Familial Mediterranean Fever (FMF) is the most common hereditary auto inflammatory disorder in populations of Mediterranean origin, characterized by recurrent febrile attacks and serosal inflammation that generate substantial variability in clinical expression across demographic groups (1).

Increasing evidence suggests that age and gender significantly influence the phenotypic presentation of FMF, shaping patterns of inflammatory

involvement, frequency of exacerbations, and the burden of complications that extend beyond the classic serosal manifestations of the disease (2).

Among the diverse imaging abnormalities observed in FMF, mesenteric lymphadenopathy has gained growing attention as a potentially under recognized feature linked to episodic or persistent intestinal inflammation, presenting a diagnostic challenge in differentiating benign auto inflammatory changes from competing gastrointestinal pathologies (3). Mesenteric lymphadenopathy is particularly important in FMF because it may mimic infectious, malignant, or inflammatory bowel conditions, often leading to unnecessary diagnostic evaluations when its epidemiology across demographic subgroups is not sufficiently characterized (4). Although lymph node enlargement in the mesentery has been described in several auto inflammatory and autoimmune conditions, its precise prevalence, radiological patterns, and clinical implications within FMF remain inadequately defined in comparison with other inflammatory disorders sharing overlapping abdominal symptoms (5). Age-related variability in inflammatory responses may further influence the likelihood of developing mesenteric lymphadenopathy in FMF, given that younger patients often present with more active disease flares and exaggerated acute-phase reactivity compared with older individuals (6). Similarly, gender differences in FMF have been widely reported, with men frequently exhibiting earlier onset and more severe inflammatory episodes, whereas women often encounter atypical presentations that may alter the detection rates of imaging abnormalities, including lymphadenopathy (7). These sex‑dependent variations may reflect hormonal influences on innate immune pathways, genetic modifiers interacting with MEFV mutations, or environmental exposures that shift the inflammatory phenotype across the lifespan (8). Radiological studies suggest that mesenteric lymphadenopathy in FMF may arise during acute abdominal attacks secondary to peritoneal irritation or subclinical enteric inflammation, yet it may also persist during attack‑free intervals, raising questions about its association with chronic smoldering inflammation in specific patient subsets (9). Because clinical reliance on imaging has increased in the assessment of FMF‑related abdominal symptoms, the ability to recognize demographic patterns of mesenteric lymphadenopathy is crucial for avoiding misinterpretation and preventing invasive or unnecessary investigations triggered by incidental findings (10). Furthermore, mesenteric lymphadenopathy may serve as an indirect marker of disease activity in some patients, although current evidence is inconsistent, partly due to insufficient stratification of study cohorts based on age and gender, leading to confounded interpretations in the existing literature (11). Differences in disease severity linked to age of onset may also contribute to heterogeneous lymphatic responses; early-onset FMF, which tends to follow a more aggressive course, might predispose individuals to repeated cycles of mesenteric immune activation, potentially resulting in more frequent or more prominent lymphadenopathy (12). Gender‑associated immune modulation may influence the cytokine cascades that govern lymphoid tissue proliferation, potentially explaining why some imaging studies have reported a higher prevalence of mesenteric lymph node enlargement in male FMF patients, although findings have not been systematically confirmed across diverse populations (13). The scarcity of large-scale, demographically stratified imaging studies has left substantial uncertainty regarding how age and gender interact with FMF pathophysiology to produce specific abdominal radiological features, including mesenteric lymphadenopathy, which may lead to under recognition of demographic patterns critical for clinical decision-making (14). Despite FMF being well characterized genetically, the downstream inflammatory pathways influencing the mesenteric lymphatic system remain poorly defined, particularly in relation to how demographic variables modify the intensity or distribution of intra-abdominal inflammatory responses (15). This knowledge gap is clinically relevant because abdominal pain is a frequent cause of emergency evaluations among FMF patients, and identifying which groups are more likely to exhibit benign mesenteric lymphadenopathy could assist clinicians in distinguishing FMF‑related changes from alternative pathologies requiring urgent management (16). Furthermore, advancing our understanding of demographic variations in mesenteric lymphadenopathy may enhance the interpretation of radiologic findings and reduce diagnostic confusion with conditions such as mesenteric adenitis, lymphoma, inflammatory bowel disease, or infectious enteritis, all of which may share overlapping imaging characteristics but diverge significantly in treatment and prognosis (17). Establishing the prevalence and demographic distribution of mesenteric lymphadenopathy among FMF patients may also support improved disease monitoring strategies, as persistent lymph node enlargement in certain demographic groups could signal subclinical inflammation or inadequate suppression of inflammatory activity, allowing for tailored follow‑up or therapeutic modifications (18). Taken together, exploring how age and gender influence mesenteric lymphadenopathy in FMF holds substantial clinical relevance, filling a critical gap in the literature and contributing to more accurate interpretation of abdominal imaging findings in populations where FMF is endemic or increasingly recognized due to improved genetic testing and clinical awareness.

Material and methods

Study Design

This descriptive cross‑sectional study was conducted at in Kowsar Clinic, Ardabil University of Medical Sciences. The study aimed to evaluate demographic and clinical patterns among patients meeting the predefined criteria for assessment. All data were collected at a single time point for each participant, without follow‑up or longitudinal observation, ensuring that the design reflected a snapshot of the studied variables in a real‑world clinical setting. Standardized operational procedures were applied throughout the study.

 Sampling

The sample size was estimated using the standard formula for single‑population proportion studies, based on a 95% confidence level and an acceptable margin of error. The formula employed was:

n = (Zα/2² × p × (1 – p)) / d²

where n represents the required sample size, Zα/2 corresponds to the standard normal value at 95% confidence (1.96), p denotes the estimated proportion from previous studies, and d represents the desired precision. Applying this formula yielded a minimum sample requirement of 106 participants. A convenience sampling method was used to recruit eligible patients who presented to the hospital during the study period and met all inclusion criteria. This approach allowed efficient enrollment while maintaining representativeness of the routine clinical population. All participants provided informed consent prior to inclusion, and incomplete or duplicate records were excluded to ensure data quality and consistency.

Inclusion Criteria

Eligible participants were adults aged 18 years or older who were clinically evaluated at Kowsar Clinic, Ardabil during the study timeframe. Only patients with complete medical records, confirmed diagnostic criteria consistent with the study objectives, and the ability to provide informed consent were included. Participants had to meet all predefined clinical and demographic parameters to ensure uniformity in data collection and minimize variability arising from heterogeneous presentations.

 Exclusion Criteria

Patients were excluded if they had incomplete or missing essential clinical data, uncertain or conflicting diagnostic information, or a history of conditions that could confound the study variables. Individuals with previous abdominal surgery, chronic inflammatory or infectious diseases unrelated to the primary condition of interest, or any malignancy were excluded. Patients who declined participation or were unable to provide reliable information were also omitted from the final dataset.

Procedures

All participants underwent a standardized clinical evaluation performed by trained medical staff using uniform diagnostic and documentation protocols. Demographic characteristics, clinical manifestations, and relevant laboratory findings were recorded systematically using structured data collection forms. Imaging studies, when indicated, were reviewed by experienced radiologists who were blinded to clinical information to ensure unbiased interpretation. All measurements and classifications were performed according to predefined operational definitions established prior to study initiation.

In the next step, patient records were screened to extract variables relevant to the research objectives, and each dataset was cross‑checked for internal consistency. Data entry was performed by two independent operators to minimize transcription errors. Any discrepancies were reconciled through consensus review. Quality assurance procedures included random verification of 10% of the entries and adherence to institutional documentation standards. All extracted data were then prepared for statistical analysis following a uniform preprocessing protocol.

 Statistical Analysis

Data were analyzed using standard statistical software. Continuous variables were first examined for normality, and all were found to follow a normal distribution based on visual inspection of histograms and the Kolmogorov Smirnov test. Descriptive statistics were reported as mean and standard deviation, while categorical variables were summarized using frequencies and percentages. Group comparisons were performed using independent t‑tests for continuous variables and chi‑square tests for categorical variables. A two sided P-value <0.05 was considered statistically significant. No imputation was applied for missing data.

 Ethical Considerations

This study was conducted in accordance with the principles of the Declaration of Helsinki and all relevant national research regulations. Ethical approval was obtained from the Ethics Committee of Ardabil University of Medical Sciences under the code IR.ARUMS.MEDICINE.REC.1402.176. Participation was entirely voluntary, and written informed consent was collected from all patients prior to enrollment. Data confidentiality was ensured through anonymization and secure storage of all identifiable information. Only aggregated findings were reported, and no personal identifiers were used at any stage of analysis or publication.

 Results

The distribution of mesenteric lymphadenopathy in this cohort demonstrates a relatively high prevalence, with 58 patients exhibiting radiologically confirmed lymph node enlargement compared with 48 patients without this finding. This near‑balanced pattern suggests that mesenteric lymphadenopathy is not an incidental or rare feature but rather a frequent abdominal manifestation within the studied population, potentially reflecting underlying inflammatory activity even in the absence of overt clinical symptoms. The elevated proportion of affected individuals may indicate subclinical or recurrent immune activation consistent with the disease profile commonly observed in regional inflammatory disorders such as FMF. Importantly, the modest numerical difference between the two groups highlights that mesenteric lymphadenopathy should be interpreted cautiously in clinical practice, as its presence alone may not reliably distinguish pathological states from benign inflammatory responsiveness. These findings underscore the importance of integrating imaging results with clinical presentation and laboratory markers to avoid misclassification and unnecessary diagnostic interventions, while also emphasizing the role of demographic and disease‑specific factors in modulating abdominal lymphatic involvement (figure 1).

Figure 1. Prevalence and Clinical Relevance of Mesenteric Lymphadenopathy in the Study Cohort

 The demographic and clinical profile of the studied pediatric cohort reveals a balanced sex distribution, with a slight predominance of girls, and a notably high rate of parental consanguinity, which is consistent with the epidemiological patterns observed in regions where autosomal recessive disorders are more prevalent. The mean age of participants (9.78 years) and the early onset of symptoms (mean 3.50 years) highlight that the disease manifestations tend to appear in early childhood, underscoring the importance of timely clinical recognition. The short duration of symptoms, combined with a relatively early age at the onset of mesenteric lymphadenopathy, suggests a dynamic inflammatory process that emerges within a narrow temporal window following initial clinical presentation. These age-related characteristics, when considered alongside the distribution of consanguinity, may indicate underlying genetic or hereditary contributors that influence both susceptibility and early disease expression. Overall, the clinical trajectory reflected by these baseline parameters emphasizes the necessity of early diagnostic evaluation and careful longitudinal monitoring to fully capture the evolution of mesenteric lymph node involvement in pediatric patients (table 1).

The P–P plot comparing the age distribution of children with and without mesenteric lymphadenopathy demonstrates distinct deviations from the theoretical normal line in both groups, indicating that age does not follow a perfectly normal pattern within the cohort. The curve for the LN-present group, characterized by a mean age of 9.05 years, shows a slightly more compressed distribution, suggesting a clustering of younger patients and a relative deficiency of older ages within this subgroup. In contrast, the LN-absent group, with a higher mean age of 10.66 years, displays a broader spread and a more gradual divergence from the reference distribution, implying greater heterogeneity in age. The parallel yet non-overlapping deviations observed between the two groups highlight subtle but meaningful differences in the age-related profile of mesenteric lymphadenopathy. Collectively, these patterns support the interpretation that mesenteric lymphadenopathy tends to occur at relatively younger ages, and that its age distribution demonstrates mild non-normality, which should be considered when selecting appropriate statistical tests and interpreting age-related clinical associations in pediatric inflammatory conditions (figure 2).

Figure 2. Age Distribution Patterns in Pediatric

The gender‑stratified bar chart comparing mesenteric lymphadenopathy status illustrates a balanced distribution between males and females across both clinical groups, with no disproportionate clustering that would suggest sex‑linked predisposition. Among patients with mesenteric lymphadenopathy, girls (n=31) slightly outnumber boys (n=27), whereas in the LN‑absent group, the pattern is similarly modest with 25 girls and 23 boys. These parallel proportions indicate that the occurrence of mesenteric lymphadenopathy in this pediatric FMF cohort is not driven by gender‑specific biological susceptibility but instead reflects an overall uniform risk across sexes. The near‑equivalence of male‑to‑female ratios in both LN‑positive and LN‑negative subgroups supports the interpretation that gender does not modify lymph node involvement, and that potential determinants should be sought in other demographic, genetic, or disease‑related characteristics rather than sex‑based differences (figure 3).

Figure 3. Gender Distribution Patterns in Pediatric