Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European–American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet’s disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10−9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet’s disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet’s disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet’s spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet’s disease and recurrent aphthous stomatitis.

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Background/Purpose: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is the most prevalent pediatric autoinflammatory fever disorder. As there is no known genetic cause or confirmatory test, diagnosis of PFAPA is challenging. Clockwork interval between episodes is a characteristic feature, which aids in diagnosis. The true prevalence and the etiology of PFAPA are not known, but genetic factors leading to immune dysregulation as well as infectious agents have been suggested as causative factors. Oral corticosteroids abort the episodes in majority of patients, and in recent years, tonsillectomy has been shown to be effective in inducing remission. Our center has a significant success rate with tonsillectomy in PFAPA patients. Using unbiased next‐generation sequencing, we investigated the presence of potential infectious agents and gene expression signatures in tonsils from patients with PFAPA, chronic tonsillitis and obstructive sleep apnea (OSA). Methods: Tonsil tissue from 3 age‐matched groups of pediatric patients was collected (6 PFAPA, 4 chronic tonsillitis and 4 OSA). Patients with PFAPA had characteristic periodic fevers in addition to at least 2 out of the 3 other described features. Total RNA extracted from punch biopsies of tonsil samples was subjected to massively parallel RNA sequencing (RNA‐Seq). The PathSeq software was used to identify and quantify microbial sequences. We compared the microbiome in PFAPA cases to those present in controls in order to identify differentially abundant microbes. RNA‐Seq data was also processed for gene expression analysis, and these data were analyzed using comparative marker analysis and unsupervised machine learning methods. Results: Computational analysis of bacterial and viral species present in PFAPA tonsillar biopsies did not reveal a known or novel candidate pathogen. Unbiased characterization of human viruses in cases and controls revealed human coxsackievirus, parechovirus and adenovirus C sequencing reads at low abundance in a subset of samples, without enrichment of any of these viruses in PFAPA cases. Unsupervised machine learning methods did not support the presence of a conserved microbial signature specific for PFAPA. We also performed comparative marker selection to identify genes whose expression is up or down regulated in PFAPA vs. control cases. This analysis showed differential expression of several genes, including genes involved in the innate immune response, in PFAPA tonsils vs. controls. Conclusion: Characterization of the tonsillar microbiome in PFAPA and control patients with this unbiased, highly sensitive sequencing‐based analysis did not demonstrate a microbial signature that was strongly correlated with PFAPA, although the power of this study is limited by the small sample size. On the other hand, the differential expression of innate immunity related genes in PFAPA samples strengthen the hypothesis of the existence of similar effector mechanisms between PFAPA and other periodic fever syndromes.

Objectives Idiopathic pain at the cochlear implant (CI) site outside of the immediate postoperative period is an uncommon occurrence but may necessitate device explantation. Our objective was to describe the clinical course for pediatric patients with CI site pain who ultimately required device explantation. Study Design Retrospective chart review. Methods We performed a retrospective database review of CIs performed at a tertiary referral center for pediatric cochlear implantation. We specifically evaluated pediatric patients who presented with pain at or near the CI device site and ultimately required explantation. Results Fifteen patients (16 CIs) had pain at or near the CI site requiring device explantation. Cultures taken during site exploration or device explantation identified bacteria in 86% and 81% of procedures, respectively. Propionibacterium acnes and Staphylococcus non‐aureus were the most commonly identified organisms. Conclusions The majority of patients with idiopathic pain in this cohort ultimately requiring CI explantation had chronic bacterial colonization. Level of Evidence 4 (Case series) Laryngoscope, 132:2044–2049, 2022