PFAPA syndrome (ORPHA:42642)
PFAPA (Periodic fever - aphthous stomatitis- pharyngitis - adenopathy) syndrome is an auto inflammatory syndrome characterized by recurrent febrile episodes associated with aphthous stomatitis, pharyngitis and cervical adenitis.
Epidemiology
Prevalence of PFAPA is unknown, over 500 cases have been reported and patients are predominantly male (>60%).
Clinical description
PFAPA usually presents during early childhood (<5 years old) with recurrent episodes of fever (>39°C) lasting 3-7 days, during which children appear very ill. Aphthous stomatitis is characterized by relatively painless small, round and shallow lesions on the tongue and oral mucosa (70% of cases) that recover completely in 10-14 days. Most patients present with tonsillitis, occasionally with white exudates (mimicking streptococci infection), and a general pharyngitis (75% of cases) with diffuse hyperemia of the entire palate. Swelling of upper cervical lymph nodes appears in >75% of cases. Abdominal pain has also been reported in many cases (65%) and generally correlates with mesenteric adenopathy. Other reported features include chills, headache, vomiting, diarrhea, hepatosplenomegaly and joint pain. Episodes recur every 3-5 weeks, often in a predictable fashion with patients describing a mild malaise the day before recurrence. Patients are in good health between episodes and generally develop normally, but leg pain and chronic fatigue are often reported.
Etiology
PFAPA is an idiopathic inflammatory condition. Elevated levels of IL-2, TNF-alpha, decreased levels of IL-10 and a significant over expression of IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes are noted during the episodes.
Diagnostic methods
PFAPA is a diagnosis of exclusion based on clinical manifestations. The regularity of acute episodes during the active phase of the disease is an important clue. Marked leukocytosis and elevated CRP levels are observed in blood samples collected during acute episodes. Oral culture swabs are negative for infection, and patients fail to respond to antipyretic or antibiotic treatment.
Differential diagnosis
Differential diagnosis includes other diseases characterized by periodic fever such as recurrent tonsillitis, streptococcal infection, juvenile idiopathic arthritis, Behçet's disease, cyclic neutropenia, familial Mediterranean fever, TRAPS syndrome, and mevalonate kinase deficiency (see these terms).
Management and treatment
PFAPA has no specific treatment. Fever does not respond to non-steroidal anti-inflammatory medications. A dose of corticosteroid (prednisone, 1-2 mg/kg, or betametasone, 0.1-0.2 mg/kg) given upon the first signs of an episode can shorten or even end the episode within hours. This treatment has, however, been reported to reduce the interval between episodes. Cimetidine and colchicine have had some success in preventing relapse through regular administration. Tonsillectomy may be considered in more severe cases with very frequent flare ups.
Prognosis
Episodes usually decrease in frequency and resolve during the patient's second decade. Tonsillectomy may cure the disease in most cases.

                            Last update: 
                            July 2014


                            - Expert reviewer(s): 
                            Pr Isabelle KONE-PAUT