Background: Familial Mediterranean Fever (FMF) is classically defined by recurrent, self-limiting episodes of fever, serositis, and arthritis. While diagnostic criterias emphasize these cardinal symptoms, their prevalence, clustering, and relationship with genetic variants in real-world patient populations are not fully delineated.Also another cluster of patient exists with more subtle symptoms still related to MEF gene mutations and they are generally gone unnoticed untill they develop amyloidosis.A precise understanding and defining clinical phenotypes associated with the later is crucial for timely diagnosis, particularly in FMF which has detrimental results undiagnosed.

Objectives: This study from a single center aimed to define the prevalence and patterns of these clinical manifestations associated with MEFV genotypes in a well-characterized cohort of 195 patients.

Methods: Study Design and Population

This cross-sectional, observational study was conducted at the Rheumatology Outpatient Clinic of Bakirköy Sadi Konuk Training and Research Hospital between 10 april 2025 and 1 january 2026. A total of 195 adult patients (≥18 years) were consecutively enrolled. Eligible patients manifested recurrent episodes of fever, serositis, arthritis, arthralgia,rash or other systemic symptoms (fatigue,weakness),had a confirmed pathogenic MEFV gene mutation, and exhibited unexplained acute-phase reactant (APR) elevation.

Inclusion and Exclusion Criteria Inclusion criteria were: (1) age ≥18 years; (2) presence of a pathogenic MEFV mutation; (3) unexplained elevation of APR (C-reactive protein and/or erythrocyte sedimentation rate); and (4) at least one of the following clinical features: recurrent fever, serositis, arthritis,arthralgia, erisipeloid rash or other systemic symptomes (fatigue,weakness) Exclusion criteria were: (1) age <18 years; (2) normal APR levels; or (3) the presence of any other inflammatory condition (e.g., rheumatoid arthritis, vasculitis, inflammatory bowel disease, psoriasis), infection, or malignancy that could explain the APR elevation and clinical symptoms.

Data Collection and Grouping A standardized questionnaire was used to collect detailed demographic and clinical data. This included age at diagnosis, symptom profile (abdominal/chest pain, arthritis,arthralgia, erysipeloid-like rash, diarrhea, vomiting, dysmenorrhea, aphthous lesions on colonoscopy,throat pain, lymphadenopathy), symptom onset date, attack duration and frequency, treatment and post-treatment attack frequency. Etnicity (endemic region?),family history of FMF or amyloidosis and the specific MEFV mutation were also recorded. Based on their dominant clinical presentation at enrollment, patients were classified into six mutually exclusive phenotypic groups: (1) Fever+Serositis+Arthritis, (2) Fever+Serositis, (3) Serositis only, (4) Arthritis only, and (5) Isolated APR elevation.

Results: A total of 195 patients meeting the inclusion criteria were analyzed. The cohort had a mean age of 42.2 (±12.8) years with a female predominance (n=129, 66.2%). All patients exhibited unexplained acute-phase reactant (APR) elevation and had a confirmed MEFV mutation.

Patients were stratified into 5 groups based on their presenting clinical triad:

• Group 1 (Fever + Serositis + Arthritis): 41 patients (21%)

• Group 2 (Fever + Serositis): 69 patients (35%)

• Group 3 (Serositis only): 41 patients (21%)

• Group 4 (Arthritis only): 10 patients (2%)

• Group 5 (Isolated APR elevation): 12 patients (6%)

The 12 patients (9 female, 3 male) presenting with isolated APR elevation or non-classical symptoms were all on colchicine. Their ages ranged from 12 to 66 years. Genetic analysis of this group revealed heterogeneity: M694V heterozygous (n=5), E148Q heterozygous (n=3, including compound heterozygotes), M680I homozygous (n=1), E148Q homozygous (n=1), and R408Q/P369S heterozygous (n=1). Four patients (33.3%) had a family history of FMF. Notably, one patient in this group had progressed to renal amyloidosis requiring transplantation.

Conclusions: This real-world analysis of a genetically confirmed FMF cohort demonstrates that the classic diagnostic triad of fever, serositis, and arthritis is present in a minority of patients (21.0%). The most common presentation is fever with serositis (35.4%), while isolated serositis also represents a major phenotype (21.0%). A significant finding is the identification of a non-classical subgroup (6.2%) characterized by isolated biochemical inflammation or atypical symptoms, yet carrying high-penetrance mutations (including M694V and M680I). This group is not devoid of severe outcomes, as evidenced by a case of renal amyloidosis. These findings underscore the broad and heterogeneous clinical spectrum of FMF , extending beyond classic symptomatic flares. They highlight the necessity of genetic testing and careful long-term monitoring even in patients without typical attacks, as biochemical inflammation in the context of a pathogenic MEFV genotype signifies an ongoing disease state with potential for serious complications.

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Acknowledgments: NIL.

Disclosure of Interests: None declared.