Autoinflammatory diseases are a heterogeneous group of disorders, characterized by sterile and chronic inflammation in the absence of specific autoantibodies formation and antigen-specific T cells. Periodic fever syndrome with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) represents the most common autoinflammatory disease of childhood. At the University Children’s Hospital Ljubljana, 130 patients were diagnosed with PFAPA from year 2006 to the end of year 2016. This clinical entity is characterized by recurrent episodes of high fever, aphthous stomatitis, pharyngitis and cervical adenitis. Symptoms begin in early childhood, lasting two to seven days and periodically repeat every few weeks. Patients are asymptomatic with normalization of laboratory markers during the remission. The disease is long-lasting, however, it generally resolves before puberty with no consequences for the patient. PFAPA is still considered as a sporadic disease. The pathogenesis of the disease has not yet been clarified, but it is presumed that the pathogenesis of the disease may include a signal pathway via AIM2 inflammasome. At the same time, more and more studies are in favor of the genetic background of the disease.
The aim of our study was clinical evaluation of PFAPA patients from University Children’s Hospital Ljubljana and further clarification of pathogenesis of PFAPA syndrome based on established genetic characteristics. Due to the overlapping clinical picture, we analyzed genes associated with other hereditary periodic fever syndromes (MEFV, NLRP3, MVK, TNFRSF1A) and genes that, due to their action and elevated protein level in patients with PFAPA, could be potential candidate genes for PFAPA syndrome (AIM2, PYCARD, SPAG7, SAA1, SAA2, CXCL10, CXCL9 and CXCR3).
114 patients with PFAPA syndrome (66 boys and 48 girls), were included in the study on clinical characteristics. We obtained data from the available medical documentation. An important part of our study was the determination of the occurrence of PFAPA in family members of our patients, where the results showed that 70 % of our patients had positive family history. Furthermore, half of PFAPA patients had more than one family member with a history of PFAPA. This finding speaks in favor of the genetic background of the disease.
In the study of genetic characteristics, 80 patients were included, where variants in the investigated genes were determined by the PCR method and Sanger sequencing. Allelic discrimination method was also used to determine certain genetic variants in healthy subjects and in additional 19 patients with PFAPA.
In total, 83 genetic variants were identified in 12 genes. Variants with a possible effect on inflammatory process were detected in MEFV, NLRP3, TNFRSF1A and CXCL10 genes in 23 patients. Seven of these patients carried two different variants. These are mostly variants that have also been detected in patients with other hereditary periodic fever syndromes or patients with other immune diseases. The most interesting gene variant was the novel variant in the NLRP3 gene, p.Pro200Thr, found in two PFAPA patients, which was considered to be pathological after the in silica analysis with CADD online tool.
We assume that these are all probably low-penetrant variants which are usually not sufficient for the appearance of a typical clinical picture of other autoinflammatory diseases. However, they are likely to have an impact on the increased susceptibility to inflammatory process and thus contribute to the pathogenesis of PFAPA syndrome. Based on the results of our study, we conclude that PFAPA syndrome is the result of the multiple low-penetrant gene variants with variable expressivity in different genes in combination with epigenetic factors and environmental factors leading to uniform clinical picture of PFAPA syndrome.