Introduction
Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an autoinflammatory disorder of childhood and little is known about the underlying etiology. While mutations involving the IL-1 pathway have been identified in other recurrent fever disorders, including TNF-receptor associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS), PFAPA syndrome is not traditionally considered to be a hereditary fever disorder.
Objectives
To evaluate pediatric patients with PFAPA for family histories suggestive of immune dysregulation and to correlate inheritability with immune phenotype.
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Methods
Patient data and detailed family histories were collected for over 170 children with recurrent fevers including 70 patients with PFAPA to create a prospective cohort over a 4-year period. DNA was isolated from blood or tonsillar tissue from recurrent fever patients, and NLRP3 and TNFRSF1A were sequenced. Quantitative real time PCR was used to evaluate IL-36 transcripts in tonsils.
Results
Our cohort reflects the diversity of San Diego, without predilection for any specific ethnic background. Family histories revealed 21% of patients have a first degree relative with recurrent fevers and 12% with tonsillitis in childhood, with only 1.4% reporting a history of recurrent infections. We have identified over 30 families with 2-8 affected members. These patients do not possess mutations commonly seen in other autoinflammatory disorders such as CAPS or TRAPS, suggesting that a novel gene may be involved. Upregulation of IL-36 mRNA expression in tonsils identifies the IL-1 family member IL-36 as a candidate gene.
Conclusion
A substantial portion of our families with PFAPA report childhood histories of recurrent fevers that resolved either spontaneously or with tonsillectomy, indicating a possible dominantly inherited trait that impacts the developing immune system, including the tonsils.
Disclosure of interest
L. Broderick: None declared, D. Carvalho: None declared, A. Magit: None declared, W. Jiang: None declared, S. Leuin: None declared, M. Bothwell: None declared, D. Kearns: None declared, S. Pransky: None declared, H. Hoffman Consultant for: Regeneron, Novartis, and Sobi
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