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Özaslan Z, Şen A, Uçar SA, Çakan M, Sanisoğlu B , et al.
European journal of pediatrics •
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.
NLRP12-associated autoinflammatory disease (NLRP12-AID) is a rarely seen periodic fever syndrome also known as familial cold autoinflammatory syndrome-2 (FCAS2), caused by autosomal dominant inherited mutations in the NLRP12 gene. We aimed to present our clinical experience constituting one of the largest paediatric NLRP12-AID cohort. The patients with preliminary diagnosis of systemic autoinflammatory disease (SAID) other than familial Mediterranean fever (FMF) and PFAPA syndrome were evaluated with the next-generation-sequence (NGS) genetic-panel analysis between January-2016 and January-2022. Among children carrying NLRP12-variant, patients with recurrent episodes of autoinflammatory disease manifestations were diagnosed with NLRP12-AID. Demographic, clinical and laboratory data, treatments and outcomes of patients were presented. Seventeen patients were diagnosed with NLRP12-AID. The mean age at diagnosis was 114.7±69.5 months. The most frequently seen clinical manifestations were respectively; fever (100%), arthritis/arthralgia (58.8%), rash (52.9%), abdominal pain (52.9%), diarrhoea (41.2%), myalgia/fatigue (53.2%) and, conjunctivitis (11.7%). Clinical manifestations were triggered by cold exposure in three patients (17.6%). Seven patients had pathogenic, one had likely pathogenic, seven had VUS, and two had novel heterozygous variants. The most common defined variant in the NLRP12 gene was R352C. Complete response was achieved in 5 patients and partial response was in 6 with colchicine treatment. Attacks were prevented with anti-IL-1 treatments in 6 patients unresponsive to colchicine. In conclusion, the disease can cause effects on various tissues, especially the musculoskeletal and gastrointestinal systems, apart from FCAS symptoms. We think that a patient who can be defined as syndrome of undifferentiated recurrent fever should also be evaluated genetically in terms of NLRP12 previously.
Gain-of-function mutations of the NLR family pyrin domain containing 3 (NLRP3) gene have been implicated in autoinflammatory diseases. The NLRP3 Q703K variant is a common variant associated with Cryopyrin-associated periodic syndromes (CAPS) and periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. However, the genotype-phenotype correlation between NLRP3 Q703K variant, CAPS and PFAPA is unclear. In this study, we aimed to investigate the frequency of the NLRP3 Q703K variant in patients with and without autoinflammatory disease and characterize the phenotype in only Q703K variant positive patients. A retrospective analysis of 639 patients with autoinflammatory symptoms was conducted. Patients underwent next-generation sequencing (NGS) panel analysis of 16 genes, including NLRP3. For the 68 patients carrying the only Q703K variant, their clinical and demographic information was evaluated. Genetic data from 1461 patients without autoinflammatory symptoms were used as the control group. Of our 639 autoinflammatory symptomatic patients, the Q703K mutation was detected in 68 (5.3% allele frequency). Heterozygous mutations were detected in 141 patients without autoinflammatory symptoms (4.8% allele frequency, p=0.4887). Of the patients with variant in Q703K, 10 patients were diagnosed with CAPS , 7 patients were diagnosed with PFAPA and the remaining 39 were diagnosed with undefined systemic autoinflammatory disease (uSAID) Conclusions. The Q703K variant, which is seen with similar frequency in the control and autoinflammatory groups, is also of higher prevalence in patients with mild CAPS symptoms and PFAPA syndrome. This variant, together with other undetected genetic variants or epigenetic modifications, may be responsible for the corresponding phenotype. As such, it is essential for clinicians to evaluate their patients using both genetic and clinical evaluations.