Validity of the Eurofever/PRINTO genetic FMF classification criteria in FMF and PFAPA patients carrying non-confirmatory MEFV gene mutations.
Familial Mediterranean Fever (FMF) and Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome are autoinflammatory diseases that may present with similar clinical symptoms. The presence of a non-confirmatory MEFV gene variant and overlapping clinical features can complicate differential diagnosis between the two conditions. The aim of this study is to evaluate the distinctive power of the Eurofever/PRINTO classification criteria, developed for FMF cases with non-confirmatory MEFV genotypes, in differentiating FMF from PFAPA. The study included 126 patients diagnosed with FMF according to the Yalcinkaya-Ozen diagnostic criteria who also carried a non-confirmatory MEFV genotype as defined in the Eurofever/PRINTO genetic and clinical FMF classification criteria. For comparison, data from 32 patients diagnosed with PFAPA according to the modified Marshall criteria and carrying a non-confirmatory MEFV genotype were also included in the analysis. The diagnostic performance of the Eurofever/PRINTO criteria was evaluated both in patients with FMF and PFAPA. The Eurofever/PRINTO genetic and clinical FMF criteria demonstrated a sensitivity of 96.8%, specificity of 71.9%, positive predictive value (PPV) of 93.1%, and negative predictive value (NPV) of 85.2%; the positive likelihood ratio (PLR) was 3.43 and the negative likelihood ratio (NLR) was 0.04. It was observed that 28.1% of PFAPA patients carrying a non-confirmatory MEFV genotype were misclassified as having FMF. The Eurofever/PRINTO genetic FMF classification criteria may serve as a helpful tool in identifying FMF patients and distinguishing them from PFAPA patients who share common genetic and clinical features. However, it should be considered that this set of criteria may lead to a misdiagnosis of FMF in PFAPA patients carrying non-confirmatory MEFV variants. Key Points • Our study highlights the high sensitivity but limited specificity of the Eurofever/PRINTO classification criteria in distinguishing FMF from PFAPA among patients with non-confirmatory MEFV variants, emphasizing the need for cautious interpretation in genetically overlapping cases. • Our findings underscore the importance of integrating clinical judgment with genetic and classification criteria when diagnosing autoinflammatory diseases in regions with a high prevalence of MEFV variants.