Genotype-phenotype relationship in non-familial mediterranean fever hereditary autoinflammatory diseases

Introduction and Aim: Autoinflammatory diseases (AIDs) constitute a challenging group of disorders due to their rare nature and limited awareness among clinicians, making diagnosis difficult. Various criteria have been established in the literature to guide clinicians in making a diagnosis. Genetic screenings are also utilized as diagnostic aids, given that many of these diseases demonstrate monogenic inheritance. In our study, we aimed to evaluate the demographic characteristics, clinical and laboratory findings of patients referred to our department with suspicion of AIDs and who consequently underwent genetic analysis. Additionally, we aimed to assess the correlation between patients' clinical presentations and both the 2019 Eurofever / PRINTO (Pediatric Rheumatology International Trials Organization) clinical classification criteria and genetic test results. Materials and Methods: Patients who presented to the Pediatric Rheumatology and Nephrology Clinics of Akdeniz University Hospital between January 2015 and December 2023, were under 18 years of age at the time of referral, and underwent autoinflammatory genetic panel testing at Ege University Hospital with a preliminary diagnosis of autoinflammatory disease were included in the study. The diagnosis of AIDs received by patients, according to clinician assessment (PFAPA, CAPS, HIDS, TRAPS, atypical FMF, and unclassified AIDs), was considered the gold standard. Correlations with both the 2019 Eurofever / PRINTO clinical classification criteria and genetic test results were examined. Results: A total of 99 patients were included in the study, of whom 52 were male. The mean age was 9.56 ± 4.82 years, with mean ages at symptom onset and initial presentation being 3.91 and 5.56 years, respectively. According to clinician assessment, 18 patients had PFAPA (18.2%), 9 had FMF (9.1%), 7 had CAPS (7.1%), and 3 each had HIDS (3%) and TRAPS (3%) diagnoses. 37 patients 76 (37.4%) were classified as unclassified autoinflammatory disease (UAID), and 10 patients (10.1%) had other group diseases (5 systemic Juvenile Idiopathic Arthritis, 2 systemic Lupus Erythematosus, 2 Chronic Recurrent Multifocal Osteomyelitis, and 1 Behçet disease); in 12 cases, AIDs were not considered. The most common symptoms were fever (94%), followed by abdominal pain (57.5%) and joint pain (57.5%). Significant genetic changes were not detected in 29 patients. Among the 70 patients with identified genetic changes, most mutations were variants of uncertain significance (VUS), while 8 (19.5%) were pathogenic. The heterozygous NLRP3 c.2113C>A mutation, observed in 39 patients (42.9%), was the most frequent mutation. Concordance evaluation between Eurofever criteria and clinician diagnoses yielded a kappa (κ) value of 0.346 (p < .001), indicating moderate agreement, whereas evaluation between genetic results and clinician diagnoses showed a kappa (κ) value of 0.09 (p < .001), indicating weak agreement. Conclusion: Our study suggests that genetic testing and diagnostic criteria can guide diagnosis in autoinflammatory diseases. However, individual assessment based on clinical symptoms, findings, and genetic results is necessary for a definitive diagnosis. Keywords: Autoinflammatory diseases, PFAPA, CAPS, TRAPS, HIDS, genotype, phenotype.