.07.2017 tarihli ve 2017/124 protokol numaralı kararla Mustafa Kemal Üniversitesi Tayfur Ata Sökmen Tıp Fakültesi (Hatay, Türkiye) Klinik Araştırmalar Etik Kurulu tarafından verilmiştir.
Supporting Institution
Hatay Mustafa Kemal Üniversitesi
References
- Chaaban A, Salman Z, Karam L, Kobeissy PH, Ibrahim JN. Updates on the role of epigenetics in familial mediterranean fever (FMF). Orphanet J Rare Dis. 2024;19:90.
- Group TFS. Familial mediterranean fever in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84:1-11.
- Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R et al. An update on familial mediterranean fever. Int J Mol Sci. 2023;24:9584.
- Tufan A, Lachmann HJ. Familial mediterranean fever from pathogenesis to treatment: a contemporary review. Turk J Med Sci. 2020;50:1591-610.
- Ozdogan H, Ugurlu S. Familial mediterranean fever. Presse Med. 2019;48:e61-76.
- Yalcinkaya F, Ozen S, Ozçakar ZB, Aktay N, Cakar N, Düzova A et al. A new set of criteria for the diagnosis of familial mediterranean fever in childhood. Rheumatology (Oxford). 2009;48:395-8.
- Batu ED, Basaran O, Bilginer Y, Ozen S. Familial mediterranean fever: how to interpret genetic results? how to treat? a quarter of a century after the association with the MEFV gene. Curr Rheumatol Rep. 2022;24:206-12.
- Infevers. Tabular list [Internet]. https://infevers.umai-montpellier.fr/web/search.php?n=1. Accessed October 28, 2024.
- Demirkaya E, Saglam C, Turker T, Koné-Paut I, Woo P, Doglio M et al. Performance of different diagnostic criteria for familial mediterranean fever in children with periodic fevers: results from a multicenter international registry. J Rheumatol. 2016;43:154-60.
- Bilge SY, Sarı I, 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.
- Ozen S. Update in familial mediterranean fever. Curr Opin Rheumatol. 2021;33:398-402.
- Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R et al. An update on familial mediterranean fever. Int J Mol Sci. 2023;24:9584.
- El Hasbani G, Jawad A, Uthman I. Update on the management of colchicine resistant familial mediterranean fever. Orphanet J Rare Dis. 2019;14:224.
- Pras E, Livneh A, Balow JE Jr, Pras E, Kastner DL, Pras M et al. Clinical differences between North African and Iraqi Jews with familial mediterranean fever. Am J Med Genet. 1998;75:216-9.
- Yalcinkaya F, Cakar N, Misirlioglu M, Tumer N, Akar N, Tekin M et al. Genotype-phenotype correlation in a large group of Turkish patients with familial mediterranean fever: evidence for mutation-independent amyloidosis. Rheumatology (Oxford). 2000;39:67-72.
- Dusunsel R, Dursun I, Gunduz Z, Poyrazoglu MH, Gurgöze MK, Dundar M. Genotype-phenotype correlation in children with familial mediterranean fever in a Turkish population. Pediatr Int. 2008;50:208-12.
- Özdemir FMA, Gülez N, Makay B. Evaluation of the international severity score for FMF (ISSF) scores in Turkish children diagnosed with FMF: a single-center experience. Clin Rheumatol. 2021;40:3219-25.
- İnandı T, Savaş N, Arslan E, Yeniçeri A, Erdem M, Durmaz E et al. Hatay’da akraba evliliği sıklığı, nedenleri, çocuk sağlığı, ilişkilerde mutluluk ve yaşam doyumu. Turk J Public Health. 2016;14:43-55.
- El Beshlawy A, Zekri AER, Ramadan MS, Selim YM, Abdel-Salam A, Hegazy MT et al. Genotype-phenotype associations in familial mediterranean fever: a study of 500 Egyptian pediatric patients. Clin Rheumatol. 2022;41:1511-21.
- Özlü SG, Ergüven M, Hamzah ÖY. Genotype and phenotype correlations in children with familial mediterranean fever. Turk J Pediatr Dis. 2015;3:171-5.
- Coşkun S, Kurtgöz S, Keskin E, Sönmez F, Bozkurt G. Frequency of mutations in Mediterranean fever gene, with gender and genotype-phenotype correlations in a Turkish population. J Genet. 2015;94:629-35.
- Ergüven M, Üçel R, Cebeci AN, Pelit M. Ailevî Akdeniz ateşinin demografik, klinik ve genetik özellikleri ile tedaviye yanıtı: 120 vakalık tek merkez deneyimi. Cocuk Sagligi ve Hastaliklari Dergisi. 2006;49:283-90.
- Wekell P, Wester T. Familial mediterranean fever may mimic acute appendicitis in children. Pediatr Surg Int. 2022;38:1099-104.
- Inal A, Yilmaz M, Guneser Kendirli S, Altintas DU, Bingol Karakoc G. The clinical and genetical features of 124 children with familial mediterranean fever: experience of a single tertiary center. Rheumatol Int. 2009;29:1279-85.
- Koné Paut I, Dubuc M, Sportouch J, Minodier P, Garnier JM, Touitou I. Phenotype-genotype correlation in 91 patients with familial mediterranean fever reveals a high frequency of cutaneomucous features. Rheumatology (Oxford). 2000;39:1275-9.
- Kaşifoğlu T, Cansu DU, Korkmaz C. Frequency of abdominal surgery in patients with familial mediterranean fever. Intern Med. 2009;48:523-6.
- Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A et al. Clinical disease among patients heterozygous for familial mediterranean fever. Arthritis Rheum. 2009;60:1862-6.
- Niemi K, Teirilä L, Lappalainen J, Rajamäki K, Baumann MH, Öörni K et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol. 2011;186:6119-28.
- Procopio V, Manti S, Bianco G, Conti G, Romeo A, Maimone F et al. Genotype-phenotype correlation in FMF patients: a "non classic" recessive autosomal or "atypical" dominant autosomal inheritance? Gene. 2018;641:279-86.
- Grossman C, Kassel Y, Livneh A, Ben-Zvi I. Familial mediterranean fever phenotype in patients homozygous to the MEFV M694V mutation. Eur J Med Genet. 2019;62:103532.
- Giancane G, Ter Haar NM, Wulffraat N, Vastert SJ, Barron K, Hentgen V et al. Evidence-based recommendations for genetic diagnosis of familial mediterranean fever. Ann Rheum Dis. 2015;74:635-41
Relationship between genetic and clinical findings in pediatric patients with Familial Mediterranean Fever
Abstract
Purpose: Familial Mediterranean Fever (FMF) (OMIM #249100) exhibits varying clinical severity, influenced by genetic mutations. This study aimed to assess the relationship between FMF genotypes and disease severity in pediatric patients.
Materials and Methods: This retrospective cross-sectional study included FMF patients aged 0-18 years who were followed up between January 1, 2016, and June 1, 2017. Demographic data, clinical findings, Pras disease severity scores (Pras score), and MEFV gene mutations were analyzed. Patients were classified into four genetic groups: homozygous, heterozygous, compound heterozygous, and those without detected mutations. Clinical characteristics and disease severity were compared.
Results: Among 126 FMF patients (49.2% female), the median age at symptom onset was 60 (12–168) months, and the median age at diagnosis was 76 (23–180) months, resulting in a median diagnostic delay of 12 (0–120) months. Common symptoms included abdominal pain (98%), fever (87.3%), arthralgia (60.3%), and myalgia (60.3%). The median Pras score was 6 (range: 4–11), with 40.5% classified as mild, 43.7% as moderate, and 15.8% as severe. Genetic analysis revealed that 50% of the individuals had compound heterozygous mutations, 30.2% had homozygous mutations, 13.5% had heterozygous mutations, and 6.3% had no mutations. No significant differences were found among mutation groups regarding clinical characteristics or disease severity.
Conclusion: Pediatric FMF exhibits clinical heterogeneity, and genotype alone may not be an effective predictor of severity. A comprehensive clinical approach remains essential for diagnosis and management.
Ethical Statement
All procedures involving human participants were conducted in accordance with the ethical standards set forth by the Declaration of Helsinki and its subsequent amendments. Ethical approval was granted by the Clinical Research Ethics Committee of Mustafa Kemal University, Tayfur Ata Sökmen Faculty of Medicine (Hatay, Turkey), with approval dated 13.07.2017 and protocol number 2017/124.
Supporting Institution
Hatay Mustafa Kemal University
References
- Chaaban A, Salman Z, Karam L, Kobeissy PH, Ibrahim JN. Updates on the role of epigenetics in familial mediterranean fever (FMF). Orphanet J Rare Dis. 2024;19:90.
- Group TFS. Familial mediterranean fever in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84:1-11.
- Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R et al. An update on familial mediterranean fever. Int J Mol Sci. 2023;24:9584.
- Tufan A, Lachmann HJ. Familial mediterranean fever from pathogenesis to treatment: a contemporary review. Turk J Med Sci. 2020;50:1591-610.
- Ozdogan H, Ugurlu S. Familial mediterranean fever. Presse Med. 2019;48:e61-76.
- Yalcinkaya F, Ozen S, Ozçakar ZB, Aktay N, Cakar N, Düzova A et al. A new set of criteria for the diagnosis of familial mediterranean fever in childhood. Rheumatology (Oxford). 2009;48:395-8.
- Batu ED, Basaran O, Bilginer Y, Ozen S. Familial mediterranean fever: how to interpret genetic results? how to treat? a quarter of a century after the association with the MEFV gene. Curr Rheumatol Rep. 2022;24:206-12.
- Infevers. Tabular list [Internet]. https://infevers.umai-montpellier.fr/web/search.php?n=1. Accessed October 28, 2024.
- Demirkaya E, Saglam C, Turker T, Koné-Paut I, Woo P, Doglio M et al. Performance of different diagnostic criteria for familial mediterranean fever in children with periodic fevers: results from a multicenter international registry. J Rheumatol. 2016;43:154-60.
- Bilge SY, Sarı I, 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.
- Ozen S. Update in familial mediterranean fever. Curr Opin Rheumatol. 2021;33:398-402.
- Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R et al. An update on familial mediterranean fever. Int J Mol Sci. 2023;24:9584.
- El Hasbani G, Jawad A, Uthman I. Update on the management of colchicine resistant familial mediterranean fever. Orphanet J Rare Dis. 2019;14:224.
- Pras E, Livneh A, Balow JE Jr, Pras E, Kastner DL, Pras M et al. Clinical differences between North African and Iraqi Jews with familial mediterranean fever. Am J Med Genet. 1998;75:216-9.
- Yalcinkaya F, Cakar N, Misirlioglu M, Tumer N, Akar N, Tekin M et al. Genotype-phenotype correlation in a large group of Turkish patients with familial mediterranean fever: evidence for mutation-independent amyloidosis. Rheumatology (Oxford). 2000;39:67-72.
- Dusunsel R, Dursun I, Gunduz Z, Poyrazoglu MH, Gurgöze MK, Dundar M. Genotype-phenotype correlation in children with familial mediterranean fever in a Turkish population. Pediatr Int. 2008;50:208-12.
- Özdemir FMA, Gülez N, Makay B. Evaluation of the international severity score for FMF (ISSF) scores in Turkish children diagnosed with FMF: a single-center experience. Clin Rheumatol. 2021;40:3219-25.
- İnandı T, Savaş N, Arslan E, Yeniçeri A, Erdem M, Durmaz E et al. Hatay’da akraba evliliği sıklığı, nedenleri, çocuk sağlığı, ilişkilerde mutluluk ve yaşam doyumu. Turk J Public Health. 2016;14:43-55.
- El Beshlawy A, Zekri AER, Ramadan MS, Selim YM, Abdel-Salam A, Hegazy MT et al. Genotype-phenotype associations in familial mediterranean fever: a study of 500 Egyptian pediatric patients. Clin Rheumatol. 2022;41:1511-21.
- Özlü SG, Ergüven M, Hamzah ÖY. Genotype and phenotype correlations in children with familial mediterranean fever. Turk J Pediatr Dis. 2015;3:171-5.
- Coşkun S, Kurtgöz S, Keskin E, Sönmez F, Bozkurt G. Frequency of mutations in Mediterranean fever gene, with gender and genotype-phenotype correlations in a Turkish population. J Genet. 2015;94:629-35.
- Ergüven M, Üçel R, Cebeci AN, Pelit M. Ailevî Akdeniz ateşinin demografik, klinik ve genetik özellikleri ile tedaviye yanıtı: 120 vakalık tek merkez deneyimi. Cocuk Sagligi ve Hastaliklari Dergisi. 2006;49:283-90.
- Wekell P, Wester T. Familial mediterranean fever may mimic acute appendicitis in children. Pediatr Surg Int. 2022;38:1099-104.
- Inal A, Yilmaz M, Guneser Kendirli S, Altintas DU, Bingol Karakoc G. The clinical and genetical features of 124 children with familial mediterranean fever: experience of a single tertiary center. Rheumatol Int. 2009;29:1279-85.
- Koné Paut I, Dubuc M, Sportouch J, Minodier P, Garnier JM, Touitou I. Phenotype-genotype correlation in 91 patients with familial mediterranean fever reveals a high frequency of cutaneomucous features. Rheumatology (Oxford). 2000;39:1275-9.
- Kaşifoğlu T, Cansu DU, Korkmaz C. Frequency of abdominal surgery in patients with familial mediterranean fever. Intern Med. 2009;48:523-6.
- Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A et al. Clinical disease among patients heterozygous for familial mediterranean fever. Arthritis Rheum. 2009;60:1862-6.
- Niemi K, Teirilä L, Lappalainen J, Rajamäki K, Baumann MH, Öörni K et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol. 2011;186:6119-28.
- Procopio V, Manti S, Bianco G, Conti G, Romeo A, Maimone F et al. Genotype-phenotype correlation in FMF patients: a "non classic" recessive autosomal or "atypical" dominant autosomal inheritance? Gene. 2018;641:279-86.
- Grossman C, Kassel Y, Livneh A, Ben-Zvi I. Familial mediterranean fever phenotype in patients homozygous to the MEFV M694V mutation. Eur J Med Genet. 2019;62:103532.
- Giancane G, Ter Haar NM, Wulffraat N, Vastert SJ, Barron K, Hentgen V et al. Evidence-based recommendations for genetic diagnosis of familial mediterranean fever. Ann Rheum Dis. 2015;74:635-41
Details
| Primary Language | English |
|---|---|
| Subjects | Pediatric Genetic Illnesses, Pediatric Rheumatology |
| Journal Section | Research |
| Authors | |
| Publication Date | June 30, 2025 |
| Submission Date | March 27, 2025 |
| Acceptance Date | May 23, 2025 |
| Published in Issue | Year 2025 Volume: 50 Issue: 2 |
