Validity of the Eurofever/PRINTO genetic FMF classification criteria in FMF and PFAPA patients carrying
Hande Ilgaz Tüzen1, Yeşim Yardımcı2, Seviye Güneş Yılmaz3
1Department of Pediatric Rheumatology, Izmir City Hospital, Izmir, Turkey.
Objective:
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.
Method:
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.
Results:
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.
Conclusions:
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.
Insights
The Eurofever/PRINTO criteria effectively identify Familial Mediterranean Fever (FMF) but may misdiagnose Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome in patients with non-confirmatory MEFV variants.
Area of Science:
- Rheumatology
- Genetics
- Pediatrics
Background:
- Familial Mediterranean Fever (FMF) and Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome are autoinflammatory diseases with overlapping clinical features.
- Differentiating FMF from PFAPA can be challenging, especially with non-confirmatory MEFV gene variants.
Purpose of the Study:
- To evaluate the diagnostic performance of the Eurofever/PRINTO classification criteria in distinguishing FMF from PFAPA in patients with non-confirmatory MEFV genotypes.
- To assess the criteria's ability to differentiate between these two autoinflammatory conditions.
Main Methods:
- The study analyzed 126 FMF patients (Yalcinkaya-Ozen criteria) and 32 PFAPA patients (modified Marshall criteria), all with non-confirmatory MEFV genotypes.
- The diagnostic accuracy of the Eurofever/PRINTO criteria was assessed in both patient groups.
Main Results:
- The Eurofever/PRINTO criteria showed high sensitivity (96.8%) and negative predictive value (85.2%) for FMF.
- Specificity was 71.9%, with 28.1% of PFAPA patients misclassified as FMF.
- Positive predictive value was 93.1%.
Conclusions:
- The Eurofever/PRINTO criteria are valuable for identifying FMF but require cautious interpretation in PFAPA patients with non-confirmatory MEFV variants.
- Integrating clinical judgment with genetic and classification criteria is crucial for accurate diagnosis of autoinflammatory diseases, particularly in high MEFV variant prevalence regions.
