PFAPA syndrome (Marshall) — management strategy by multidisciplinary specialists
Abstract
Introduction. PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis) syndrome (Marshall syndrome) is a rare disease predominantly found in young children. This pathology is of particular interest due to its peculiar clinical picture, characterized by periodic fever, aphthous stomatitis, pharyngitis and adenitis. The main feature of PFAPA syndrome is regular, cyclically recurring attacks of high fever, during which children become lethargic, complain of severe sore throat, they have flushing and enlarged tonsils, which is often accompanied by purulent plaque. Another noticeable symptom is cervical lymphadenitis — the lymph nodes in the neck are noticeably enlarged, sometimes reaching 4–6 cm in diameter, which causes anxiety in parents. Aphthous stomatitis is considered an equally significant manifestation — the appearance of painful ulcers in the mouth, which cause significant discomfort to the child. Despite the severity of symptoms, between attacks, children feel absolutely healthy, develop normally and do not lose body weight. This serves as an important difference between PFAPA and most other autoimmune or infectious diseases, in which the course is usually more severe and accompanied by long-term disorders of the general condition. The purpose of the study — to analyze the features of the course of Marshall syndrome in two patients with different clinical manifestations, drawing attention to the difficulties of differential diagnosis and key criteria for making a diagnosis. Materials and methods. Retrospective analysis of two clinical cases in patients with a confirmed diagnosis of PFAPA syndrome (according to the criteria of Marshall et al. or Gattorno et al.). Results. Clinical cases show the need for a multidisciplinary approach in the management of patients with Marshall syndrome to improve quality of life and minimize complications of the disease. Proper understanding of the clinical picture is extremely important for timely diagnosis, selection of effective therapy and improvement of the quality of life of both the children themselves and their parents.
References
Салугина С.О., Кузьмина Н.Н., Федоров Е.С. Аутовоспалительные синдромы — новая мультидисциплинарная задача современной педиатрии и ревматологии. Педиатрия. Журнал им. Г.Н. Сперанского. 2012;91(5):120–132. Salugina S.O., Kuzmina N.N., Fedorov E.S. Autoinflammatory syndromes — a new multidisciplinary challenge for modern pediatrics and rheumatology. Pediatrics. Journal n.a. G.N. Speransky. 2012;91(5):120–132. (In Russian).
Kastner D.L., Aksentijevich I., Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell. 2010;140(6):784–790. DOI: 10.1016/j.cell.2010.03.002.
Майданник В.Г. Современные подходы к диагностике и терапии синдрома периодической лихорадки с афтозным стоматитом и шейным лимфаденитом (синдром Маршалла) у детей. Международный журнал педиатрии, акушерства и гинекологии. 2013;3(3):63–74. Maidannik V.G. Modern approaches to the diagnosis and therapy of periodic fever syndrome with aphthous stomatitis and cervical lymphadenitis (Marshall syndrome) in children. International Journal of Pediatrics, Obstetrics and Gynecology. 2013;3(3):63–74. (In Russian).
Marshall G.S., Edwards K.M., Butler J., Lawton A.R. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43–46. DOI: 10.1016/S0022-3476(87)80285-8.
Кузьмина Н.Н., Салугина С.О., Федоров Е.С. Аутовоспалительные заболевания и синдромы у детей. М.: ИМА-ПРЕСС; 2012. Kuzmina N.N., Salugina S.O., Fedorov E.S. Autoinflammatory diseases and syndromes in children. Moscow: IMA PRESS; 2012. (In Russian).
Feder H.M., Salazar J.C. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr. 2010; 99(2):178–184. DOI: 10.1111/j.1651-2227.2009.01554.x.
Førsvoll J., Kristoffersen E.K., Øymar K. Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study. Acta Paediatr. 2013;102(2):187–192. DOI: 10.1111/apa.12069.
Wurster V.M., Carlucci J.G., Feder H.M. Jr., Edwards K.M. Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr. 2011;159(6):958–964. DOI: 10.1016/j.jpeds.2011.06.004.
Hofer M., Pillet P., Cochard M.M. et al. International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients. Rheumatology (Oxford). 2014;53(6):1125–1129. DOI: 10.1093/rheumatology/ket460.
Adachi M., Watanabe A., Nishiyama A. et al. Familial cases of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr. 2011;158(1):155–159. DOI: 10.1016/j.jpeds.2010.09.054.
Antón-Martín P., Ortiz Movilla R., Guillén Martín S. et al. PFAPA syndrome in siblings. Is there a genetic background? Eur J Pediatr. 2011;170(12):1563–1568. DOI: 10.1007/s00431-011-1479-5.
Jesus A.A., Canna S.W., Liu Y., Goldbach-Mansky R. Molecular mechanisms in genetically defined autoinflammatory diseases — disorders of amplified danger signaling. Annu Rev Immunol. 2015;33:823–874. DOI: 10.1146/annurev-immunol-032414-112227.
Masters S.L., Simon A., Aksentijevich I., Kastner D.L.. Horror autoinflammaticus — the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–668. DOI: 10.1146/annurev.immunol.25.022106.141627.
Hoffman H.M., Mueller J.L., Broide D.H., Wanderer A.A., Kolodner R.D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301–305. DOI: 10.1038/ng756.
Stojanov S., Lapidus S., Chitkara P., Feder H., Salazar J.C., Fleisher T.A., Brown M.R., Edwards K.M., Ward M.M., Colbert R.A., Sun H.W., Wood G.M., Barham B.K., Jones A., Aksentijevich I., Goldbach-Mansky R., Athreya B., Barron K.S., Kastner D.L. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci U S A. 2011;108(17):7148–7153. DOI: 10.1073/pnas.1103681108.
Manz M.G., Boettcher S. Emergency granulopoiesis. Nat Rev Immunol. 2014; 14(5):302–314. DOI: 10.1038/nri3660.
Sundqvist M., Wekell P., Osla V., Bylund J., Christenson K., Sävman K., Foell D., Cabral D.A., Fasth A., Berg S., Brown K.L., Karlsson A. Increased intracellular oxygen radical production in neutrophils during febrile episodes of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. Arthritis Rheum. 2013;65(11):2971–2983. DOI: 10.1002/art.38134.
Peridis S., Koudoumnakis E., Theodoridis A., Stefanaki K., Helmis G., Houlakis M. Surgical outcomes and histology findings after tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. Am J Otolaryngol. 2010;31(6):472–475. DOI: 10.1016/j.amjoto.2009.06.005.
Dytrych P., Krol P., Kotrova M., Kuzilkova D., Hubacek P., Krol L., Katra R., Hrusak O., Kabelka Z., Dolezalova P., Kalina T., Fronkova E. Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome. Mol Immunol. 2015;65(1):139–147. DOI: 10.1016/j.molimm.2015.01.004.
Valenzuela P.M., Araya A., Pérez C.I., Maul X., Serrano C., Beltrán C., Harris P.R., Talesnik E. Profile of inflammatory mediators in tonsils of patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Clin Rheumatol. 2013;32(12):1743–1749. DOI: 10.1007/s10067-013-2334-z.
Førsvoll J., Janssen E.A., Møller I., Wathne N., Skaland I., Klos J., Kristoffersen E.K., Øymar K. Reduced number of CD8+ cells in tonsillar germinal centres in children with the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome. Scand J Immunol. 2015;82(1):76–83. DOI: 10.1111/sji.12303.
Cantarini L., Vitale A., Bartolomei B. et al. Diagnosis of PFAPA syndrome applied to a cohort of 17 adults with unexplained recurrent fevers. Clin Exp Rheumatol. 2012;30(2):269–271.
Dagan E., Gershoni-Baruch R., Khatib I. et al. MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int. 2010;30(5):633–636. DOI: 10.1007/s00296-009-1037-x.
Di Gioia S.A., Bedoni N., von Scheven-Gête A. et al. Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Sci Rep. 2015;5:10200. DOI: 10.1038/srep10200.
Manthiram K., Nesbitt E., Morgan T., Edwards K.M. Family History in Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. Pediatrics. 2016;138(3):e20154572. DOI: 10.1542/peds.2015-4572.
Burton M.J., Pollard A.J., Ramsden J.D., Chong L.Y., Venekamp R.P. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev. 2014;(9):CD008669. DOI: 10.1002/14651858.CD008669.pub2.
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. Semin Arthritis Rheum. 2011;40(5):467–472. DOI: 10.1016/j.semarthrit.2010.06.009.
Lachmann H.J., Sengül B., Yavuzşen T.U., Booth D.R., Booth S.E., Bybee A., Gallimore J.R., Soytürk M., Akar S., Tunca M., Hawkins P.N. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford). 2006;45(6):746–750. DOI: 10.1093/rheumatology/kei279.
Yüksel S., Ekim M., Ozçakar Z.B., Yalçınkaya F., Acar B., Oztuna D., Akar N. The value of procalcitonin measurements in children with familial Mediterranean fever. Rheumatol Int. 2012;32(11):3443–3447. DOI: 10.1007/s00296-011-2206-2.
Ter Haar N., Lachmann H., Özen S., Woo P., Uziel Y., Modesto C., Koné Paut I., Cantarini L., Insalaco A., Neven B., Hofer M., Rigante D., Al Mayouf S., Touitou I., Gallizzi R., Papadopoulou Alataki E., Martino S., Kuemmerle Deschner J., Obici L., Iagaru N., Simon A., Martini A., Manna R., Ruperto N., Gattorno M., Frenkel J. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72(5):678–685. DOI: 10.1136/annrheumdis-2011-201268.
Козлова А.Л., Леонтьева М.Е., Велиева П.Т., Калинина М.П., Деордиева Е.А., Швец О.А., Кузьменко Н.Б., Мухина А.А., Грачев Н.С., Новичкова Г.А., Щербина А.Ю. Аутовоспалительное заболевание — синдром PFAPA: опыт одного Центра. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2022;21(3):56–64. DOI: 10.24287/1726-1708-2022-21-3-56-64. Kozlova A.L., Leontieva M.E., Velieva P.T., Kalinina M.P., Deordieva E.A., Shvets O.A., Kuzmenko N.B., Mukhina A.A., Grachev N.S., Novichkova G.A., Shcherbina A.Y. An autoinflammatory disease — PFAPA syndrome: a single-center experience. Pediatric Hematology/Oncology and Immunopathology. 2022;21(3):56–64. (In Russian). DOI: 10.24287/1726-1708-2022-21-3-56-64.
