Clinical features of children with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: an analysis of 13 cases
HUANG Ji-Qian, YE Xiao-Hua, YANG Kang-Kang, SHANGGUAN Yao-Yao, DONG Yi-Wei, ZHENG Wen-Jie
Department of Pediatric Rheumatology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Abstract：Objective To study the clinical features of children with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, a polygenic and multifactorial autoinflammatory disease with unknown pathogenesis. Methods A retrospective analysis was performed on the medical data of 13 children with PFAPA syndrome. Results All 13 children had disease onset within the age of 3 years, with a mean age of onset of (14±10) months. They all had periodic fever, with 8-18 attacks each year. The mean interictal period of fever was (30±5) days. Pharyngitis, cervical adenitis, and aphthous stomatitis were the three cardinal symptoms, with incidence rates of 100% (13/13), 85% (11/13), and 38% (5/13) respectively. There were increases in white blood cells, C-reactive protein, and erythrocyte sedimentation rate during fever. Of all the 13 children, 6 underwent whole exome sequencing and 7 underwent panel gene detection for autoinflammatory disease, and the results showed single heterozygous mutations in the MEFV gene in 6 children (46%). Recurrent fever in all children gradually returned to normal without antibiotics. Ten children were treated with a single dose of glucocorticoids, and fever was relieved after treatment. Of all the children, 4 were treated with cimetidine, among whom 2 had response; 4 children were treated with colchicine, among whom 2 had response and 2 were withdrawn from the drug due to adverse reactions. Tonsillectomy was performed for 2 children, among whom 1 was followed up for 3 years without recurrence and 1 still had recurrence. Conclusions For children with unexplained periodic fever with early onset accompanied by pharyngitis, cervical adenitis, aphthous stomatitis, elevated inflammatory indices, and good response to glucocorticoids, PFAPA syndrome should be considered. This disorder has good prognosis, and early diagnosis can avoid the long-term repeated use of antibiotics.
HUANG Ji-Qian,YE Xiao-Hua,YANG Kang-Kang et al. Clinical features of children with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: an analysis of 13 cases[J]. CJCP, 2021, 23(2): 143-147.
Rigante D. The broad-ranging panorama of systemic autoinflammatory disorders with specific focus on acute painful symptoms and hematologic manifestations in children[J]. Mediterr J Hematol Infect Dis, 2018, 10(1):e2018067.
[2]
Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases:an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency 2015[J]. J Clin Immunol, 2015, 35(8):696-726.
[3]
Hofer M, Pillet P, Cochard MM, et al. International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort:description of distinct phenotypes in 301 patients[J]. Rheumatology (Oxford), 2014, 53(6):1125-1129.
Thomas KT, Feder HM Jr, Lawton AR, et al. Periodic fever syndrome in children[J]. J Pediatr, 1999, 135(1):15-21.
[7]
Marshall GS, Edwards KM, Butler J, et al. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis[J]. J Pediatr, 1987, 110(1):43-46.
[8]
Førsvoll J, Kristoffersen EK, Øymar K. Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study[J]. Acta Paediatr, 2013, 102(2):187-192.
[9]
Padeh S. Periodic fever syndromes[J]. Pediatr Clin North Am, 2005, 52(2):577-609.
[10]
Kutsuna S, Ohmagari N, Tanizaki R, et al. The first case of adult-onset PFAPA syndrome in Japan[J]. Mod Rheumatol, 2016, 26(2):286-287.
[11]
Berkun Y, Levy R, Hurwitz A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome[J]. Semin Arthritis Rheum, 2011, 40(5):467-472.
[12]
Obici L, Merlini G. Amyloidosis in autoinflammatory syndromes[J]. Autoimmun Rev, 2012, 12(1):14-17.
[13]
Gazi U, Agada ME, Ozkayalar H, et al. Tonsillar antimicrobial peptide (AMP) expression profiles of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) patients[J]. Int J Pediatr Otorhinolaryngol, 2018, 110:100-104.
[14]
Batu ED, Sönmez HE, Bilginer Y, et al. A patient heterozygous for R92Q mutation with periodic fever and aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome-like phenotype[J]. Turk J Pediatr, 2018, 60(6):726-728.
[15]
Cochard M, Clet J, Le L, et al. PFAPA syndrome is not a sporadic disease[J]. Rheumatology (Oxford), 2010, 49(10):1984-1987.
[16]
Butbul Aviel Y, Harel L, Abu Rumi M, et al. Familial Mediterranean fever is commonly diagnosed in children in Israel with periodic fever aphthous stomatitis, pharyngitis, and adenitis syndrome[J]. J Pediatr, 2019, 204:270-274.
[17]
Salehzadeh F, Vahedi M, Hosseini-Asl S, et al. PFAPA and 12 common MEFV gene mutations our clinical experience[J]. Iran J Pediatr, 2014, 24(1):64-68.
[18]
Haytoglu Z, Gundeslioglu OO. Mediterranean fever gene variants and colchicine therapy in periodic fever, aphthous stomatitis pharyngitis, adenitis syndrome in a Mediterranean region[J]. Expert Rev Clin Immunol, 2019, 15(5):571-575.
[19]
Vanoni F, Theodoropoulou K, Hofer M. PFAPA syndrome:a review on treatment and outcome[J]. Pediatr Rheumatol Online J, 2016, 14(1):38.
[20]
Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever[J]. Ann Rheum Dis, 2016, 75(4):644-651.
[21]
Feder HM Jr. Cimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis[J]. Pediatr Infect Dis J, 1992, 11(4):318-321.
[22]
Burton MJ, Pollard AJ, Ramsden JD, et al. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA)[J]. Cochrane Database Syst Rev, 2019, 12(12):CD008669.
[23]
Niu H, Wang R, Jia YT, et al. Pidotimod, an immunostimulant in pediatric recurrent respiratory tract infections:a meta-analysis of randomized controlled trials[J]. Int Immunopharmacol, 2019, 67:35-45.
[24]
Valentini D, Di Camillo C, Mirante N, et al. Effects of pidotimod on recurrent respiratory infections in children with down syndrome:a retrospective Italian study[J]. Ital J Pediatr, 2020, 46(1):31.
[25]
Manti S, Filosco F, Parisi GF, et al. Proposal for a new therapeutic high dosage of Pidotimod in children with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome:a randomized controlled study[J]. Ital J Pediatr, 2020, 46(1):106.
