International Journal of Pediatric Otorhinolaryngology Extra
Volume 3, Issue 1 , Pages 10-13, January 2008

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: A Tunisian report

Pediatric Department, Pediatrician Hopital of Tunis, 1007 Jabbari Street, Bab Saadoun, Tunis, Tunisia

Received 5 August 2007; received in revised form 16 August 2007; accepted 16 August 2007. published online 28 November 2007.

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Summary 

PFAPA syndrome is a rare entity characterized by periodic fever, adenitis, pharyngitis, and aphthous stomatitis. The authors report a case with PFAPA syndrome. A 7-year-old girl had recurrent pharyngitis and aphthous stomatitis since the age of 6 years. She was hospitalized in orthopaedic care because of coxalgia. A septic arthritis was excluded. She was subsequently admitted in paediatric unit because of fever, chills and vomits. At physical examination, we found a feverish child having a pharyngitis and cervical adenitis. Laboratory analysis showed signs of inflammation. The girl was treated by azithromycin. One month later, she developed an aphthous stomatitis, fever and painful cervical lymphadenopathy treated by a single dose of prednisone (2mg/kg). She was diagnosed as having PFAPA syndrome. Her complaints dramatically and completely disappeared after administration of the drug. During the 10 months of follow-up, two similar attacks were noted. She was treated by a single dose of steroids. After the second relapse, she was put under cimetidine (40mg/(kgday)) with a good outcome.

Keywords: Periodic fever, Pharyngitis, Aphthous stomatitis, Marshall syndrome, PFAPA

 

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1. Introduction 

PFAPA is a particular chronic fever syndrome characterized by a relapsing periodic fever accompanied by aphthous stomatitis, pharyngitis, and cervical adenitis [1], [2], [3]. This is relatively a new clinical entity which was first described in 1987 by Marshall et al. [1], [4], [7], [10].

It is recognised as part of the differential diagnosis for pyrexia of unknown origin in children, but remains a relatively obscure entity among the periodic fever syndromes, which also include familial Mediterranean fever and cyclic neutropenia [4], [8].

Through the exceptional case of a child presenting PFAPA syndrome, the authors describe clinical, biologic characteristics and therapeutic aspects of this disease.

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2. Case report 

A 7-year-old girl had a past history of recurrent urinary and upper respiratory tract infections since the age of 6 years. One month before her hospitalization, she developed mouth ulcers which were treated with corticoids during 5 days by a paediatrician of free practice. Five days later, she complained about muscle pain and left coxalgia. The magnetic resonance imaging of the pelvis showed an intra-articular coxofemoral effusion. In the orthopaedic care, a septic arthritis was suspected but the girl was apyretic and she was improved by the drive and the immobilization of the limb. The evolution was marked by fever, chills and vomits. So, she was admitted for complement management. Physical examination revealed a feverish child with a temperature of 39.4°C. The weight and height were within normal limits. The general state was good. Pharynx was hyperaemic. There was cervical lymphadenopathy. She had no mouth ulcers on the mucous membranes of the mouth. The rest of the physical findings were normal.

Laboratory examination revealed signs of inflammation. White blood cell count was 16,600mm−3 with polynucleosis (13,300mm−3). C-reactive protein level reached a value of 122.8mg/l. Haemoglobin was 12.9g/dl. Platelet count was 482,000mm−3. Renal and liver function tests were normal. Levels of type D immunoglobulin could not be performed in Tunisia. The urinary analysis was normal. A throat sample was negative. We suspected a Behcet disease despite the absence of other criteria for diagnosis. HLA type was done and was A26 A29 B44 B35. A chest X-ray study and a hip ultrasonogram were normal.

The child was put under azithromycin during 3 days. She became apyretic 2 days later. Twenty-nine days after the exit of the hospital, the child presented again an aphthous stomatitis associated to a fever, a pharyngitis and bilateral cervical painful adenitis measuring 2cm/1cm. Based on the clinical findings associating recurrent mouth ulcers, a periodic fever, pharyngitis and cervical adenitis, the patient was diagnosed as having PFAPA syndrome. The child received a single dose of 2mg/kg of prednisone. Her complaints were completely disappeared after the treatment. During 10 months of follow-up, the patient presented two other attacks. The period between the two attacks was about 3 weeks. She presented a similar febrile attack lasting 3 days with painful mouth ulcers. These two relapses were controlled by a single use of prednisone. Between attacks, she had a good health and the biologic examinations were normal. During the attacks, the girl could not go to school. She had a bad general state with asthenia and anorexia. The mouth ulcers were painful. She had signs of inflammation: sedimentation rate, C-reactive protein and blood leukocyte count were, respectively, in the limits of 75mm at the first hour, 80mg/l and 15,000mm−3. The parents were worried and they did not accept to treat every attack by prednisone, so she was treated since December 2006 by cimetidine (40mg/(kgday)). The febrile episodes disappeared completely. Until June 2007, she was usually treated by cimetidine with a very good outcome.

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3. Discussion 

PFAPA, FAPA or Marshall syndrome is a relatively rare and little-known entity. The first description was made in 1987 [1], [4], [5], [9]. About 365 cases have been documented in the literature [1]. Its pathogenesis remains unknown, but certain infectious vectors are incriminated in the etiology of recurrent fevers [1], [4]. No link between geographic or ethnic factors with this syndrome is found [4]. The PFAPA syndrome is characterized by periodic episodes of high fever (>39°C) lasting 3–6 days and recurring every 3–8 weeks, associated with aphthous stomatitis, pharyngitis, and cervical adenitis [3], [9]. It occurs in children younger than 5 years of age with a male predominance [1], [4], [11], [12]. Its frequency is not known [4]. In Tunisia, it is the first case reported for our knowledge. Patients present a regularly recurring fever with an early age of onset (<5 years of age). Fever is associated with constitutional symptoms with at least one of the following clinical signs: aphthous stomatitis, cervical lymphadenitis or pharyngitis. Constitutional symptoms include chills, sweats, headache, muscle and bone pain, digestive symptoms and cranial neuritis [1], [3], [4], [9]. In our case, the diagnosis of PFAPA is reached by clinical signs, normal growth and development and symptom-free evolution between episodes as reported in the literature [1], [2], [4], [7]. We also exclude other periodic fever syndromes and other etiologies of oral aphtosis as Behcet disease and cyclic neutropenia.

Other etiologies of fever such as familial Mediterranean fever (FMF), hyper-IgD syndrome and tumor necrosis factor-associated periodic syndrome (TRAPS) are classically discussed in the literature [1], [3]. They can be excluded in our case, because of the absence of abdominal or chest pain and rash for FMF, the absence of rash and the earliest onset in the hyper-IgD syndrome (less than 1 year of age). In this last syndrome, the febrile episodes are recurrent but not periodic [1], [5]. In the TRAPS, patients are unresponsive to steroid therapy [1].

The joint manifestations are possible in all these syndromes but arthritis, as in our case, is uncommon in Marshall syndrome.

In 1999, Thomas et al. [3] described clinical course and long-term follow-up of 94 patients with PFAPA referred over a 10-year period. PFAPA episodes lasted a mean of 4.8 days and recurred at a mean of 28 days. Prodromes of aphthous stomatitis, malaise, fatigue, irritability, or headaches occurring 24h or less before the onset of fever were reported in 78%. Pharyngitis occurs in 65% of cases. Cervical lymphadenopathy is present in 77% of cases. Abdominal pain, nausea and diarrhoea are, respectively, present in 45, 52 and 30% of all cases.

In 2000, Ovetchkine et al. carried out in France a national retrospective study including 22 cases of PFAPA [5]. The onset of symptoms occurred between the age of 3 months and 12 years, with a mean age of 5 years. Pharangitis and aphthous stomatitis are found in 77% of cases. Cervical adenopathies are found in 86% of cases. The main constitutional symptoms include asthenia (86%), headaches (77%), arthralgia (59%), abdominal pains (49%) and chills (41%).

In 2003, Atas et al. [6] described the case of a 9-year-old Turkish child having recurrent fever, aphthous stomatitis, sore throat, headache and general body pains, lasting 2–3 days since 3.5 years of age.

In 2006, Markopoulos et al. [9] reported a new case in which, for the first time, a mild conjunctivitis was observed. The diagnosis of PFAPA syndrome in this patient was based on diagnostic criteria of the syndrome.

In 2006, Leong et al. [4] carried out a medline search using the terms PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. In this systematic review of the English literature, pharyngitis appears to be the next most common symptom after fever (between 72 and 100%), followed by cervical adenopathy (61–100%). Aphthous ulcers, which are usually small and relatively painless, are the symptom most likely to be missed which explains the wide variation in prevalence (33–68%). Additional manifestations include abdominal pains (between 18 and 65%), headache (between 18 and 60%). In this article, the authors report the role of medical or surgical treatment in patients with PFAPA syndrome. They conclude that PFAPA syndrome has the tendency to self-resolve. The resolution of symptoms cannot be solely attributed to the surgical procedure. Given that current evidence of the effectiveness of tonsillectomy in PFAPA is extremely weak, tonsillectomy should not be performed.

In fact, treatment of PFAPA syndrome is controversial owing to the lack of epidemiologic information about the prevalence of the disease and the absence of controlled studies. Non-steroidal anti-inflammatory agents and antibiotics are ineffective [1], [4]. A single dose of an oral corticosteroid (1–2mg/kgprednisone) leads to rapid resolution of the fever in most patients [1], [4], [7]. There is no effect on the natural history of the disease. Some authors increase the dosage of corticosteroids up to 7 days. Cimetidine is used in dosages of 150mg once or twice a day and 20–40mg/(kgday) [1], [3]. Feder [13] reported a successful treatment with cimetidine in three cases. Thomas et al. [3] reported a 43% efficacy of cimetidine in a group of 28 patients. Dahn et al. [14] described the failure of the use of cimetidine in a child [14]. Colchicine is used for therapy of FMF but has no efficacy in patients with PFAPA syndrome. In our case, corticosteroids are used with success but do not prevent the relapses. Cimetidine is dramatically successful for preventing recurrence of symptoms.

In 2007, Renko et al. [7] carried out a prospective, randomized, controlled trial to clarify the effect of tonsillectomy on the clinical course of PFAPA syndrome. Twenty-six children are recruited and are randomly allocated to tonsillectomy or follow-up alone. Six months after randomization, all 14 children in the tonsillectomy group and 6/12 (50%) children in the control group are free of symptoms. They conclude that tonsillectomy appears to be effective for treating PFAPA syndrome. Nevertheless, the sample is small.

In 2007, Marque et al. [15] reported a successful treatment with thalidomide in a 22-year-old man affected by this rare disease since the age of 5 years. Adenoidectomy at the age of 6 years and oral tonsillectomy at the age of 10 years failed to improve the symptoms. Oral colchicine at the dosage of 1mg/day was discontinued after 1 year because of the partial efficacy on the general symptoms and recurrence of oral aphthous ulcerations. Thalidomide is started at the dosage of 50mg/day. Dramatic improvement was noted with complete clearing of the oral ulcerations 1 month later. The dose of thalidomide was therefore decreased to 50mg every 2 or 3 days. Tolerance of this treatment was adequate, with no side effects, particularly no peripheral neuropathy.

PFAPA syndrome usually resolves spontaneously after several years, but persistence of the attacks in adults is possible [15].

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4. Conclusion 

The PFAPA syndrome is a rare chronic syndrome characterized by periodic fever, adenitis, aphthous stomatitis, pharyngitis, and adenitidis. The cause of this disease is still unknown. The diagnosis must be considered in any child with recurrent unexplained fevers. In the treatment, a single dose of a corticosteroid leads to rapid resolution of the fever in most patients. Typical PFAPA syndrome is benign and the affected children have no long-term sequelae.

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References 

  1. Pinto A, Lindemeyer RG, Sollecito TP. The PFAPA syndrome in oral medicine: differential diagnosis and treatment. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2006;102(1):35–39
  2. Long SS. Syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)—What it isn’t. What is it?. J. Pediatr. 1999;135(1):1–5
  3. Thomas KT, Feder HM, Lawton AR, Edwards KM. Periodic fever syndrome in children. J. Pediatr. 1999;135(1):15–21
  4. Leong SCL, Karkos PD, Apostolidou MT. Is there a role for the otolaryngologist in PFAPA syndrome? A systematic review. Int. J. Pediatr. Otorhinolaryngol. 2006;70(11):1841–1845
  5. Ovetchkine P, Bry ML. Syndrome de Marshall: résultats d’une enquête nationale rétrospective. Archives de Pédiatrie. 2000;7(Suppl. 3):S578–S582
  6. Bülent A, Hüseyin Ç, Sükrü A, Oguz T, Ercan K, Dursun O. PFAPA syndrome mimicking familial Mediterranean fever: report of a Turkish child. J. Emerg. Med. 2003;25(4):383–385
  7. Renko M, Salo E, Putto-Laurila A, Saxen H, Mattila PS, Luotonen J, et al. A randomized, controlled trial of tonsillectomy in periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. J. Pediatr. 2007;151(3):289–292Epub 2007 June 14
  8. La Regina M, Nucera G, Diaco M, Manna R, Gasbarrini G. Differential diagnosis of periodic fevers. Arch. Dis. Child. 2003;88:92
  9. Markopoulos AK, Kolokotronis A, Antoniades DZ. PFAPA syndrome: case report and description of conjunctivitis as a new sign. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2005;100(2):196
  10. Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis and aphthous stomatitis. J. Pediatr. 1987;110:43–46
  11. Padeh S. Periodic fever syndromes. Pediatr. Clin. North Am. 2005;52:577–609
  12. Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, et al. Periodic fever, aphthous stomatitis, pharyngitis and adenopathy syndrome: clinical characteristics and outcome. J. Pediatr. 1999;135:98–101
  13. Feder HM. Cimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis. Pediatr. Infect. Dis. J. 1992;11:318–321
  14. Dahn KA, Glode MP, Chan KH. Periodic fever and pharyngitis in young children: a new disease for the otolaryngologist?. Arch. Otolaryngol. Head Neck Surg. 2000;126:1146–1149
  15. Marque M, Guillaud B, Bessis D. Thalidomide for treatment of PFAPA syndrome. Oral Med. Oral Pathol. Oral Radiol. Endod. 2007;103(3):306–307

PII: S1871-4048(07)00068-8

doi:10.1016/j.pedex.2007.08.004

International Journal of Pediatric Otorhinolaryngology Extra
Volume 3, Issue 1 , Pages 10-13, January 2008

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