Vanoni F, Caorsi R, Aeby S, Cochard M, Antón J , et al.
Pediatric rheumatology online journal •
Diagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall's criteria, but no validated evidence based classification criteria for PFAPA has been established so far. A multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria. In the second phase the new classification criteria and the modified Marshall's criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance. The Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall's criteria when applied on our cohort of patients. Our work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA.
Vanoni F, Federici S, Antón J, Barron KS, Brogan P , et al.
Pediatric rheumatology online journal •
Diagnosis of Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is currently based on a set of criteria proposed in 1999 modified from Marshall's criteria. Nevertheless no validated evidence based set of classification criteria for PFAPA has been established so far. The aim of this study was to identify candidate classification criteria PFAPA syndrome using international consensus formation through a Delphi questionnaire survey. A first open-ended questionnaire was sent to adult and pediatric clinicians/researchers, asking to identify the variables thought most likely to be helpful and relevant for the diagnosis of PFAPA. In a second survey, respondents were asked to select, from the list of variables coming from the first survey, the 10 features that they felt were most important, and to rank them in descending order from most important to least important. The response rate to the first and second Delphi was respectively 109/124 (88%) and 141/162 (87%). The number of participants that completed the first and second Delphi was 69/124 (56%) and 110/162 (68%). From the first Delphi we obtained a list of 92 variables, of which 62 were selected in the second Delphi. Variables reaching the top five position of the rank were regular periodicity, aphthous stomatitis, response to corticosteroids, cervical adenitis, and well-being between flares. Our process led to identification of features that were felt to be the most important as candidate classification criteria for PFAPA by a large sample of international rheumatologists. The performance of these items will be tested further in the next phase of the study, through analysis of real patient data.
The syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA syndrome) is the most common cause of periodic fever in childhood. The current pharmacological treatment includes corticosteroids, which usually are efficacious in the management of fever episodes, colchicine, for the prophylaxis of febrile episodes, and other medication for which efficacy has not been proven so far. Tonsillectomy is an option for selected patients. Usually PFAPA syndrome resolves during adolescence, but there is increasing evidence that this condition may persist into adulthood.
Di Gioia SA, Bedoni N, von Scheven-Gête A, Vanoni F, Superti-Furga A , et al.
Scientific reports •
PFAPA syndrome is the most common autoinflammatory syndrome in children from Western countries. In spite of its strong familial clustering, its genetic basis and inheritance pattern are still unknown. We performed a comprehensive genetic study on 68 individuals from 14 families. Linkage analysis suggested a susceptibility locus on chromosome 8, but direct molecular sequencing did not support this initial statistical finding. Exome sequencing revealed the absence of any gene that was mutated in all patients. Exhaustive screening of genes involved in other autoinflammatory syndromes or encoding components of the human inflammasome showed no DNA variants that could be linked to PFAPA molecular pathology. Among these, the previously-reported missense mutation V198M in the NLRP3 gene was clearly shown not to co-segregate with PFAPA. Our results on this relatively large cohort indicate that PFAPA syndrome is unlikely to be a monogenic condition. Moreover, none of the several genes known to be involved in inflammation or in autoinflammatory disorders seem to be relevant, alone, to its etiology, suggesting that PFAPA results from oligogenic or complex inheritance of variants in multiple disease genes and/or non-genetic factors.
Cochard M, Clet J, Le L, Pillet P, Onrubia X , et al.
Rheumatology (Oxford, England) •
To determine whether PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) patients have a positive family history (FH) for recurrent fever syndromes. For all patients with PFAPA seen in two paediatric rheumatology centres (Romandy, Switzerland and Bordeaux, France), parents were interviewed to record the FH for periodic fever. As controls, we interviewed a group of children without history of recurrent fever. We recruited 84 patients with PFAPA and 47 healthy children. The FH for recurrent fever (without an infectious cause and recurring for at least half a year) was positive in 38/84 (45%), and was positive for PFAPA (diagnosis confirmed by a physician) in 10/84 (12%) of the PFAPA patients. For 29 of the 38 patients with positive FH, the affected person was a sibling or a parent. None of the healthy children had a positive FH for recurrent fever or PFAPA. A positive FH for rheumatological diseases was seen in both groups of children. These data show that a significant percentage of PFAPA patients present a positive FH of recurrent fever and PFAPA. This familial susceptibility suggests a potential genetic origin for this syndrome.
The autoinflammatory diseases should be considered in the differential diagnosis of recurrent fever in childhood. These diseases are characterized by inflammatory episodes without an evident cause. Some of these diseases, like the Familial Mediterranean Fever, have a genetic origin and need a chronic treatment to avoid severe complications on the long term. PFAPA syndrome is the most frequent cause of recurrent fever and is diagnosed based on unspecific criteria. The treatment is still controversial. One dose of Prednisone is able to interrupt the flare and tonsillectomy may induce a remission in the majority of the cases.