First described in 1987 (Marshall et al., 1987
), PFAPA syndrome is a clinical entity characterized by recurrent episodes of fevers without an identifiable source of infection. Despite better understanding of some the basic aspects of the disease, the etiology of PFAPA syndrome is still unknown and the question remains as to whether PFAPA syndrome is or not a distinct medical entity.
The diagnosis is established on the basis of clinical criteria that require the presence of a recurrent fever of early onset (<5 years) with a clockwork periodicity (usual interval <4 weeks) and ≥1 of the 3 associated symptoms (aphthosis, cervical adenitis, and pharyngitis), in the absence of upper respiratory tract infections and cyclic neutropenia (Marshall et al., 1989
). The primary complaint is the periodic fever rather than the stomatitis. There is a level of uncertainty about the pattern of intraoral ulcers in PFAPA, but they are generally described as few to several, non-clustered, small (<5 mm), shallow ulcers that heal over 5 to 10 days (Long, 1999
). However, it has been suggested that those ulcers could just mimic typical aphthae and the term aphthous-like ulcers has been consequentially used (Femiano et al., 2008
). In 1999, the diagnostic criteria were partially modified to exclude leukocytosis and elevated sedimentation rate as these frequently accompany febrile illnesses and do not add specificity for the diagnosis (Thomas et al., 1999
By definition, the diagnosis of PFAPA syndrome requires exclusion of other monogenic periodic fevers, which are hereditary conditions and include Familial Mediterranean Fever (FMF), the spectrum of mevalonate kinase deficiencies (MKD) (such as Hyper Ig-D syndrome and mevalonate aciduria), and tumor necrosis factor-associated periodic syndrome (TRAPS) amongst others (Scully et al., 2008
), each characterized by a specific genetic mutation involving the mediterranean fever (MEFV
), mevalonate kinase (MVK)
and tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A)
gene, respectively. However, genetic tests have been only sporadically used to support the PFAPA diagnosis despite the fact that current PFAPA syndrome diagnostic criteria have very low specificity.
Several Authors have indeed expressed concern about the diagnostic accuracy of the revised criteria (Brown et al., 2010
, Hofer, 2008
, Lierl, 2007
). When comparing the clinical manifestations of published PFAPA cohorts (), the heterogeneity is evident, particularly regarding the presence of aphthae sometimes just reported in a minority of the cases. This is possibly due to selective referral patterns as most of the cohorts are seen by pediatric, ENT or rheumatologic groups.
Distribution of main clinical manifestations associated with fever episodes in different cohorts of patients with PFAPA
A relevant number of patients with monogenic periodic fevers also meet the diagnostic criteria for PFAPA syndrome (Gattorno et al., 2008
). In a preliminary experience, 83% of patients with MKD, 57% of patients with TRAPS, and 8% of patients with FMF satisfied the criteria for PFAPA syndrome, which shows that the criteria have limited utility in differentiating PFAPA syndrome from monogenic periodic fevers. Importantly, oral aphthosis was found to be independently associated with a positive genetic test result indirectly suggesting the possible lack of specificity of this clinical feature for PFAPA diagnosis (Gattorno et al., 2008
Moreover, a recent large multicenter multinational study employing genetic tests to distinguish PFAPA from other inherited periodic fevers clearly confirmed that PFAPA syndrome criteria are not able to distinguish genetically positive patients (i.e. patients likely without PFAPA but with a PFAPA-like phenotype) from genetically negative patients (the likely PFAPA affected). In this case-control study of 210 children that met the clinical criteria for PFAPA syndrome, 38% were genetically positive for either MKD, FMF, TRAPS or displayed low penetrance or incomplete mutations, and 62% had negative genetic testing profiles (Gattorno et al., 2009
). Among the genetically positive individuals, the frequency of diarrhea, vomiting, abdominal pain, rash and arthralgias was higher, whereas exudative pharyngitis was more common in genetically negative patients. Cardinal features of the PFAPA syndrome, such as oral aphthosis and enlargement of cervical lymph nodes, were observed with similar frequencies in genetically negative patients and in subjects positive for MKD and FMF.
The authors then applied the Gaslini diagnostic score (Gattorno et al., 2008
), which takes into account several clinical features to predict the likelihood that a patient would have positive genetic markers. This score identified 91% of the genetically positive individuals and those at risk for carrying genes associated with monogenic periodic fevers. The authors concluded that low-risk patients can be diagnosed as having PFAPA syndrome without genetic testing, conversely, those at high-risk should be diagnosed with PFAPA syndrome only in light of negative genetic markers as they would likely evolve into monogenic periodic fevers (Gattorno et al., 2009
PFAPA syndrome may not be as sporadic as initially thought. With the aid of a European registry encompassing 14 rheumatological centers in 8 countries Cochard et al. noted that many PFAPA patients had a positive family history (FH+) of periodic fever. The authors recruited 84 PFAPA patients and 47 healthy children and found 45% of PFAPA patients FH+ for recurrent fever, with the affected family member being a sibling or parent in 76% of the cases. The recurrent fever was indeed PFAPA in 26% of FH+. All healthy children had a negative family history of PFAPA or recurrent fever (Cochard et al., 2010
). However, in a previously cited large study (Gattorno et al., 2008
) only 14% of PFAPA patients were FH+.
In addition to genetic testing, the measure of procalcitonin has been recently proposed as a marker for PFAPA syndrome, the hypothesis being that elevated procalcitonin levels would rule out PFAPA syndrome since procalcitonin is reported to be a sensitive marker for systemic bacterial infection, which by definition should be absent in PFAPA (Yoshihara et al., 2007
Lastly, the mainstay of treatment for PFAPA syndrome is the systemic administration of corticosteroids, just one or two doses of either prednisone or prednisolone (1–2 mg/kg/dose) normally result in rapid resolution of fever and the associated symptoms (Thomas et al., 1999
). Early studies have also examined the therapeutic use of cimetidine and found that it was efficacious in both treating the condition and inducing remission (Feder, 1992
). In recent years, however, a role for tonsillectomy for treatment of this syndrome has been suggested (Garavello et al., 2009
, Wong et al., 2008
). Nonetheless, since prednisone is an effective, inexpensive and relatively safe medication and since patients typically outgrow the condition by age 10–11 without further recurrence or sequelae, the role of tonsillectomy is still a matter of controversy (Hofer, 2008
, Leong et al., 2006
In conclusion, it seems that the question that needs to be addressed is not “Is PFAPA syndrome a distinct medical entity?”, but rather, “How to differentiate PFAPA from other similar diseases causing recurring fever?”. In that regard, the importance of oral aphthous ulcers in PFAPA is still questionable and further specific studies are clearly warranted to better describe oral ulcerations in PFAPA patients and at large to set up specific and reliable diagnostic criteria.