Diagnostic Challenges in Atypical Familial Mediterranean Fever: Enhancing Diagnostic Accuracy Through Clinical and Genetic Criteria

Abstract

We read with great interest the recent case report, “Can Peritoneal Biopsy Diagnose Atypical Cases of Familial Mediterranean Fever?: A Case Report,” describing a 36-year-old Arab female with Familial Mediterranean Fever (FMF) and chronic low-gradient ascites [1]. This case underscores the diagnostic difficulty associated with atypical FMF presentations; nonetheless, multiple methodological flaws, most notably the overreliance on nonspecific peritoneal biopsy results and the exclusion of MEFV mutation analysis, call into question the diagnosis's validity. Given the absence of definitive histopathological markers for FMF, the presence of neutrophilic infiltration alone is insufficient for diagnosis, as this finding is observed in various infectious such as tuberculosis, and bacterial peritonitis; Autoimmune such as lupus peritonitis; and autoinflammatory disorders such as TNF receptor-associated periodic syndrome [1-3]. Furthermore, the lack of fibrin deposits occasionally seen in acute FMF and the absence of amyloidosis, a late-stage complication, further weaken the histological rationale [4-6]. Diagnostic accuracy in FMF necessitates adherence to established clinical criteria, such as the Tel Hashomer guidelines, which prioritize major criteria (recurrent febrile serositis lasting 12–72 h, colchicine responsiveness, and amyloidosis in untreated cases) and minor criteria (family history, incomplete or atypical attacks, and heterozygous MEFV variants) [7]. Unlike infectious or autoimmune mimics, FMF follows a characteristic episodic, self-limiting course, with colchicine responsiveness serving as a distinguishing feature. However, colchicine response alone lacks specificity, as it is shared with conditions such as Behçet's disease, gout, and idiopathic serositis, necessitating genetic confirmation or rigorous exclusion of alternative etiologies. In tuberculosis-endemic regions, misdiagnosis remains a significant concern, particularly given that peritoneal tuberculosis may lack granulomas in up to 50% of cases and can mimic FMF's neutrophilic inflammatory patterns [7, 8]. The patient's presentation of chronic ascites without recurrent febrile episodes does not align with the major diagnostic criteria for FMF, and the omission of family history further weakens diagnostic plausibility in an autosomal recessive disease. Additionally, the absence of ascitic fluid analysis, including serum-ascites albumin gradient (SAAG), PCR for Mycobacterium tuberculosis, and adenosine deaminase (ADA) testing, limits the exclusion of alternative diagnoses [9]. To mitigate misclassification, we advocate for targeted MEFV sequencing (M694V/V726A variants in Arab populations), incorporation of SAAG-guided differential diagnostic protocols [10], and strict adherence to established criteria with explicit symptom-criteria correlation. Moving forward, more research should focus on discovering biomarkers of colchicine resistance and providing low-cost genetic testing panels for underprivileged areas. Long-term monitoring for amyloidosis remains critical for determining disease progression in suspected instances. This case underscores the necessity of a comprehensive diagnostic framework integrating clinical assessment, genetic validation, and systematic exclusion of infectious and autoimmune mimics to enhance diagnostic precision in atypical FMF presentations.

The authors declare no conflicts of interest.