Sönmez HE

The first proteomics analysis of tonsils in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA).

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a recurrent fever syndrome. The exact etiopathogenesis of PFAPA syndrome remains unknown. Biological fluids or tissues may provide disease-specific biomarkers that may help clinicians to find new pathogenic pathways. Tonsil tissues of seven patients with PFAPA were collected during the tonsillectomy. Seven patients who underwent tonsillectomy for reasons other than chronic tonsillitis were enrolled as a control group. The nHPLC LC-MS/MS system was used for protein identification and label-free quantification. Bioinformatics analysis was carried out using the UniProt accession numbers of the identified proteins. Proteomics analysis revealed to identity of proteins of which at least 23 were up and 57 were downregulated. Bioinformatics analysis of differentially regulated proteins by STRING indicated that protein folding and clearance machinery were interrupted in PFAPA patients compared to the controls. The affected pathways underlined the importance of the mitochondrial electron transport chain and ATP biosynthesis process. Although it is not clear that changes in tonsil protein expression whether directly related to pathogenesis or simply result of chronic inflammation, the identification of tonsil biomarkers for PFAPA may provide clinicians an opportunity to understand disease pathogenesis or develop new molecular targets for treatments. Proteomics analyses of tonsils revealed the identity of 80 proteins of which at least 23 were up and 57 were downregulated. Bioinformatics analysis underlined the importance of mitochondrial ETC and regulation of ATP biosynthetic process. This is the first study evaluating the proteomics of the tonsils of PFAPA patients. The identification of tonsil biomarkers for PFAPA may provide clinicians an opportunity to understand disease pathogenesis or develop new molecular targets for treatments.

Exploring factors for predicting colchicine responsiveness in children with PFAPA.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) are the most common autoinflammatory syndromes in children. This study aimed to evaluate the clinical and laboratory parameters that may predict colchicine responsiveness.This retrospective, multicenter, cross-sectional study involved nine pediatric rheumatology centers from our country., The patients diagnosed with PFAPA were compared on the basis of their responses to colchicine. In the 806 (42.3% female 57.7% male) patients, the most common clinical findings were fever (100%), exudative tonsillitis (86.5%), pharyngitis (80.9%), and aphthous stomatitis (50.5%). The mean attack frequency was 13.5 ± 6.8 attacks per year lasting for a mean of 3.9 ± 1.1 days. Colchicine treatment was attempted in 519 (64.4%) patients, with 419 (80.7%) showing a favorable response. In patients who underwent MEFV gene analysis (70.8%), the most common variant was M694V heterozygous (16.8%). The presence of pharyngitis (p = 0.03, 95% CI 0.885 to 0.994), the presence of arthralgia (p = 0.04, 95% CI 0.169 to 0.958), and having more frequent attacks (p = 0.001, 95% CI 0.028 to 0.748) were found to be associated with colchicine unresponsiveness, whereas the carriage of the M694V variant (p = 0.001, 95% CI 0.065 to 0.242) was associated with colchicine responsiveness. This study identified the presence of pharyngitis, arthralgia, and increased attack frequency in patients with PFAPA as factors predicting colchicine unresponsiveness, whereas the carriage of the M694V variant emerged as a predictor of colchicine responsiveness. Predicting colchicine response at disease onset may facilitate a more effective management of PFAPA. • Colchicine treatment can be used in the prophylaxis of PFAPA disease. • Having the MEFV variant is the most commonly known factor in predicting response to colchicine. • The presence of pharyngitis or arthralgia, and more frequent attacks in PFAPA disease were found to be independently associated with colchicine unresponsiveness. • Carrying the M694V variant was identified as the sole factor predicting colchicine responsiveness.

Editorial: Hereditary Periodic Fevers and Autoinflammatory Diseases.

A patient heterozygous for R92Q mutation with periodic fever and aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome-like phenotype.

Batu ED, Sönmez HE, Bilginer Y, Özen S. A patient heterozygous for R92Q mutation with periodic fever and aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome-like phenotype. Turk J Pediatr 2018; 60: 726-728. Tumor necrosis factor receptor associated periodic syndrome (TRAPS) is an autosomal dominant disease caused by mutations located on the type 1 tumor necrosis factor receptor (TNFRSF1A) gene. Here we present a 3-year-old boy heterozygous for R92Q mutation in TNFRSF1A gene expressing a periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome-like phenotype. However, some of his symptoms such as myalgia and the long duration of fever attacks were not typical for PFAPA. He was treated with methylprednisolone during the attacks and also responded to colchicine. The family history revealed that his grandfather, mother, and uncle suffered from similar attacks, and interestingly all of them responded to tonsillectomy. PFAPA-like features have already been reported in patients with the R92Q mutation. However, this case is interesting with the response to colchicine treatment and response to tonsillectomy in his relatives.