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Objective: The new classification criteria for the hereditary recurrent fever (HRF) syndrome [cryopyrin-associated periodic syndrome (CAPS), TNF-α receptor-associated periodic syndrome (TRAPS), FMF and mevalonate kinase deficiency] have been published recently. These criteria define two core sets of criteria for each HRF: mixed criteria, including genetic and clinical variables, and clinical criteria, relying on clinical variables only. Our aim was to validate the criteria for HRF in an independent cohort, the JIR Cohort database, an international repository of systemic inflammatory diseases., Methods: We enrolled patients with HRF, periodic fever, adenitis, pharyngitis and aphthous stomatitis syndrome (PFAPA) and syndrome of undefined recurrent fever (SURF). A score ranging from zero to two was attributed to their respective genotypes: zero (no mutation), one (non-confirmatory genotype) or two (confirmatory genotype). The criteria were applied to all patients based on genotype scoring. The treating physician's diagnosis served as the gold standard for the determination of specificity., Results: We included 455 patients. The classification criteria showed excellent specificity for CAPS and TRAPS (98% specificity each), fair specificity for FMF (88%), but poor specificity for mevalonate kinase deficiency (58%). Sub-analysis showed excellent accuracy of the mixed criteria for all four HRFs. Misclassification was mainly attributable to clinical criteria sets, with false-positive patients in all four HRF clinical criteria sets., Conclusion: This study represents the final validation step of the HRF classification criteria as recommended by the ACR. Genetic data appear to be necessary to classify patients with HRF correctly., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common autoinflammatory disease in children and is often grouped together with hereditary periodic fever syndromes, although its cause and hereditary nature remain unexplained. We investigated whether differential DNA methylation was present in DNA from peripheral blood mononuclear cells (PBMC) in patients with PFAPA vs. healthy controls. A whole-epigenome analysis (MeDIP and MBD) was performed using pooled DNA libraries enriched for methylated genomic regions and identified candidate genes, two of which were further evaluated with methylation-specific restriction enzymes coupled with qPCR (MSRE-qPCR). The analysis showed that the PIK3AP1 and SPON2 gene regions are differentially methylated in patients with PFAPA. MSRE-qPCR proved to be a quick, reliable, and cost-effective method of confirming results from MeDIP and MBD. Our findings indicate that a B-cell adapter protein ( PIK3AP1 ), as the PI3K binding inhibitor of inflammation, and spondin-2 ( SPON2 ), as a pattern recognition molecule and integrin ligand, could play a role in the etiology of PFAPA. Their role and the impact of changed DNA methylation in PFAPA etiology and autoinflammation need further investigation., (Copyright © 2020 Lovšin, Kovač, Tesovnik, Toplak, Perko, Rozmarič, Debeljak and Avčin.)

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a complex autoinflammatory disease with a clinical phenotype characterised by recurrent episodes of fever, systemic inflammation and symptoms and signs depicted in disease acronym. Although PFAPA is the most common autoinflammatory disease among children in many parts of the world, the condition is still an enigma, which include the regular episodes, the prompt responses to corticosteroids, the genetic bases for the familial clustering and therapeutic effects of tonsillectomy. This review explores PFAPA syndrome with the aim of describing the current clinical and scientific understanding of the condition., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Purpose of Review: This review aims at summarizing the current knowledge of A20 haploinsufficiency and other paediatric inflammatory disorders with mucosal involvement., Recent Findings: A20 haploinsufficiency is a newly described autoinflammatory disease caused by loss-of-function mutations in TNFAIP3 that result in the activation of the nuclear factor (NF)-kB pathway. Patients may present with dominantly inherited, early-onset systemic inflammation and a Behçet-like disease, or a variety of autoinflammatory and autoimmune features. In Behçet disease, recent literature provides insights into genetic susceptibility and emerging treatment options; in addition, the first paediatric classification criteria were published. Recent advances in periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) suggest that the disease has a complex underlying genetic mechanism and in some cases is inherited in an autosomal dominant pattern with reduced penetrance phenotype in many family members. Activation of the pyrin inflammasome through the RoA signalling pathway uncovers an interesting molecular connection between hyperimmunoglobulinemia D syndrome and familial Mediterranean fever. The description of new monogenic types of inflammatory bowel disease (IBD) may provide novel insights into disease pathogenesis. Finally, recent studies highlighted the role of gut microorganisms and dysbiosis in IBD., Summary: Monogenic diseases such as A20 haploinsufficiency may help to advance our understanding of disease pathogenesis and to develop targeted therapies for more common, multifactorial disorders with mucosal inflammation.

Objective: Periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome is a periodic fever syndrome of childhood with an unknown etiology. Our aim was to compare the features between PFAPA syndrome patients from Turkey and those from the US, and patients with and without MEFV variants, and to test the performance of the Eurofever criteria in excluding other autoinflammatory disorders., Methods: Seventy-one children with PFAPA syndrome, followed in Hacettepe University, in Ankara, Turkey, and 60 patients at Boston Children's Hospital in the US were enrolled. MEFV gene-variant analysis was performed in 56 patients with Sanger sequencing., Results: In patients from Turkey, symptom onset was at a younger age, fever attacks were of shorter duration, and pharyngitis was more frequent, whereas adenitis, headache, and nausea/vomiting were less frequent during attacks, when compared to patients from the US (P < 0.05). More patients from the Turkish cohort were classified in the familial Mediterranean fever (FMF) group according to the Eurofever criteria than patients from the US (66.2% versus 10%; P < 0.001). Two patients were diagnosed with FMF after MEFV analysis. Twenty-one patients (37.5%) had a single MEFV variant. No significant differences in phenotype were found between patients with and without MEFV variants., Conclusion: The differences between patients from the Turkish and US cohorts may be due to epigenetic or environmental factors. In addition, the Eurofever FMF criteria may perform better in certain areas, if the weight of ethnic origin parameter or cutoff values were modified., (© 2016, American College of Rheumatology.)

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.

We report three familial cases of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome, including a pair of monozygotic twins and their mother. It suggests that periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome may have a certain monogenetic background., (Copyright © 2011 Mosby, Inc. All rights reserved.)

PFAPA is a periodic fever disease, of unknown etiology, characterized by aphthous stomatitis, pharyngitis and cervical adenitis. To inquire whether genes implicated in other auto-inflammatory diseases might be involved in its pathogenesis, predominant mutations in the genes causing familial Mediterranean fever, TNF receptor-associated periodic fever syndrome, Crohn's disease and Muckel-Wells syndrome were analyzed in PFAPA patients. Patients (n = 57) with PFAPA, according to previously published criteria were recruited, at the Meyer Children Hospital during 2006-2007. Clinical information was complemented during physicians-parents encounter. Predominant mutations in MEFV, TNF1rA, CARD15/NOD2 and NLRP3 genes were tested. Mean age at diagnosis was 30.64 +/- 16.4 months. Boys (n = 33; 58%) were diagnosed earlier than girls (n = 21; 42%) at 26.18 +/- 13.83 and 36.41 +/- 18.32 months, respectively (P = 0.05). Fifteen patients (27%) carried an MEFV mutation; two patients (3.6%) a CARD15 mutation, one patient (1.8%) a variance in TNF1rA and another had both an MEFV and a CARD15 mutation. Clinical symptoms were equally manifested in carriers and non-carriers. The high carrier rate of MEFV mutations in our PFAPA cases compares well with that of the general population in Israel. It is debated whether MEFV mutations, when mediated by the presence of additional modifiers, may expose a transient fever condition, namely PFAPA.